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Parlantza MA, Pitsikas N. Involvement of the GABAergic and the serotonergic systems in the anxiolytic effects expressed by the nitric oxide (NO) donor sodium nitroprusside (SNP) in the male rat. Psychopharmacology (Berl) 2025; 242:793-801. [PMID: 39964469 PMCID: PMC11890370 DOI: 10.1007/s00213-025-06759-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 02/08/2025] [Indexed: 03/09/2025]
Abstract
RATIONALE Anxiety is a chronic severe psychiatric disorder. In a series of studies, the implication of the gaseous molecule nitric oxide (NO) in anxiety has been evidenced. Further, the outcome of preclinical research suggests that different NO donors, including sodium nitroprusside (SNP), have expressed an anxiolytic profile revealed in animal models of anxiety. Regardless of this, it is not yet clarified the mechanism(s) of action by which SNP induces its beneficial effects on anxiety. In this context, it has been hypothesized that these effects might be attributed to a potential interaction of this NO donor with the GABA type A and the 5-HT1A serotonergic receptors. OBJECTIVES The current study was designed to investigate this issue in the male rat. METHODS To this end, the light/dark box and the open field tests were utilized. RESULTS SNP (1 mg/kg, i.p.) applied acutely induced an anti-anxiety-like effect evidenced either in the light/dark box or in the open field test. Either the GABAA receptor antagonist flumazenil (10 mg/kg, i.p.) or the 5-HT1A serotonin receptor agonist 8-OH-DPAT (0.25 mg/kg, i.p.) suppressed the above reported anxiolytic effects of SNP. CONCLUSIONS The results here reported propose a functional interaction between SNP with the GABAergic and the serotonergic systems on anxiety and thus, might offer a plausible explanation for SNP's anxiolytic effects.
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Affiliation(s)
- Maria Anastasia Parlantza
- Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Thessaly, Panepistimiou 3, Biopolis, Larissa, 415-00, Greece
| | - Nikolaos Pitsikas
- Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Thessaly, Panepistimiou 3, Biopolis, Larissa, 415-00, Greece.
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do Rêgo AGDO, D'Amico F, D'Angelo V, Cardarelli S, Cutuli D, Decandia D, Landolfo E, Petrosini L, Pellegrini M, D'Amelio M, Mercuri NB, Giorgi M, Sancesario G. Haploinsufficiency of PDE2A causes in mice increased exploratory behavior associated with upregulation of neural nitric oxide synthase in the striatum. Neurobiol Dis 2025; 205:106781. [PMID: 39733958 DOI: 10.1016/j.nbd.2024.106781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 12/21/2024] [Accepted: 12/21/2024] [Indexed: 12/31/2024] Open
Abstract
Phosphodiesterase 2 A (PDE2A) function is stimulated by cGMP to catabolize cAMP. However, neurological and neurochemical effects of PDE2A deficiency are poorly understood. To address this gap, we studied behavioral characteristics and cerebral morpho-chemical changes of adult male heterozygous C57BL/6-PDE2A+/- (HET), and wild type C57BL/6-PDE2A+/+ (WT) mice. Behavioral functions of mice were evaluated by a wide test battery. HET mice exhibited greater tendency to explore novel environments in comparison to WT mice, but spatial working memory, anxiety, and sociability were similar in adult HET and WT mice. In HET mice, PDE2A mRNA, PDE2A protein expression, and cGMP hydrolyzing enzymatic activity were consistently reduced by about 50 %. Consequently, the cyclic nucleotide levels were significantly increased in HET mice, but unexpectedly the mean percentage variation was higher for cGMP equal to 153.23 %, and lower for cAMP equal to 16.41 %. Therefore, to try to explain the preponderant increase of cGMP to cAMP we evaluated other PDE enzymes functionally related to PDE2A. Surprisingly, results were quite contradictory: in HET mice protein levels of the other dual-specificity enzyme PDE3A and PDE10A were reduced, whereas the expressions of PDE5A and PDE9A that selectively hydrolyze cGMP were increased. Therefore, we investigated the involvement of neuronal nitric oxide synthase (nNOS) expression, as determinant of a possible increased synthesis of NO/cGMP signaling. Interestingly, in HET mice the expression level of brain nNOS, measured by western blot and immune-histochemistry was significantly increased, particularly in interneurons from the striatum. In conclusion, the deficiency of PDE2A could be compensated in the striatum by upregulating nNOS/NO/cGMP pathway, which in turn likely upregulates PDE2A-dependent cAMP hydrolysis. The neuroanatomical correlation between striatal nNOS upregulation and the behavioral phenotype of increased exploratory behavior in HET mice is advanced.
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Affiliation(s)
| | - Francesca D'Amico
- Department of Biology and Biotechnology "Charles Darwin", Sapienza University, 00185 Rome, Italy
| | - Vincenza D'Angelo
- Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy
| | - Silvia Cardarelli
- Department of Biology and Biotechnology "Charles Darwin", Sapienza University, 00185 Rome, Italy
| | - Debora Cutuli
- IRCCS Santa Lucia Foundation, 00179 Rome, Italy; Department of Psychology, Sapienza University, 00185 Rome, Italy
| | - Davide Decandia
- IRCCS Santa Lucia Foundation, 00179 Rome, Italy; Department of Psychology, Sapienza University, 00185 Rome, Italy
| | | | | | - Manuela Pellegrini
- Institute of Biochemistry and Cell Biology, IBBC-CNR, 00015 Monterotondo Scalo, Rome, Italy
| | - Marcello D'Amelio
- IRCCS Santa Lucia Foundation, 00179 Rome, Italy; Department of Medicine, Campus Biomedico University, 00128 Rome, Italy
| | - Nicola Biagio Mercuri
- Department of Systems Medicine, Tor Vergata University, 00133 Rome, Italy; IRCCS Santa Lucia Foundation, 00179 Rome, Italy
| | - Mauro Giorgi
- Department of Biology and Biotechnology "Charles Darwin", Sapienza University, 00185 Rome, Italy.
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L’Heureux JE, Corbett A, Ballard C, Vauzour D, Creese B, Winyard PG, Jones AM, Vanhatalo A. Oral microbiome and nitric oxide biomarkers in older people with mild cognitive impairment and APOE4 genotype. PNAS NEXUS 2025; 4:pgae543. [PMID: 39876877 PMCID: PMC11773611 DOI: 10.1093/pnasnexus/pgae543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 11/18/2024] [Indexed: 01/31/2025]
Abstract
Apolipoprotein E4 (APOE4) genotype and nitric oxide (NO) deficiency are risk factors for age-associated cognitive decline. The oral microbiome plays a critical role in maintaining NO bioavailability during aging. The aim of this study was to assess interactions between the oral microbiome, NO biomarkers, and cognitive function in 60 participants with mild cognitive impairment (MCI) and 60 healthy controls using weighted gene co-occurrence network analysis and to compare the oral microbiomes between APOE4 carriers and noncarriers in a subgroup of 35 MCI participants. Within the MCI group, a high relative abundance of Neisseria was associated with better indices of cognition relating to executive function (Switching Stroop, rs = 0.33, P = 0.03) and visual attention (Trail Making, rs = -0.30, P = 0.05), and in the healthy group, Neisseria correlated with working memory (Digit Span, rs = 0.26, P = 0.04). High abundances of Haemophilus (rs = 0.38, P = 0.01) and Haemophilus parainfluenzae (rs = 0.32, P = 0.03), that co-occurred with Neisseria correlated with better scores on executive function (Switching Stroop) in the MCI group. There were no differences in oral nitrate (P = 0.48) or nitrite concentrations (P = 0.84) between the MCI and healthy groups. Linear discriminant analysis Effect Size identified Porphyromonas as a predictor for MCI and Prevotella intermedia as a predictor of APOE4-carrier status. The principal findings of this study were that a greater prevalence of oral P. intermedia is linked to elevated genetic risk for dementia (APOE4 genotype) in individuals with MCI prior to dementia diagnosis and that interventions that promote the oral Neisseria-Haemophilus and suppress Prevotella-dominated modules have potential for delaying cognitive decline.
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Affiliation(s)
- Joanna E L’Heureux
- Faculty of Health and Life Sciences, University of Exeter Medical School, University of Exeter, St Luke's campus, Exeter EX1 2LU, United Kingdom
| | - Anne Corbett
- Faculty of Health and Life Sciences, University of Exeter Medical School, University of Exeter, St Luke's campus, Exeter EX1 2LU, United Kingdom
| | - Clive Ballard
- Faculty of Health and Life Sciences, University of Exeter Medical School, University of Exeter, St Luke's campus, Exeter EX1 2LU, United Kingdom
| | - David Vauzour
- Norwich Medical School, University of East Anglia, Norwich NR4 7TJ, United Kingdom
| | - Byron Creese
- Department of Life Sciences, University of Brunel, London UB8 3PH, United Kingdom
| | - Paul G Winyard
- Faculty of Health and Life Sciences, University of Exeter Medical School, University of Exeter, St Luke's campus, Exeter EX1 2LU, United Kingdom
| | - Andrew M Jones
- Faculty of Health and Life Sciences, University of Exeter Medical School, University of Exeter, St Luke's campus, Exeter EX1 2LU, United Kingdom
| | - Anni Vanhatalo
- Faculty of Health and Life Sciences, University of Exeter Medical School, University of Exeter, St Luke's campus, Exeter EX1 2LU, United Kingdom
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Pessoa RT, Santos da Silva LY, Alcântara IS, Silva TM, Silva EDS, da Costa RHS, da Silva AB, Ribeiro-Filho J, Pereira Bezerra Martins AOB, Coutinho HDM, Sousa JCP, Chaves AR, Marreto RN, de Menezes IRA. Antinociceptive Potential of Ximenia americana L. Bark Extract and Caffeic Acid: Insights into Pain Modulation Pathways. Pharmaceuticals (Basel) 2024; 17:1671. [PMID: 39770512 PMCID: PMC11677608 DOI: 10.3390/ph17121671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 11/28/2024] [Accepted: 12/07/2024] [Indexed: 01/11/2025] Open
Abstract
Background/Objectives: This study evaluated the antinociceptive effect of the Ximenia americana L. bark extract (HEXA) and its primary component, caffeic acid (CA), through in vivo assays. Methods: The antinociceptive properties were assessed using abdominal writhing, hot plate, and Von Frey tests. Additionally, the study investigated the modulation of various pain signaling pathways using a pharmacological approach. Results: The results demonstrated that all doses of the HEXA significantly increased latency in the hot plate test, decreased the number of abdominal contortions, reduced hyperalgesia in the Von Frey test, and reduced both phases of the formalin test. Caffeic acid reduced licking time in the first phase of the formalin test at all doses, with the highest dose showing significant effects in the second phase. The HEXA potentially modulated α2-adrenergic (52.99%), nitric oxide (57.77%), glutamatergic (33.66%), vanilloid (39.84%), cyclic guanosine monophosphate (56.11%), and K+ATP channel-dependent pathways (38.70%). Conversely, CA influenced the opioid, glutamatergic (53.60%), and vanilloid (34.42%) pathways while inhibiting nitric oxide (52.99%) and cyclic guanosine monophosphate (38.98%). Conclusions: HEXA and CA exhibit significant antinociceptive effects due to their potential interference in multiple pain signaling pathways. While the molecular targets remain to be fully investigated, HEXA and CA demonstrate significant potential for the development of new analgesic drugs.
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Affiliation(s)
- Renata Torres Pessoa
- Laboratory of Pharmacology and Molecular Chemistry, Department of Chemical Biology, Regional University of Cariri (URCA), Rua Coronel Antônio Luis 1161, Pimenta, Crato 63105-000, Ceará, Brazil; (R.T.P.); (L.Y.S.d.S.); (I.S.A.); (T.M.S.); (E.d.S.S.); (R.H.S.d.C.); (A.B.d.S.); (J.R.-F.); (A.O.B.P.B.M.)
| | - Lucas Yure Santos da Silva
- Laboratory of Pharmacology and Molecular Chemistry, Department of Chemical Biology, Regional University of Cariri (URCA), Rua Coronel Antônio Luis 1161, Pimenta, Crato 63105-000, Ceará, Brazil; (R.T.P.); (L.Y.S.d.S.); (I.S.A.); (T.M.S.); (E.d.S.S.); (R.H.S.d.C.); (A.B.d.S.); (J.R.-F.); (A.O.B.P.B.M.)
| | - Isabel Sousa Alcântara
- Laboratory of Pharmacology and Molecular Chemistry, Department of Chemical Biology, Regional University of Cariri (URCA), Rua Coronel Antônio Luis 1161, Pimenta, Crato 63105-000, Ceará, Brazil; (R.T.P.); (L.Y.S.d.S.); (I.S.A.); (T.M.S.); (E.d.S.S.); (R.H.S.d.C.); (A.B.d.S.); (J.R.-F.); (A.O.B.P.B.M.)
| | - Tarcísio Mendes Silva
- Laboratory of Pharmacology and Molecular Chemistry, Department of Chemical Biology, Regional University of Cariri (URCA), Rua Coronel Antônio Luis 1161, Pimenta, Crato 63105-000, Ceará, Brazil; (R.T.P.); (L.Y.S.d.S.); (I.S.A.); (T.M.S.); (E.d.S.S.); (R.H.S.d.C.); (A.B.d.S.); (J.R.-F.); (A.O.B.P.B.M.)
| | - Eduardo dos Santos Silva
- Laboratory of Pharmacology and Molecular Chemistry, Department of Chemical Biology, Regional University of Cariri (URCA), Rua Coronel Antônio Luis 1161, Pimenta, Crato 63105-000, Ceará, Brazil; (R.T.P.); (L.Y.S.d.S.); (I.S.A.); (T.M.S.); (E.d.S.S.); (R.H.S.d.C.); (A.B.d.S.); (J.R.-F.); (A.O.B.P.B.M.)
| | - Roger Henrique Sousa da Costa
- Laboratory of Pharmacology and Molecular Chemistry, Department of Chemical Biology, Regional University of Cariri (URCA), Rua Coronel Antônio Luis 1161, Pimenta, Crato 63105-000, Ceará, Brazil; (R.T.P.); (L.Y.S.d.S.); (I.S.A.); (T.M.S.); (E.d.S.S.); (R.H.S.d.C.); (A.B.d.S.); (J.R.-F.); (A.O.B.P.B.M.)
| | - Aparecida Barros da Silva
- Laboratory of Pharmacology and Molecular Chemistry, Department of Chemical Biology, Regional University of Cariri (URCA), Rua Coronel Antônio Luis 1161, Pimenta, Crato 63105-000, Ceará, Brazil; (R.T.P.); (L.Y.S.d.S.); (I.S.A.); (T.M.S.); (E.d.S.S.); (R.H.S.d.C.); (A.B.d.S.); (J.R.-F.); (A.O.B.P.B.M.)
| | - Jaime Ribeiro-Filho
- Laboratory of Pharmacology and Molecular Chemistry, Department of Chemical Biology, Regional University of Cariri (URCA), Rua Coronel Antônio Luis 1161, Pimenta, Crato 63105-000, Ceará, Brazil; (R.T.P.); (L.Y.S.d.S.); (I.S.A.); (T.M.S.); (E.d.S.S.); (R.H.S.d.C.); (A.B.d.S.); (J.R.-F.); (A.O.B.P.B.M.)
- Oswaldo Cruz Foundation (FIOCRUZ), Fiocruz Ceará, R. São José, S/N—Precabura, Eusébio 61773-270, Ceará, Brazil
| | - Anita Oliveira Brito Pereira Bezerra Martins
- Laboratory of Pharmacology and Molecular Chemistry, Department of Chemical Biology, Regional University of Cariri (URCA), Rua Coronel Antônio Luis 1161, Pimenta, Crato 63105-000, Ceará, Brazil; (R.T.P.); (L.Y.S.d.S.); (I.S.A.); (T.M.S.); (E.d.S.S.); (R.H.S.d.C.); (A.B.d.S.); (J.R.-F.); (A.O.B.P.B.M.)
| | - Henrique Douglas Melo Coutinho
- Laboratory of Microbiology and Molecular Biology, Department of Biological Chemistry, Regional University of Cariri (URCA), Crato 63105-000, Ceará, Brazil;
| | - Jean Carlos Pereira Sousa
- Institute of Chemistry, Federal University of Goiás, Goiânia 74001-970, Goiás, Brazil; (J.C.P.S.); (A.R.C.)
| | - Andréa Rodrigues Chaves
- Institute of Chemistry, Federal University of Goiás, Goiânia 74001-970, Goiás, Brazil; (J.C.P.S.); (A.R.C.)
| | | | - Irwin Rose Alencar de Menezes
- Laboratory of Pharmacology and Molecular Chemistry, Department of Chemical Biology, Regional University of Cariri (URCA), Rua Coronel Antônio Luis 1161, Pimenta, Crato 63105-000, Ceará, Brazil; (R.T.P.); (L.Y.S.d.S.); (I.S.A.); (T.M.S.); (E.d.S.S.); (R.H.S.d.C.); (A.B.d.S.); (J.R.-F.); (A.O.B.P.B.M.)
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Akyürek EG, Altınok A, Karabay A. Concurrent consumption of cocoa flavanols and caffeine does not acutely modulate working memory and attention. Eur J Nutr 2024; 64:35. [PMID: 39607519 PMCID: PMC11604789 DOI: 10.1007/s00394-024-03514-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 10/09/2024] [Indexed: 11/29/2024]
Abstract
PURPOSE Consumption of cocoa flavanols and caffeine might acutely enhance cognition, particularly in synergy. Due to the use of multifaceted tasks in prior research, it is unclear precisely which cognitive functions are implicated. Here we aimed to assess the acute effects of the (joint) ingestion of cocoa flavanols and caffeine on temporal attention, spatial attention, and working memory. METHODS In four separate sessions of a randomized, double-blind, placebo-controlled, crossover trial, 48 young adult participants consumed a placebo drink, a cocoa flavanols (415 mg) drink, a caffeine (215 mg) drink, and a drink containing both concurrently. In each session, after ingestion, we tested performance in three cognitive tasks. We tested temporal attention in a dual-target rapid serial visual presentation paradigm, known to elicit the attentional blink, in which the time between the targets was manipulated. We measured spatial attention in a visual search task, where we varied the number of distractors that appeared simultaneously with the target. We tested working memory in a delayed recall task, in which the number of stimuli to be remembered was manipulated. RESULTS We obtained the expected performance pattern in each task, but found no evidence for modulation of response accuracy or reaction times by the ingestion of either substance, nor of their combined ingestion, even in the most challenging task conditions. CONCLUSIONS We conclude that, even when jointly ingested, neither the tested amount of cocoa flavanols nor caffeine have acute effects that are robustly measurable on cognitive tasks that target attention and working memory specifically.
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Affiliation(s)
- Elkan G Akyürek
- Department of Experimental Psychology, University of Groningen, Grote Kruisstraat 2/1, 9712 TS, Groningen, The Netherlands.
| | - Ahmet Altınok
- Department of Experimental Psychology, University of Groningen, Grote Kruisstraat 2/1, 9712 TS, Groningen, The Netherlands
| | - Aytaç Karabay
- Department of Experimental Psychology, University of Groningen, Grote Kruisstraat 2/1, 9712 TS, Groningen, The Netherlands
- Department of Psychology, New York University Abu Dhabi, Abu Dhabi, United Arab Emirates
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Molaei E, Molaei A, Dashti-Khavidaki S, Nasiri-Toosi M, Abbasi MR, Jafarian A. Could the administration of SGLT2i agents serve as a viable prophylactic approach against CNI-induced toxicities? Med Hypotheses 2024; 189:111417. [DOI: 10.1016/j.mehy.2024.111417] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Barbaresi P, Fabri M, Lorenzi T, Sagrati A, Morroni M. Intrinsic organization of the corpus callosum. Front Physiol 2024; 15:1393000. [PMID: 39035452 PMCID: PMC11259024 DOI: 10.3389/fphys.2024.1393000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Accepted: 05/16/2024] [Indexed: 07/23/2024] Open
Abstract
The corpus callosum-the largest commissural fiber system connecting the two cerebral hemispheres-is considered essential for bilateral sensory integration and higher cognitive functions. Most studies exploring the corpus callosum have examined either the anatomical, physiological, and neurochemical organization of callosal projections or the functional and/or behavioral aspects of the callosal connections after complete/partial callosotomy or callosal lesion. There are no works that address the intrinsic organization of the corpus callosum. We review the existing information on the activities that take place in the commissure in three sections: I) the topographical and neurochemical organization of the intracallosal fibers, II) the role of glia in the corpus callosum, and III) the role of the intracallosal neurons.
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Affiliation(s)
- Paolo Barbaresi
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Marche Polytechnic University, Ancona, Italy
| | - Mara Fabri
- Department of Life and Environmental Sciences, Marche Polytechnic University, Ancona, Italy
| | - Teresa Lorenzi
- Department of Experimental and Clinical Medicine, Section of Neuroscience and Cell Biology, Marche Polytechnic University, Ancona, Italy
| | - Andrea Sagrati
- Department of Life and Environmental Sciences, Marche Polytechnic University, Ancona, Italy
| | - Manrico Morroni
- Electron Microscopy Unit, Azienda Ospedaliero-Universitaria, Ancona, Italy
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Pawar A, Pardasani KR. Modelling Cross Talk in the Spatiotemporal System Dynamics of Calcium, IP 3 and Nitric Oxide in Neuron Cells. Cell Biochem Biophys 2024; 82:787-803. [PMID: 38376737 DOI: 10.1007/s12013-024-01229-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Accepted: 02/05/2024] [Indexed: 02/21/2024]
Abstract
The bioenergetic system of calcium ([Ca2+]), inositol 1, 4, 5-trisphophate (IP3) and nitric oxide (NO) regulate the diverse mechanisms in neurons. The dysregulation in any or all of the calcium, IP3 and nitric oxide dynamics may cause neurotoxicity and cell death. Few studies are noted in the literature on the interactions of two systems like [Ca2+] with IP3 and [Ca2+] with nitric oxide in neuron cells, which gives limited insights into regulatory and dysregulatory processes in neuron cells. But, no study is available on the cross talk in dynamics of three systems [Ca2+], IP3 and NO in neurons. Thus, the cross talk in the system dynamics of [Ca2+], IP3 and NO regulation processes in neurons have been studied using mathematical model. The two-way feedback process between [Ca2+] and IP3 and two-way feedback process between [Ca2+] and NO through cyclic guanosine monophosphate (cGMP) with plasmalemmal [Ca2+]-ATPase (PMCA) have been incorporated in the proposed model. This coupling handles the indirect two-way feedback process between IP3 and nitric oxide in neuronal cells automatically. The numerical outcomes were acquired by employing the finite element method (FEM) with the Crank-Nicholson scheme (CNS). The present model incorporating the sodium-calcium exchanger (NCX) and voltage-gated calcium channel (VGCC) provides novel insights into the various regulatory and dysregulatory processes due to buffer, IP3-receptor, ryanodine receptor, cGMP kinetics through PMCA channel, etc. and their impacts on the interactive spatiotemporal system dynamics of [Ca2+], IP3 and NO in neurons. It is concluded that the behavior of different crucial mechanisms is quite different for interactions of two systems of [Ca2+] and NO and the interactions of three systems of [Ca2+], IP3 and nitric oxide in neuronal cell due to mutual regulatory adjustments. The association of several neurological disorders with the alterations in calcium, IP3 and NO has been explored in neurons.
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Affiliation(s)
- Anand Pawar
- Department of Mathematics, Bioinformatics and Computer Applications, Maulana Azad National Institute of Technology, Bhopal, 462003, Madhya Pradesh, India.
| | - Kamal Raj Pardasani
- Department of Mathematics, Bioinformatics and Computer Applications, Maulana Azad National Institute of Technology, Bhopal, 462003, Madhya Pradesh, India.
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Francis G, Petrovic P, Lundström JN, Thunell E. Induction of nitric oxide via humming does not improve short-term cognitive performance or influence emotional processing. PLoS One 2024; 19:e0301268. [PMID: 38573928 PMCID: PMC10994277 DOI: 10.1371/journal.pone.0301268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/13/2024] [Indexed: 04/06/2024] Open
Abstract
Nitric oxide (NO) is involved in a variety of biological functions including blood vessel dilation and neurotransmitter release. In animals, NO has been demonstrated to affect multiple behavioral outcomes, such as memory performance and arousal, whereas this link is less explored in humans. NO is created in the paranasal sinuses and studies show that humming releases paranasal NO to the nasal tract and that NO can then cross the blood brain barrier. Akin to animal models, we hypothesized that this NO may traverse into the brain and positively affect information processing. In contrast to our hypothesis, an articulatory suppression memory paradigm and a speeded detection task found deleterious effects of humming while performing the task. Likewise, we found no effect of humming on emotional processing of photos. In a fourth experiment, participants hummed before each trial in a speeded detection task, but we again found no effect on response time. In conclusion, either nasal NO does not travel to the brain, or NO in the brain does not have the expected impact on cognitive performance and emotional processing in humans. It remains possible that NO influences other cognitive processes not tested for here.
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Affiliation(s)
- Gregory Francis
- Department of Psychological Sciences, Purdue University, West Lafayette, Indiana, United States of America
| | - Predrag Petrovic
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Johan N. Lundström
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Monell Chemical Senses Center, Philadelphia, PA, United States of America
| | - Evelina Thunell
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
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Li Z, Gao Z, Chang C, Gao Z. Anticonvulsive Effect of Glucosyl Xanthone Mangiferin on Pentylenetetrazol (PTZ)-Induced Seizure-Provoked Mice. Appl Biochem Biotechnol 2024; 196:2161-2175. [PMID: 37486538 DOI: 10.1007/s12010-023-04651-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/04/2023] [Indexed: 07/25/2023]
Abstract
Anxiety and depression are major side effects induced by currently available antiepileptic drugs; apart from this, they also diminish intelligence and language skills which cause hepatic failure, anemia, etc. Hence, in this study, we assessed antiepileptic effect of a phytochemical mangiferin. Epilepsy, a prevalent non communicable neurological disorder, affects infants and older population throughout the world. Epilepsy-induced comorbidities are more severe and if not treated cautiously lead to disability and even worse cases, mortality. The onset and duration of convulsion were observed. Seizure severity score was assessed by provoking kindling with 35 mg/kg PTZ. Prooxidants and antioxidants were measured to assess the antioxidant effect of mangiferin. Inflammatory markers were measured to determine the anti-inflammatory effect of mangiferin. The levels of neurotransmitters and ATPases were quantified to evaluate the neuroprotective effect of mangiferin. Mangiferin significantly decreased the onset and duration convulsion. It also decreased the seizure severity score, locomotor activity, and immobilization effectively. The excitatory neurotransmitter was reduced, and inhibitory neurotransmitter was increased in mice treated with mangiferin. Overall, our results confirm that mangiferin efficiently protects mice from PTZ-induced seizures. It can be subjected to further research to be prescribed as a potent antiepileptic drug.
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Affiliation(s)
- Zhaoxia Li
- Department of Pediatric, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China
| | - Zhiliang Gao
- Department of Pediatric, Binzhou Hospital of Traditional Chinese Medicine, Binzhou, 256600, China
| | - Cong Chang
- Department of Rehabilitation Medicine, Binzhou Municipal Hospital, Binzhou, 256600, China
| | - Zhuanglei Gao
- Department of Gastrointestinal Surgery, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250033, China.
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11
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da Costa Rodrigues K, da Silva Neto MR, Dos Santos Barboza V, Hass SE, de Almeida Vaucher R, Giongo JL, Schumacher RF, Wilhelm EA, Luchese C. New curcumin-loaded nanocapsules as a therapeutic alternative in an amnesia model. Metab Brain Dis 2024; 39:589-609. [PMID: 38351421 DOI: 10.1007/s11011-023-01329-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 11/22/2023] [Indexed: 04/23/2024]
Abstract
This study aimed to investigate the action of two different formulations of curcumin (Cur)-loaded nanocapsules (Nc) (Eudragit [EUD] and poly (ɛ-caprolactone) [PCL]) in an amnesia mice model. We also investigated the formulations' effects on scopolamine-induced (SCO) depressive- and anxiety-like comorbidities, the cholinergic system, oxidative parameters, and inflammatory markers. Male Swiss mice were randomly divided into five groups (n = 8): group I (control), group II (Cur PCL Nc 10 mg/kg), group III (Cur EUD Nc 10 mg/kg), group IV (free Cur 10 mg/kg), and group V (SCO). Treatments with Nc or Cur (free) were performed daily or on alternate days. After 30 min of treatment, the animals received the SCO and were subjected to behavioral tests 30 min later (Barnes maze, open-field, object recognition, elevated plus maze, tail suspension tests, and step-down inhibitory avoidance tasks). The animals were then euthanized and tissue was removed for biochemical assays. Our results demonstrated that Cur treatment (Nc or free) protected against SCO-induced amnesia and depressive-like behavior. The ex vivo assays revealed lower acetylcholinesterase (AChE) and catalase (CAT) activity, reduced thiobarbituric species (TBARS), reactive species (RS), and non-protein thiols (NSPH) levels, and reduced interleukin-6 (IL-6) and tumor necrosis factor (TNF) expression. The treatments did not change hepatic markers in the plasma of mice. After treatments on alternate days, Cur Nc had a more significant effect than the free Cur protocol, implying that Cur may have prolonged action in Nc. This finding supports the concept that it is possible to achieve beneficial effects in nanoformulations, and treatment on alternate days differs from the free Cur protocol regarding anti-amnesic effects in mice.
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Affiliation(s)
- Karline da Costa Rodrigues
- Programa de Pós-Graduação em Bioquímica e Bioprospecção, Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Grupo de Pesquisa em Neurobiotecnologia (GPN), Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, CEP 96010-900, Brazil
| | - Manoel Rodrigues da Silva Neto
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Pampa, Campus Uruguaiana BR 472, Km 7, Uruguaiana, RS, 97500-970, Brazil
| | - Victor Dos Santos Barboza
- Laboratório de Pesquisa em Bioquímica e Biologia Molecular de Micro-organismos (LaPeBBioM), Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, CEP 96010-900, Brazil
| | - Sandra Elisa Hass
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Pampa, Campus Uruguaiana BR 472, Km 7, Uruguaiana, RS, 97500-970, Brazil
| | - Rodrigo de Almeida Vaucher
- Laboratório de Pesquisa em Bioquímica e Biologia Molecular de Micro-organismos (LaPeBBioM), Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, CEP 96010-900, Brazil
| | - Janice Luehring Giongo
- Laboratório de Pesquisa em Bioquímica e Biologia Molecular de Micro-organismos (LaPeBBioM), Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, CEP 96010-900, Brazil
| | | | - Ethel Antunes Wilhelm
- Programa de Pós-Graduação em Bioquímica e Bioprospecção, Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Grupo de Pesquisa em Neurobiotecnologia (GPN), Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, CEP 96010-900, Brazil
| | - Cristiane Luchese
- Programa de Pós-Graduação em Bioquímica e Bioprospecção, Laboratório de Pesquisa em Farmacologia Bioquímica (LaFarBio), Grupo de Pesquisa em Neurobiotecnologia (GPN), Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Universidade Federal de Pelotas (UFPel), Pelotas, RS, CEP 96010-900, Brazil.
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12
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Kimura H. Hydrogen Sulfide (H 2S)/Polysulfides (H 2S n) Signalling and TRPA1 Channels Modification on Sulfur Metabolism. Biomolecules 2024; 14:129. [PMID: 38275758 PMCID: PMC10813152 DOI: 10.3390/biom14010129] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/11/2024] [Accepted: 01/17/2024] [Indexed: 01/27/2024] Open
Abstract
Hydrogen sulfide (H2S) and polysulfides (H2Sn, n ≥ 2) produced by enzymes play a role as signalling molecules regulating neurotransmission, vascular tone, cytoprotection, inflammation, oxygen sensing, and energy formation. H2Sn, which have additional sulfur atoms to H2S, and other S-sulfurated molecules such as cysteine persulfide and S-sulfurated cysteine residues of proteins, are produced by enzymes including 3-mercaptopyruvate sulfurtransferase (3MST). H2Sn are also generated by the chemical interaction of H2S with NO, or to a lesser extent with H2O2. S-sulfuration (S-sulfhydration) has been proposed as a mode of action of H2S and H2Sn to regulate the activity of target molecules. Recently, we found that H2S/H2S2 regulate the release of neurotransmitters, such as GABA, glutamate, and D-serine, a co-agonist of N-methyl-D-aspartate (NMDA) receptors. H2S facilitates the induction of hippocampal long-term potentiation, a synaptic model of memory formation, by enhancing the activity of NMDA receptors, while H2S2 achieves this by activating transient receptor potential ankyrin 1 (TRPA1) channels in astrocytes, potentially leading to the activation of nearby neurons. The recent findings show the other aspects of TRPA1 channels-that is, the regulation of the levels of sulfur-containing molecules and their metabolizing enzymes. Disturbance of the signalling by H2S/H2Sn has been demonstrated to be involved in various diseases, including cognitive and psychiatric diseases. The physiological and pathophysiological roles of these molecules will be discussed.
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Affiliation(s)
- Hideo Kimura
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, 1-1-1 Daigaku-Dori, Sanyo-Onoda 756-0884, Yamaguchi, Japan
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13
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Tempone MH, Borges-Martins VP, César F, Alexandrino-Mattos DP, de Figueiredo CS, Raony Í, dos Santos AA, Duarte-Silva AT, Dias MS, Freitas HR, de Araújo EG, Ribeiro-Resende VT, Cossenza M, P. Silva H, P. de Carvalho R, Ventura ALM, Calaza KC, Silveira MS, Kubrusly RCC, de Melo Reis RA. The Healthy and Diseased Retina Seen through Neuron-Glia Interactions. Int J Mol Sci 2024; 25:1120. [PMID: 38256192 PMCID: PMC10817105 DOI: 10.3390/ijms25021120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 01/10/2024] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
The retina is the sensory tissue responsible for the first stages of visual processing, with a conserved anatomy and functional architecture among vertebrates. To date, retinal eye diseases, such as diabetic retinopathy, age-related macular degeneration, retinitis pigmentosa, glaucoma, and others, affect nearly 170 million people worldwide, resulting in vision loss and blindness. To tackle retinal disorders, the developing retina has been explored as a versatile model to study intercellular signaling, as it presents a broad neurochemical repertoire that has been approached in the last decades in terms of signaling and diseases. Retina, dissociated and arranged as typical cultures, as mixed or neuron- and glia-enriched, and/or organized as neurospheres and/or as organoids, are valuable to understand both neuronal and glial compartments, which have contributed to revealing roles and mechanisms between transmitter systems as well as antioxidants, trophic factors, and extracellular matrix proteins. Overall, contributions in understanding neurogenesis, tissue development, differentiation, connectivity, plasticity, and cell death are widely described. A complete access to the genome of several vertebrates, as well as the recent transcriptome at the single cell level at different stages of development, also anticipates future advances in providing cues to target blinding diseases or retinal dysfunctions.
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Affiliation(s)
- Matheus H. Tempone
- Laboratory of Neurochemistry, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21949-000, Brazil; (M.H.T.); (F.C.); (D.P.A.-M.); (V.T.R.-R.)
| | - Vladimir P. Borges-Martins
- Department of Physiology and Pharmacology, Biomedical Institute and Program of Neurosciences, Federal Fluminense University, Niterói 24020-150, Brazil; (V.P.B.-M.); (A.A.d.S.); (M.C.); (R.C.C.K.)
| | - Felipe César
- Laboratory of Neurochemistry, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21949-000, Brazil; (M.H.T.); (F.C.); (D.P.A.-M.); (V.T.R.-R.)
| | - Dio Pablo Alexandrino-Mattos
- Laboratory of Neurochemistry, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21949-000, Brazil; (M.H.T.); (F.C.); (D.P.A.-M.); (V.T.R.-R.)
| | - Camila S. de Figueiredo
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niterói 24020-141, Brazil; (C.S.d.F.); (A.T.D.-S.); (E.G.d.A.); (R.P.d.C.); (A.L.M.V.); (K.C.C.)
| | - Ícaro Raony
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (Í.R.); (H.R.F.)
| | - Aline Araujo dos Santos
- Department of Physiology and Pharmacology, Biomedical Institute and Program of Neurosciences, Federal Fluminense University, Niterói 24020-150, Brazil; (V.P.B.-M.); (A.A.d.S.); (M.C.); (R.C.C.K.)
| | - Aline Teixeira Duarte-Silva
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niterói 24020-141, Brazil; (C.S.d.F.); (A.T.D.-S.); (E.G.d.A.); (R.P.d.C.); (A.L.M.V.); (K.C.C.)
| | - Mariana Santana Dias
- Laboratory of Gene Therapy and Viral Vectors, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21949-000, Brazil; (M.S.D.); (H.P.S.)
| | - Hércules Rezende Freitas
- Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, Brazil; (Í.R.); (H.R.F.)
| | - Elisabeth G. de Araújo
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niterói 24020-141, Brazil; (C.S.d.F.); (A.T.D.-S.); (E.G.d.A.); (R.P.d.C.); (A.L.M.V.); (K.C.C.)
- National Institute of Science and Technology on Neuroimmunomodulation—INCT-NIM, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, Brazil
| | - Victor Tulio Ribeiro-Resende
- Laboratory of Neurochemistry, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21949-000, Brazil; (M.H.T.); (F.C.); (D.P.A.-M.); (V.T.R.-R.)
| | - Marcelo Cossenza
- Department of Physiology and Pharmacology, Biomedical Institute and Program of Neurosciences, Federal Fluminense University, Niterói 24020-150, Brazil; (V.P.B.-M.); (A.A.d.S.); (M.C.); (R.C.C.K.)
| | - Hilda P. Silva
- Laboratory of Gene Therapy and Viral Vectors, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21949-000, Brazil; (M.S.D.); (H.P.S.)
| | - Roberto P. de Carvalho
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niterói 24020-141, Brazil; (C.S.d.F.); (A.T.D.-S.); (E.G.d.A.); (R.P.d.C.); (A.L.M.V.); (K.C.C.)
| | - Ana L. M. Ventura
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niterói 24020-141, Brazil; (C.S.d.F.); (A.T.D.-S.); (E.G.d.A.); (R.P.d.C.); (A.L.M.V.); (K.C.C.)
| | - Karin C. Calaza
- Department of Neurobiology and Program of Neurosciences, Institute of Biology, Federal Fluminense University, Niterói 24020-141, Brazil; (C.S.d.F.); (A.T.D.-S.); (E.G.d.A.); (R.P.d.C.); (A.L.M.V.); (K.C.C.)
| | - Mariana S. Silveira
- Laboratory for Investigation in Neuroregeneration and Development, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21949-000, Brazil;
| | - Regina C. C. Kubrusly
- Department of Physiology and Pharmacology, Biomedical Institute and Program of Neurosciences, Federal Fluminense University, Niterói 24020-150, Brazil; (V.P.B.-M.); (A.A.d.S.); (M.C.); (R.C.C.K.)
| | - Ricardo A. de Melo Reis
- Laboratory of Neurochemistry, Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21949-000, Brazil; (M.H.T.); (F.C.); (D.P.A.-M.); (V.T.R.-R.)
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14
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Pawar A, Pardasani KR. Study of disorders in regulatory spatiotemporal neurodynamics of calcium and nitric oxide. Cogn Neurodyn 2023; 17:1661-1682. [PMID: 37974582 PMCID: PMC10640555 DOI: 10.1007/s11571-022-09902-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 09/26/2022] [Accepted: 10/14/2022] [Indexed: 11/10/2022] Open
Abstract
Experimental studies have reported the dependence of nitric oxide (NO) on the regulation of neuronal calcium ([Ca2+]) dynamics in neurons. But, there is no model available to estimate the disorders caused by various parameters in their regulatory dynamics leading to various neuronal disorders. A mathematical model to analyze the impacts due to alterations in various parameters like buffer, ryanodine receptor, serca pump, source influx, etc. leading to regulation and dysregulation of the spatiotemporal calcium and NO dynamics in neuron cells is constructed using a system of reaction-diffusion equations. The numerical simulation is performed with the finite element approach. The disturbances in the different constitutive processes of [Ca2+] and nitric oxide including source influx, buffer mechanism, ryanodine receptor, serca pump, IP3 receptor, etc. can be responsible for the dysregulation in the [Ca2+] and NO dynamics in neurons. Also, the results reveal novel information about the magnitude and intensity of disorders in response to a range of alterations in various parameters of this neuronal dynamics, which can cause dysregulation leading to neuronal diseases like Parkinson's, cerebral ischemia, trauma, etc.
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Affiliation(s)
- Anand Pawar
- Department of Mathematics, Bioinformatics and Computer Applications, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh 462003 India
| | - Kamal Raj Pardasani
- Department of Mathematics, Bioinformatics and Computer Applications, Maulana Azad National Institute of Technology, Bhopal, Madhya Pradesh 462003 India
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15
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Sharma B, Koren DT, Ghosh S. Nitric oxide modulates NMDA receptor through a negative feedback mechanism and regulates the dynamical behavior of neuronal postsynaptic components. Biophys Chem 2023; 303:107114. [PMID: 37832215 DOI: 10.1016/j.bpc.2023.107114] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 09/22/2023] [Accepted: 09/24/2023] [Indexed: 10/15/2023]
Abstract
Nitric oxide (NO) is known to be an important regulator of neurological processes in the central nervous system which acts directly on the presynaptic neuron and enhances the release of neurotransmitters like glutamate into the synaptic cleft. Calcium influx activates a cascade of biochemical reactions to influence the production of nitric oxide in the postsynaptic neuron. This has been modeled in the present work as a system of ordinary differential equations, to explore the dynamics of the interacting components and predict the dynamical behavior of the postsynaptic neuron. It has been hypothesized that nitric oxide modulates the NMDA receptor via a feedback mechanism and regulates the dynamic behavior of postsynaptic components. Results obtained by numerical analyses indicate that the biochemical system is stimulus-dependent and shows oscillations of calcium and other components within a limited range of concentration. Some of the parameters such as stimulus strength, extracellular calcium concentration, and rate of nitric oxide feedback are crucial for the dynamics of the components in the postsynaptic neuron.
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Affiliation(s)
- Bhanu Sharma
- Department of Biophysics, University of Delhi South Campus, New Delhi 110021, India
| | | | - Subhendu Ghosh
- Department of Biophysics, University of Delhi South Campus, New Delhi 110021, India.
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16
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Milton AL. Drug memory reconsolidation: from molecular mechanisms to the clinical context. Transl Psychiatry 2023; 13:370. [PMID: 38040677 PMCID: PMC10692359 DOI: 10.1038/s41398-023-02666-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 11/07/2023] [Accepted: 11/13/2023] [Indexed: 12/03/2023] Open
Abstract
Since its rediscovery at the beginning of the 21st Century, memory reconsolidation has been proposed to be a therapeutic target for reducing the impact of emotional memories that can go awry in mental health disorders such as drug addiction (substance use disorder, SUD). Addiction can be conceptualised as a disorder of learning and memory, in which both pavlovian and instrumental learning systems become hijacked into supporting drug-seeking and drug-taking behaviours. The past two decades of research have characterised the details of the molecular pathways supporting the reconsolidation of pavlovian cue-drug memories, with more recent work indicating that the reconsolidation of instrumental drug-seeking memories also relies upon similar mechanisms. This narrative review considers what is known about the mechanisms underlying the reconsolidation of pavlovian and instrumental memories associated with drug use, how these approaches have translated to experimental medicine studies, and the challenges and opportunities for the clinical use of reconsolidation-based therapies.
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Affiliation(s)
- Amy L Milton
- Department of Psychology, University of Cambridge, Cambridge, UK.
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17
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Bonato JM, de Mattos BA, Oliveira DV, Milani H, Prickaerts J, de Oliveira RMW. Blood-Brain Barrier Rescue by Roflumilast After Transient Global Cerebral Ischemia in Rats. Neurotox Res 2023; 41:311-323. [PMID: 36922461 DOI: 10.1007/s12640-023-00639-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 02/28/2023] [Accepted: 03/03/2023] [Indexed: 03/18/2023]
Abstract
Phosphodiesterase 4 inhibitors (PDE4-I), which selectively increase cyclic adenosine monophosphate (cAMP) levels, have shown neuroprotective effects after several neurological injuries inducing blood-brain barrier (BBB) damage including local/focal cerebral ischemia. The present investigated whether roflumilast confers BBB neuroprotection in the hippocampus after transient global cerebral ischemia (TGCI) in rats. TGCI resulted in whole BBB disruption as measured by the increase of Evans blue (EB) and IgG extravasation, neurodegeneration, and downregulation of claudin-5 and endothelial nitric oxide synthase (eNOS) levels in the CA1 hippocampal subfield of ischemic rats. Roflumilast attenuated BBB disruption and restored the levels of eNOS in the CA1 hippocampal area. Moreover, roflumilast increased the levels of B2 cell lymphoma (BcL-2) and neuron-glial antigen-2 (NG2) in the CA1 subfield after global ischemia in rats. The protective effects of roflumilast against TGCI-induced BBB breakdown might involve preservation of BBB integrity, vascularization and angiogenesis, and myelin repair.
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Affiliation(s)
- Jéssica Mendes Bonato
- Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, CEP, 5790, 87020-900, Maringá, Paraná, Brazil
| | - Bianca Andretto de Mattos
- Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, CEP, 5790, 87020-900, Maringá, Paraná, Brazil
| | - Daniela Velasquez Oliveira
- Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, CEP, 5790, 87020-900, Maringá, Paraná, Brazil
| | - Humberto Milani
- Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, CEP, 5790, 87020-900, Maringá, Paraná, Brazil
| | - Jos Prickaerts
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
| | - Rúbia Maria Weffort de Oliveira
- Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, CEP, 5790, 87020-900, Maringá, Paraná, Brazil.
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18
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Edinoff AN, Flanagan CJ, Sinnathamby ES, Pearl NZ, Jackson ED, Wenger DM, Cornett EM, Kaye AM, Kaye AD. Treatment of Acute Pain in Patients on Naltrexone: A Narrative Review. Curr Pain Headache Rep 2023; 27:183-192. [PMID: 37115486 DOI: 10.1007/s11916-023-01110-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/20/2023] [Indexed: 04/29/2023]
Abstract
PURPOSE OF REVIEW The tissue damage and trauma associated with surgery almost always result in acute postoperative pain. The intensity of postoperative pain can range from mild to severe. Naltrexone is suitable for patients who do not wish to be on an agonist treatment such as methadone or buprenorphine. However, naltrexone has been shown to complicate postoperative pain management. RECENT FINDINGS Multiple studies have found that the use of naltrexone can increase the opioid requirement for postoperative pain control. Other modalities exist that can help outside of opioids such as ketamine, lidocaine/bupivacaine, duloxetine, and non-pharmacological management can help manage pain. Multimodal pain regiments should also be employed in patients. In addition to traditional methods for postoperative pain management, other methods of acute pain control exist that can help mitigate opioid dependence and help control pain in patients who use naltrexone for their substance use disorders.
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Affiliation(s)
- Amber N Edinoff
- Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, 55 Fruit St, Boston, MA, 02114, USA.
- Louisiana Addiction Research Center, Shreveport, LA, 71103, USA.
| | - Chelsi J Flanagan
- School of Osteopathic Medicine, University of the Incarnate Word, San Antonio, TX, 78235, USA
| | - Evan S Sinnathamby
- School of Medicine, Louisiana State University Health Science Center at New Orleans, New Orleans, LA, 70112, USA
| | - Nathan Z Pearl
- School of Medicine, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA
| | - Eric D Jackson
- University of Arizona College of Medicine- Phoenix, Phoenix, AZ, 85004, USA
| | - Danielle M Wenger
- University of Arizona College of Medicine- Phoenix, Phoenix, AZ, 85004, USA
| | - Elyse M Cornett
- Louisiana Addiction Research Center, Shreveport, LA, 71103, USA
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA
| | - Adam M Kaye
- Thomas J. Long School of Pharmacy and Health Sciences, Department of Pharmacy Practice, University of the Pacific, Stockton, CA, 95211, USA
| | - Alan D Kaye
- Louisiana Addiction Research Center, Shreveport, LA, 71103, USA
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, Shreveport, LA, 71103, USA
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Neuronal nitric oxide synthase positive neurons in the human corpus callosum: a possible link with the callosal blood-oxygen-level dependent (BOLD) effect. Brain Struct Funct 2023; 228:511-523. [PMID: 36460768 DOI: 10.1007/s00429-022-02599-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 11/18/2022] [Indexed: 12/04/2022]
Abstract
Brain functions have been investigated in the past decades via the blood-oxygen-level dependent (BOLD) effect using functional magnetic resonance imaging. One hypothesis explaining the BOLD effect involves the Nitric Oxide (NO) gaseous neurotransmitter, possibly released also by cells in the corpus callosum (CC). The eventual presence of NO releasing neurons and/or glial cells in the CC can be assessed by immunohistochemistry. Serial sections both from paraffin-embedded and frozen samples of CC obtained from adult human brains autopsy were studied with immunohistochemistry and immunofluorescence analysis, using an antibody against the neuronal isoform of Nitric Oxide Synthase (nNOS), the enzyme synthetizing the NO. The staining revealed the presence of many nNOS-immunopositive cells in the CC, shown to be neurons with immunofluorescence. Neuronal NOS-positive neurons presented different morphologies, were more numerous 4 mm apart from the midline, and displayed a peak in the body of the CC. In some cases, they were located at the upper boundary of the CC, more densely packed in the proximity of the callosal arterioles. The significant presence of nNOS-immunopositive neurons within the commissure suggests their probable role in the CC neurovascular regulation in the adult brain and could explain the BOLD effect detected in human CC.
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The opposite effect of convulsant drugs on neuronal and endothelial nitric oxide synthase - A possible explanation for the dual proconvulsive/anticonvulsive action of nitric oxide. ACTA PHARMACEUTICA (ZAGREB, CROATIA) 2023; 73:59-74. [PMID: 36692466 DOI: 10.2478/acph-2023-0004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/21/2022] [Indexed: 01/25/2023]
Abstract
Nitric oxide (NO) participates in processes such as endothelium-dependent vasodilation and neurotransmission/neuromodulation. The role of NO in epilepsy is controversial, attributing it to anticonvulsant but also proconvulsant properties. Clarification of this dual effect of NO might lead to the development of new antiepileptic drugs. Previous results in our laboratory indicated that this contradictory role of NO in seizures could depend on the nitric oxide synthase (NOS) isoform involved, which could play opposite roles in epileptogenesis, one of them being proconvulsant but the other anticonvulsant. The effect of convulsant drugs on neuronal NO (nNO) and endothelial NO (eNO) levels was investigated. Considering the distribution of neuronal and endothelial NOS in neurons and astrocytes, resp., primary cultures of neurons and astrocytes were used as a study model. The effects of convulsant drugs pentylenetetrazole, thiosemicarbazide, 4-aminopyridine and bicuculline on NO levels were studied, using a spectrophotometric method. Their effects on NO levels in neurons and astrocytes depend on the concentration and time of treatment. These convulsant drugs caused an increase in nNO, but a decrease in eNO was proportional to the duration of treatment in both cases. Apparently, nNO possesses convulsant properties mediated by its effect on the glutamatergic and GABAergic systems, probably through GABAA receptors. Anticonvulsant properties of eNO may be the consequence of its effect on endothelial vasodilation and its capability to induce angiogenesis. Described effects last as seizures do. Considering the limitations of these kinds of studies and the unexplored influence of inducible NO, further investigations are required.
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21
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Vitamin C Modes of Action in Calcium-Involved Signaling in the Brain. Antioxidants (Basel) 2023; 12:antiox12020231. [PMID: 36829790 PMCID: PMC9952025 DOI: 10.3390/antiox12020231] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/15/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
Vitamin C (ascorbic acid) is well known for its potent antioxidant properties, as it can neutralize ROS and free radicals, thereby protecting cellular elements from oxidative stress. It predominantly exists as an ascorbate anion and after oxidation to dehydroascorbic acid and further breakdown, is removed from the cells. In nervous tissue, a progressive decrease in vitamin C level or its prolonged deficiency have been associated with an increased risk of disturbances in neurotransmission, leading to dysregulation in brain function. Therefore, understanding the regulatory function of vitamin C in antioxidant defence and identification of its molecular targets deserves more attention. One of the key signalling ions is calcium and a transient rise in its concentration is crucial for all neuronal processes. Extracellular Ca2+ influx (through specific ion channels) or Ca2+ release from intracellular stores (endoplasmic reticulum, mitochondria) are precisely controlled. Ca2+ regulates the functioning of the CNS, including growth, development, myelin formation, synthesis of catecholamines, modulation of neurotransmission and antioxidant protection. A growing body of evidence indicates a unique role for vitamin C in these processes. In this short review, we focus on vitamin C in the regulation of calcium-involved pathways under physiological and stress conditions in the brain.
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22
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Fruekilde SK, Bailey CJ, Lambertsen KL, Clausen BH, Carlsen J, Xu NL, Drasbek KR, Gutiérrez-Jiménez E. Disturbed microcirculation and hyperaemic response in a murine model of systemic inflammation. J Cereb Blood Flow Metab 2022; 42:2303-2317. [PMID: 35999817 PMCID: PMC9670001 DOI: 10.1177/0271678x221112278] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Systemic inflammation affects cognitive functions and increases the risk of dementia. This phenomenon is thought to be mediated in part by cytokines that promote neuronal survival, but the continuous exposure to which may lead to neurodegeneration. The effects of systemic inflammation on cerebral blood vessels, and their provision of adequate oxygen to support critical brain parenchymal cell functions, remains unclear. Here, we demonstrate that neurovascular coupling is profoundly disturbed in lipopolysaccharide (LPS) induced systemic inflammation in awake mice. In the 24 hours following LPS injection, the hyperaemic response of pial vessels to functional activation was attenuated and delayed. Concurrently, under steady-state conditions, the capillary network displayed a significant increase in the number of capillaries with blocked blood flow, as well as increased duration of 'capillary stalls'-a phenomenon previously reported in animal models of stroke and Alzheimer's disease pathology. We speculate that vascular changes and impaired oxygen availability may affect brain functions following acute systemic inflammation and contribute to the long-term risk of neurodegenerative changes associated with chronic, systemic inflammation.
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Affiliation(s)
- Signe Kirk Fruekilde
- Center for Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, 1006Aarhus University, Aarhus C, Denmark.,Sino-Danish Center for Education and Research (SDC), University of Chinese Academy of Sciences, Beijing, P.R. China
| | - Christopher J Bailey
- Center for Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, 1006Aarhus University, Aarhus C, Denmark.,Sino-Danish Center for Education and Research (SDC), University of Chinese Academy of Sciences, Beijing, P.R. China
| | - Kate Lykke Lambertsen
- Department of Neurobiology Research, Institute of Molecular Medicine, 6174University of Southern Denmark, Odense C, Denmark.,BRIDGE - Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, 6174University of Southern Denmark, Odense C, Denmark.,Department of Neurology, Odense University Hospital, Odense C, Denmark
| | - Bettina Hjelm Clausen
- Department of Neurobiology Research, Institute of Molecular Medicine, 6174University of Southern Denmark, Odense C, Denmark.,BRIDGE - Brain Research - Inter-Disciplinary Guided Excellence, Department of Clinical Research, 6174University of Southern Denmark, Odense C, Denmark
| | - Jasper Carlsen
- Research Unit for Molecular Medicine (MMF), Department of Clinical Medicine, 1006Aarhus University, Aarhus N, Denmark
| | - Ning-Long Xu
- Sino-Danish Center for Education and Research (SDC), University of Chinese Academy of Sciences, Beijing, P.R. China.,Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, P.R. China
| | - Kim Ryun Drasbek
- Center for Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, 1006Aarhus University, Aarhus C, Denmark.,Sino-Danish Center for Education and Research (SDC), University of Chinese Academy of Sciences, Beijing, P.R. China
| | - Eugenio Gutiérrez-Jiménez
- Center for Functionally Integrative Neuroscience (CFIN), Department of Clinical Medicine, 1006Aarhus University, Aarhus C, Denmark
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Lacroix PG, Malfant I, Labra-Vázquez P, Fárfan N, Ramos-Ortiz G. Two-photon absorption-based delivery of nitric oxide from ruthenium nitrosyl complexes. Dalton Trans 2022; 51:14833-14841. [PMID: 36169419 DOI: 10.1039/d2dt02553a] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Since the discovery of the numerous physiological roles exhibited by nitric oxide (NO), ruthenium nitrosyl (RuNO) complexes have been regarded as one of the most promising NO donors, stable, well tolerated by the body and capable of releasing NO locally and quantitatively, under light irradiation. This release can be achieved by two-photon absorption (TPA) processes, which allow the irradiation to be performed in the near infrared domain, where light has its maximum depth of penetration in biological tissues. This review provides a short introduction on the biological properties of NO, on RuNO complexes with photo-releasing capabilities, and on the origin of TPA properties in molecules. Then, the RuNO complexes with TPA capabilities are thoroughly discussed either as monometallic or polymetallic species.
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Affiliation(s)
- Pascal G Lacroix
- Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, F-31077 Toulouse, France.
| | - Isabelle Malfant
- Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, F-31077 Toulouse, France.
| | - Pablo Labra-Vázquez
- Laboratoire de Chimie de Coordination du CNRS, 205 route de Narbonne, F-31077 Toulouse, France. .,Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, 04510 México D.F., Mexico
| | - Norberto Fárfan
- Facultad de Química, Departamento de Química Orgánica, Universidad Nacional Autónoma de México, 04510 México D.F., Mexico
| | - Gabriel Ramos-Ortiz
- Centro de Investigaciones en Óptica (CIO), A.P. 1-948, 37000 León, Gto, Mexico
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Effects of low doses of different nitric oxide (NO) donors in rat models of obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). Nitric Oxide 2022; 129:1-7. [PMID: 36084795 DOI: 10.1016/j.niox.2022.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 09/01/2022] [Accepted: 09/01/2022] [Indexed: 11/22/2022]
Abstract
Several lines of evidence suggest that the intra- and inter-cellular messenger nitric oxide (NO) is critically involved in anxiety. Contrasting findings are reported, however, regarding the effects of NO donors in preclinical models of anxiety. Previous research has shown that challenge with a low dose range of the NO donors sodium nitroprusside (SNP) and molsidomine induce anti-anxiety-like effects in rodents. There is poor information concerning the effects of these NO donors on preclinical models mimicking the obsessive-compulsive disorder (OCD) and the post-traumatic stress disorder (PTSD). The present research was designed to investigate this issue in the rat. To this end, the mCPP-induced excessive self-grooming and the contextual fear conditioning (CFC) test which are behavioural paradigms resembling OCD and PTSD respectively in rodents were used. Acute administration of SNP (1 mg/kg) and molsidomine (4 mg/kg) attenuated excessive self-grooming induced by the 5-HT2C receptor agonist mCPP (0.6 mg/kg). Further, at the same dosage, both these NO donors reduced freezing behaviour evidenced in the CFC test. The present results suggest that NO donors are efficacious in attenuating abnormal behaviours revealed in animal models of OCD and PTSD which are among the most severe pathologies of anxiety.
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25
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Zaia CTBV, Uchôa ET, Santos AATD, Ribeiro RCDA, Batista ACS, Crespigio J, Utida L, Moura GB, Brownlow ML, Garnica-Siqueira MC, Reis WL, Antunes-Rodrigues J, Zaia DAM. Vasoactive intestinal peptide promotes hypophagia and metabolic changes: role of paraventricular hypothalamic nucleus and nitric oxide. Brain Res Bull 2022; 189:102-110. [PMID: 36029978 DOI: 10.1016/j.brainresbull.2022.08.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 08/03/2022] [Accepted: 08/21/2022] [Indexed: 11/02/2022]
Abstract
Vasoactive intestinal peptide (VIP), a neuromodulator present in the hypothalamus, plays an important role in the regulation of food intake. Paraventricular nucleus of the hypothalamus (PVN) is involved in ingestive responses and regulates the nitric oxide (NO) pathway. The main objectives of this study were to investigate metabolic changes established after different doses and times of VIP microinjection on the PVN, and the effect of VIP microinjection on the PVN on food intake and the role of NO in this control. In anesthetized rats, increased blood plasma glucose and insulin levels were observed following the doses of 40 and 80ng/g of body weight. At the dose of 40ng/g, VIP promoted hyperglycemia and hyperinsulinemia 5, 10, and 30min after microinjection, and increased free fatty acids and total lipids plasma levels after 5min, and triglycerides after 10min. In awake animals, once again, VIP administration increased plasmatic levels of glucose, free fatty acids, corticosterone, and insulin 10min after the microinjection. Moreover, VIP promoted hypophagia in the morning and night periods, and L-arginine (L-Arg) and monosodium glutamate (MSG) or a combination of both attenuated VIP-induced reduction on food intake. In addition, nitrate concentration in the PVN was decreased after VIP microinjection. Our data show that the PVN participates in the anorexigenic and metabolic effects of VIP, and that VIP-induced hypophagia is likely mediated by reduction of NO.
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Affiliation(s)
- Cássia Thaïs Bussamra Vieira Zaia
- Laboratório de Fisiologia Neuroendócrina e Metabolismo, Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina; Londrina, PR, Brazil; Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas, Universidade Estadual de Londrina, Londrina, PR, Brazil.
| | - Ernane Torres Uchôa
- Laboratório de Fisiologia Neuroendócrina e Metabolismo, Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina; Londrina, PR, Brazil; Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas, Universidade Estadual de Londrina, Londrina, PR, Brazil.
| | | | - Rachel Cezar de Andrade Ribeiro
- Laboratório de Fisiologia Neuroendócrina e Metabolismo, Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina; Londrina, PR, Brazil
| | - Ana Carolina Seidel Batista
- Programa Multicêntrico de Pós-Graduação em Ciências Fisiológicas, Universidade Estadual de Londrina, Londrina, PR, Brazil
| | - Jefferson Crespigio
- Laboratório de Fisiologia Neuroendócrina e Metabolismo, Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina; Londrina, PR, Brazil
| | - Lawrence Utida
- Laboratório de Fisiologia Neuroendócrina e Metabolismo, Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina; Londrina, PR, Brazil
| | - Galiano Brazuna Moura
- Laboratório de Fisiologia Neuroendócrina e Metabolismo, Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina; Londrina, PR, Brazil
| | - Milene Lara Brownlow
- Laboratório de Fisiologia Neuroendócrina e Metabolismo, Departamento de Ciências Fisiológicas, Universidade Estadual de Londrina; Londrina, PR, Brazil
| | | | - Wagner Luis Reis
- Departamento de Ciências Fisiológicas, Universidade Federal de Santa Catarina; Florianópolis, SC, Brazil
| | - Jose Antunes-Rodrigues
- Departamento de Fisiologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo; Ribeirão Preto, SP, Brazil
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26
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Jiang H, Li L, Zhang L, Zang G, Sun Z, Wang Z. Role of endothelial cells in vascular calcification. Front Cardiovasc Med 2022; 9:895005. [PMID: 35928939 PMCID: PMC9343736 DOI: 10.3389/fcvm.2022.895005] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 06/28/2022] [Indexed: 11/13/2022] Open
Abstract
Vascular calcification (VC) is active and regulates extraosseous ossification progress, which is an independent predictor of cardiovascular disease (CVD) morbidity and mortality. Endothelial cells (ECs) line the innermost layer of blood vessels and directly respond to changes in flow shear stress and blood composition. Together with vascular smooth muscle cells, ECs maintain vascular homeostasis. Increased evidence shows that ECs have irreplaceable roles in VC due to their high plasticity. Endothelial progenitor cells, oxidative stress, inflammation, autocrine and paracrine functions, mechanotransduction, endothelial-to-mesenchymal transition (EndMT), and other factors prompt ECs to participate in VC. EndMT is a dedifferentiation process by which ECs lose their cell lineage and acquire other cell lineages; this progress coexists in both embryonic development and CVD. EndMT is regulated by several signaling molecules and transcription factors and ultimately mediates VC via osteogenic differentiation. The specific molecular mechanism of EndMT remains unclear. Can EndMT be reversed to treat VC? To address this and other questions, this study reviews the pathogenesis and research progress of VC, expounds the role of ECs in VC, and focuses on the regulatory factors underlying EndMT, with a view to providing new concepts for VC prevention and treatment.
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Affiliation(s)
- Han Jiang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lihua Li
- Department of Pathology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lili Zhang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Guangyao Zang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhen Sun
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Zhongqun Wang
- Department of Cardiology, Affiliated Hospital of Jiangsu University, Zhenjiang, China
- *Correspondence: Zhongqun Wang,
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Ranjana M, Sunil D. Naphthalimide derivatives as fluorescent probes for imaging endogenous gasotransmitters. Chem Biol Interact 2022; 363:110022. [PMID: 35753358 DOI: 10.1016/j.cbi.2022.110022] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 05/07/2022] [Accepted: 06/17/2022] [Indexed: 11/03/2022]
Abstract
Gasotransmitters have gained significant recognition attributed to their evident biological impacts, and is accepted as a promising and less-explored area with immense research scope. The three-member family comprising of nitric oxide, carbon monoxide and hydrogen sulphide as endogenous gaseous signaling molecules have been found to elicit a plethora of crucial biological functions, spawning a new research area. The sensing of these small molecules is vital to gain deeper insights into their functions, as they can act both as a friend or a foe in mammalian systems. The initial sections of the review present the physiological and pathophysiological roles of these endogenous gas transmitters and their synergistic interactions. Further, various detection approaches, especially the usage of fascinating features of 1,8-naphthalimide as fluorescent probe in the detection and monitoring of these small signaling molecules are highlighted. The current limitations and the future scope of improving the sensing of the three gasotransmitters are also discussed.
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Affiliation(s)
- M Ranjana
- Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576 104, Karnataka, India
| | - Dhanya Sunil
- Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, 576 104, Karnataka, India.
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28
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Perovic D, Milavic M, Dokuzovic S, Krezic I, Gojkovic S, Vranes H, Bebek I, Bilic V, Somun N, Brizic I, Skorak I, Hriberski K, Sikiric S, Lovric E, Strbe S, Kubat M, Boban Blagaic A, Skrtic A, Seiwerth S, Sikiric P. Novel Therapeutic Effects in Rat Spinal Cord Injuries: Recovery of the Definitive and Early Spinal Cord Injury by the Administration of Pentadecapeptide BPC 157 Therapy. Curr Issues Mol Biol 2022; 44:1901-1927. [PMID: 35678659 PMCID: PMC9164058 DOI: 10.3390/cimb44050130] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/22/2022] [Accepted: 04/24/2022] [Indexed: 12/17/2022] Open
Abstract
Recently, marked therapeutic effects pertaining to the recovery of injured rat spinal cords (1 min compression injury of the sacrocaudal spinal cord (S2-Co1) resulting in tail paralysis) appeared after a single intraperitoneal administration of the stable gastric pentadecapeptide BPC 157 at 10 min post-injury. Besides the demonstrated rapid and sustained recovery (1 year), we showed the particular points of the immediate effect of the BPC 157 therapy that began rapidly after its administration, (i) soon after injury (10 min), or (ii) later (4 days), in the rats with a definitive spinal cord injury. Specifically, in counteracting spinal cord hematoma and swelling, (i) in rats that had undergone acute spinal cord injury, followed by intraperitoneal BPC 157 application at 10 min, we focused on the first 10-30 min post-injury period (assessment of gross, microscopic, and gene expression changes). Taking day 4 post-injury as the definitive injury, (ii) we focused on the immediate effects after the BPC 157 intragastric application over 20 min of the post-therapy period. Comparable long-time recovery was noted in treated rats which had definitive tail paralysis: (iii) the therapy was continuously given per orally in drinking water, beginning at day 4 after injury and lasting one month after injury. BPC 157 rats presented only discrete edema and minimal hemorrhage and increased Nos1, Nos2, and Nos3 values (30 min post-injury, (i)) or only mild hemorrhage, and only discrete vacuolation of tissue (day 4, (ii)). In the day 4-30 post-injury study (iii), BPC 157 rats rapidly presented tail function recovery, and no demyelination process (Luxol fast blue staining).
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Affiliation(s)
- Darko Perovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
- Department of Surgery, Clinical Hospital Dubrava, 10000 Zagreb, Croatia
| | - Marija Milavic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.M.); (S.S.); (E.L.); (S.S.)
| | - Stjepan Dokuzovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Ivan Krezic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Slaven Gojkovic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Hrvoje Vranes
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Igor Bebek
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Vide Bilic
- Clinical Hospital of Traumatology, Sestre Milosrdnice University Hospital Center, 10000 Zagreb, Croatia;
| | - Nenad Somun
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Ivan Brizic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Ivan Skorak
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Klaudija Hriberski
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Suncana Sikiric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.M.); (S.S.); (E.L.); (S.S.)
| | - Eva Lovric
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.M.); (S.S.); (E.L.); (S.S.)
| | - Sanja Strbe
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Milovan Kubat
- Department of Forensic Medicine and Criminology, School of Medicine, 10000 Zagreb, Croatia;
| | - Alenka Boban Blagaic
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
| | - Anita Skrtic
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.M.); (S.S.); (E.L.); (S.S.)
| | - Sven Seiwerth
- Department of Pathology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (M.M.); (S.S.); (E.L.); (S.S.)
| | - Predrag Sikiric
- Department of Pharmacology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (D.P.); (S.D.); (I.K.); (S.G.); (H.V.); (I.B.); (N.S.); (I.B.); (I.S.); (K.H.); (S.S.); (A.B.B.)
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29
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Johnson KN, Chilukurib B, Fisherb ZE, Hippsa KW, Mazura U. Role of the Supporting Surface in the Thermodynamics and Cooperativity of Axial Ligand Binding to Metalloporphyrins at Interfaces. CURR ORG CHEM 2022. [DOI: 10.2174/1385272826666220209122508] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Abstract:
: Metalloporphyrins have been shown to bind axial ligands in a variety of environments including the vacuum/solid and solution/solid interfaces. Understanding the dynamics of such interactions is a desideratum for the design and implementation of next generation molecular devices which draw inspiration from biological systems to accomplish diverse tasks such as molecular sensing, electron transport, and catalysis to name a few. In this article, we review the current literature of axial ligand coordination to surface-supported porphyrin receptors. We will focus on the coordination process as monitored by scanning tunneling microscopy (STM) that can yield qualitative and quantitative information on the dynamics and binding affinity at the single molecule level. In particular, we will address the role of the substrate and intermolecular interactions in influencing cooperative effects (positive or negative) in the binding affinity of adjacent molecules based on experimental evidence and theoretical calculations.
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Affiliation(s)
- Kristen N. Johnson
- Department of Chemistry and Material Science and Engineering Program, Washington State University, Pullman, 99164-4630, WA, USA
| | - Bhaskar Chilukurib
- Department of Chemistry, Illinois State University, Normal, IL, 61790-4160, USA
| | - Zachary E. Fisherb
- Department of Chemistry, Illinois State University, Normal, IL, 61790-4160, USA
| | - K. W. Hippsa
- Department of Chemistry and Material Science and Engineering Program, Washington State University, Pullman, 99164-4630, WA, USA
| | - Ursula Mazura
- Department of Chemistry and Material Science and Engineering Program, Washington State University, Pullman, 99164-4630, WA, USA
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Pombal MA, Megías M, Lozano D, López JM. Neuromeric Distribution of Nicotinamide Adenine Dinucleotide Phosphate-Diaphorase Activity in the Adult Lamprey Brain. Front Neuroanat 2022; 16:826087. [PMID: 35197830 PMCID: PMC8859838 DOI: 10.3389/fnana.2022.826087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/10/2022] [Indexed: 11/13/2022] Open
Abstract
This study reports for the first time the distribution and morphological characterization of nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d; a reliable marker of nitric oxide synthase activity) positive elements in the central nervous system of the adult river lamprey (Lampetra fluviatilis) on the framework of the neuromeric model and compares their cytoarchitectonic organization with that of gnathostomes. Both NADPH-d exhibiting cells and fibers were observed in all major divisions of the lamprey brain as well as in the spinal cord. In the secondary prosencephalon, NADPH-d positive cells were observed in the mitral cell layer of the olfactory bulb, evaginated pallium, amygdala, dorsal striatum, septum, lateral preoptic nucleus, caudal paraventricular area, posterior entopeduncular nucleus, nucleus of the stria medullaris, hypothalamic periventricular organ and mamillary region sensu lato. In the lamprey diencephalon, NADPH-d labeled cells were observed in several nuclei of the prethalamus, epithalamus, pretectum, and the basal plate. Especially remarkable was the staining observed in the right habenula and several pretectal nuclei. NADPH-d positive cells were also observed in the following mesencephalic areas: optic tectum (two populations), torus semicircularis, nucleus M5 of Schöber, and a ventral tegmental periventricular nucleus. Five different cell populations were observed in the isthmic region, whereas the large sensory dorsal cells, some cells located in the interpeduncular nucleus, the motor nuclei of most cranial nerves, the solitary tract nucleus, some cells of the reticular nuclei, and small cerebrospinal fluid-contacting (CSF-c) cells were the most evident stained cells of the rhombencephalon proper. Finally, several NADPH-d positive cells were observed in the rostral part of the spinal cord, including the large sensory dorsal cells, numerous CSF-c cells, and some dorsal and lateral interneurons. NADPH-d positive fibers were observed in the olfactory pathways (primary olfactory fibers and stria medullaris), the fasciculus retroflexus, and the dorsal column tract. Our results on the distribution of NADPH-d positive elements in the brain of the adult lamprey L. fluviatilis are significantly different from those previously reported in larval lampreys and demonstrated that these animals possess a complex nitrergic system readily comparable to those of other vertebrates, although important specific differences also exist.
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Affiliation(s)
- Manuel A. Pombal
- Neurolam Group, Facultade de Bioloxía-IBIV, Departamento de Bioloxía Funcional e Ciencias da Saúde, Universidade de Vigo, Vigo, Spain
- *Correspondence: Manuel A. Pombal,
| | - Manuel Megías
- Neurolam Group, Facultade de Bioloxía-IBIV, Departamento de Bioloxía Funcional e Ciencias da Saúde, Universidade de Vigo, Vigo, Spain
| | - Daniel Lozano
- Department of Cellular Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain
| | - Jesús M. López
- Department of Cellular Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain
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31
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Somani A, Singh AK, Gupta B, Nagarkoti S, Dalal PK, Dikshit M. Oxidative and Nitrosative Stress in Major Depressive Disorder: A Case Control Study. Brain Sci 2022; 12:brainsci12020144. [PMID: 35203908 PMCID: PMC8870258 DOI: 10.3390/brainsci12020144] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/17/2022] [Accepted: 01/17/2022] [Indexed: 01/27/2023] Open
Abstract
Introduction: The role of increased oxidative stress and alterations to the nitric oxide (NO) pathway have been implicated in major depressive disorder (MDD). The two pathways interact closely with each other but have not been studied simultaneously in MDD. This study aimed to assess and compare the levels of oxidative and nitrosative stress in the neutrophils (PMNs) of drug-naive MDD patients and their first-degree relatives. Methods: 29 drug-naive MDD patients and 27 healthy first-degree relatives and healthy controls aged 18–45 years were included in this study. An assessment of the levels of reactive oxygen species (ROS), nitrites, neuronal NO synthase (nNOS), and myeloperoxidase in PMNs, and cortisol in serum was carried out. Results: Compared to healthy controls, the generation of free radicals, myeloperoxidase activity, and nNOS mRNA expression in PMNs, and cortisol level in serum were significantly higher in drug-naive depression patients. Indeed, increased levels of myeloperoxidase and serum cortisol were also noted in first-degree relatives. The total nitrite content in the PMNs and plasma however was significantly lower in both patients and first-degree relatives. Interestingly, a positive correlation was established in the ROS levels in the PMNs, plasma and neutrophil nitrite, and the serum cortisol level between MDD patients and their first-degree relatives. Conclusion: The results of this study contribute towards a better understanding of the familial association of depressive disorder, and demonstrate for the first time that neutrophil ROS/RNS, plasma nitrite, and serum cortisol levels are positively correlated between MDD patients and their first-degree relatives. However, further studies in larger, more diverse samples are needed to extend these pathways as potential biomarkers to identify persons at high risk for psychopathology at an early stage.
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Affiliation(s)
- Aditya Somani
- Department of Psychiatry, King George’s Medical University, Lucknow 226003, India; (A.S.); (B.G.); (P.K.D.)
| | - Abhishek Kumar Singh
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; (A.K.S.); (S.N.)
| | - Bandna Gupta
- Department of Psychiatry, King George’s Medical University, Lucknow 226003, India; (A.S.); (B.G.); (P.K.D.)
| | - Sheela Nagarkoti
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; (A.K.S.); (S.N.)
| | - Pronob Kumar Dalal
- Department of Psychiatry, King George’s Medical University, Lucknow 226003, India; (A.S.); (B.G.); (P.K.D.)
| | - Madhu Dikshit
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, India; (A.K.S.); (S.N.)
- Correspondence:
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32
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Altınok A, Karabay A, Akyürek EG. Acute effects of cocoa flavanols on visual working memory: maintenance and updating. Eur J Nutr 2022; 61:1665-1678. [PMID: 35031887 DOI: 10.1007/s00394-021-02767-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 11/30/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND Consumption of cocoa flavanols may have acute physiological effects on the brain due to their ability to activate nitric oxide synthesis. Nitric oxide mediates vasodilation, which increases cerebral blood flow, and can also act as a neurotransmitter. OBJECTIVES This study aimed to examine whether cocoa flavanols have an acute influence on visual working memory (WM). METHODS Two separate randomised, double-blind, placebo-controlled, counterbalanced crossover experiments were conducted on normal healthy young adult volunteers (NExp1 = 48 and NExp2 = 32, gender-balanced). In these experiments, 415 mg of cocoa flavanols were administered to test their acute effects on visual working memory. In the first experiment, memory recall precision was measured in a task that required only passive maintenance of grating orientations in WM. In the second experiment, recall was measured after active updating (mental rotation) of WM contents. Habitual daily flavanols intake, body mass index, and gender were also considered in the analysis. RESULTS The results suggested that neither passive maintenance in visual WM nor active updating of WM were acutely enhanced by consumption of cocoa flavanols. Exploratory analyses with covariates (body mass index and daily flavanols intake), and the between-subjects factor of gender also showed no evidence for effects of cocoa flavanols, neither in terms of reaction time, nor accuracy. CONCLUSIONS Overall, cocoa flavanols did not improve visual working memory recall performance during maintenance, nor did it improve recall accuracy after memory updating.
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Affiliation(s)
- Ahmet Altınok
- Department of Experimental Psychology, University of Groningen, Grote Kruisstraat 2/1, 9712 TS, Groningen, The Netherlands.
| | - Aytaç Karabay
- Department of Experimental Psychology, University of Groningen, Grote Kruisstraat 2/1, 9712 TS, Groningen, The Netherlands
| | - Elkan G Akyürek
- Department of Experimental Psychology, University of Groningen, Grote Kruisstraat 2/1, 9712 TS, Groningen, The Netherlands
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33
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Kajita Y, Mushiake H. Heterogeneous GAD65 Expression in Subtypes of GABAergic Neurons Across Layers of the Cerebral Cortex and Hippocampus. Front Behav Neurosci 2021; 15:750869. [PMID: 34803625 PMCID: PMC8595203 DOI: 10.3389/fnbeh.2021.750869] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/16/2021] [Indexed: 11/13/2022] Open
Abstract
Gamma-aminobutyric acid (GABA), a major inhibitory transmitter in the central nervous system, is synthesized via either of two enzyme isoforms, GAD65 or GAD67. GAD65 is synthesized in the soma but functions at synaptic terminals in an activity-dependent manner, playing a distinct role in excitatory-inhibitory balance. However, the extent to which each GABAergic subtype expresses GAD65 in the resting state remains unclear. In this study, we compared GAD65 expression among six GABAergic subtypes: NPY+, nNOS+, PV+, SOM+, CR+, and CCK+. According to the results, the GABAergic subtypes were classified into two groups per region based on GAD65 expression levels: high-expression (NPY+ and nNOS+) and low-expression groups (PV+, SOM+, CR+, and CCK+) in the cerebral cortex and high-expression (NPY+, nNOS+, and CCK+) and low-expression groups (PV+, SOM+, and CR+) in the hippocampus. Moreover, these expression patterns revealed a distinct laminar distribution in the cerebral cortex and hippocampus. To investigate the extent of GAD65 transport from the soma to synaptic terminals, we examined GAD65 expression in colchicine-treated rats in which GAD65 was synthesized in the soma but not transported to terminals. We found a significant positive correlation in GAD65 expression across subtypes between colchicine-treated and control rats. In summary, each GABAergic subtype exhibits a distinct GAD65 expression pattern across layers of the cerebral cortex and hippocampus. In addition, the level of GAD65 expression in the soma can be used as a proxy for the amount of GAD65 in the cytoplasm. These findings suggest that exploration of the distinct profiles of GAD65 expression among GABAergic subtypes could clarify the roles that GABAergic subtypes play in maintaining the excitatory-inhibitory balance.
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Affiliation(s)
- Yuki Kajita
- Department of Physiology, Graduate School of Medicine, Tohoku University, Sendai, Japan
| | - Hajime Mushiake
- Department of Physiology, Graduate School of Medicine, Tohoku University, Sendai, Japan
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34
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Xu H, Zhong Y, Yuan S, Wu Y, Ma Z, Hao Z, Ding H, Wu H, Liu G, Pang M, Liu N, Wang C, Zhang N. Nitric Oxide Synthase Type 1 Methylation Is Associated With White Matter Microstructure in the Corpus Callosum and Greater Panic Disorder Severity Among Panic Disorder Patients. Front Neurol 2021; 12:755270. [PMID: 34733233 PMCID: PMC8559336 DOI: 10.3389/fneur.2021.755270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 09/06/2021] [Indexed: 11/28/2022] Open
Abstract
Objectives: Methylation of the neuronal nitric oxide synthase (NOS1/nNOS) gene has recently been identified as a promising biomarker of psychiatric disorders. NOS1 plays an essential role in neurite outgrowth and may thus affect the microstructure development of white matter (WM) in the corpus callosum (CC), which is known to be altered in panic disorder (PD). We examined the relationship between NOS1 methylation, WM tracts in the CC, and symptoms based on this finding. Methods: Thirty-two patients with PD and 22 healthy controls (HCs) were recruited after age, gender, and the education level were matched. The cell type used was whole-blood DNA, and DNA methylation of NOS1 was measured at 20 CpG sites in the promoter region. Although 25 patients with PD were assessed with the Panic Disorder Severity Scale (PDSS), diffusion tensor imaging (DTI) scans were only collected from 16 participants with PD. Results: We observed that the PD group showed lower methylation than did the HCs group and positive correlations between the symptom severity of PD and methylation at CpG4 and CpG9. In addition, CpG9 methylation was significantly correlated with the fractional anisotropy (FA) and mean diffusivity (MD) values of the CC and its major components (the genu and the splenium) in the PD group. Furthermore, path analyses showed that CpG9 methylation offers a mediating effect for the association between the MD values of the genu of the CC and PD symptom severity (95% CI = −1.731 to −0.034). Conclusions: The results suggest that CpG9 methylation leads to atypical development of the genu of the CC, resulting in higher PD symptom severity, adding support for the methylation of NOS1 as a future prognostic indicator of PD.
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Affiliation(s)
- Huazhen Xu
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China.,The First Affiliated Hospital With Nanjing Medical University, Nanjing, China
| | - Yuan Zhong
- School of Psychology, Nanjing Normal University, Nanjing, China.,Jiangsu Key Laboratory of Mental Health and Cognitive Science, Nanjing Normal University, Nanjing, China
| | - Shiting Yuan
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Yun Wu
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Zijuan Ma
- School of Psychology, South China Normal University, Guangzhou, China
| | - Ziyu Hao
- School of Psychology, Nanjing Normal University, Nanjing, China
| | - Huachen Ding
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Huiqing Wu
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Gang Liu
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Manlong Pang
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Na Liu
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China.,Cognitive Behavioral Therapy Institute of Nanjing Medical University, Nanjing, China
| | - Chun Wang
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China.,School of Psychology, Nanjing Normal University, Nanjing, China.,Cognitive Behavioral Therapy Institute of Nanjing Medical University, Nanjing, China.,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, China
| | - Ning Zhang
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China.,Cognitive Behavioral Therapy Institute of Nanjing Medical University, Nanjing, China.,Functional Brain Imaging Institute of Nanjing Medical University, Nanjing, China
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35
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Zinni M, Pansiot J, Léger PL, El Kamouh M, Baud O. Sildenafil-Mediated Neuroprotection from Adult to Neonatal Brain Injury: Evidence, Mechanisms, and Future Translation. Cells 2021; 10:cells10102766. [PMID: 34685745 PMCID: PMC8534574 DOI: 10.3390/cells10102766] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/28/2021] [Accepted: 10/07/2021] [Indexed: 12/12/2022] Open
Abstract
Cerebral stroke, traumatic brain injury, and hypoxic ischemic encephalopathy are among the most frequently occurring brain injuries. A complex pathogenesis, characterized by a synergistic interaction between alterations of the cerebrovascular system, cell death, and inflammation, is at the basis of the brain damage that leads to behavioral and neurodevelopmental disabilities in affected subjects. Sildenafil is a selective inhibitor of the enzyme phosphodiesterase 5 (PDE5) that is able to cross the blood-brain barrier. Preclinical data suggest that sildenafil may be a good candidate for the prevention or repair of brain injury in both adults and neonates. The aim of this review is to summarize the evidence supporting the neuroprotective action of sildenafil and discuss the possible benefits of the association of sildenafil with current therapeutic strategies.
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Affiliation(s)
- Manuela Zinni
- Inserm UMR1141 NeuroDiderot, Université de Paris, 75019 Paris, France; (M.Z.); (J.P.); (M.E.K.)
| | - Julien Pansiot
- Inserm UMR1141 NeuroDiderot, Université de Paris, 75019 Paris, France; (M.Z.); (J.P.); (M.E.K.)
| | - Pierre-Louis Léger
- Pediatric and Neonatal Intensive Care Unit, Armand-Trousseau University Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne University, 75019 Paris, France;
| | - Marina El Kamouh
- Inserm UMR1141 NeuroDiderot, Université de Paris, 75019 Paris, France; (M.Z.); (J.P.); (M.E.K.)
- Laboratoire de Physiologie et Génomique des Poissons-INRAE, 35700 Rennes, France
| | - Olivier Baud
- Laboratory of Child Growth and Development, University of Geneva, 1211 Geneva, Switzerland
- Division of Neonatology and Pediatric Intensive Care, Children’s University Hospital of Geneva, 1211 Geneva, Switzerland
- Correspondence: ; Tel.: +41-795-534-204
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36
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Influence of Nitric Oxide-Cyclic GMP and Oxidative STRESS on Amyloid-β Peptide Induced Decrease of Na,K-ATPase Activity in Rat Hippocampal Slices. J Membr Biol 2021; 254:463-473. [PMID: 34327545 DOI: 10.1007/s00232-021-00196-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 07/19/2021] [Indexed: 12/11/2022]
Abstract
Amyloid-β peptide (Aβ) has been shown to cause synaptic dysfunction and can render neurons vulnerable to excitotoxicity and oxidative stress. Na,K-ATPase plays an important role to maintain cell ionic equilibrium and it can be modulated by N-methyl-D-aspartate (NMDA)-nitric oxide (NO)-cyclic GMP pathway. Disruption of NO synthase (NOS) activity and reactive oxygen species (ROS) production could lead to changes in Na,K-ATPase isoforms' activities that may be detrimental to the cells. Our aim was to evaluate the signaling pathways of Aβ in relation to NMDA-NOS-cyclic GMP versus oxidative stress on α1-/α2,3-Na,K-ATPase activities in rat hippocampal slices. Aβ1-40 induced a concentration-dependent increase of NOS activity and increased cyclic guanosine monophosphate (cGMP), TBARS (thiobarbituric acid reactive substances), and 3-Nitrotyrosine (3-NT)-modified protein levels in rat hippocampal slices. The increase in NOS activity and cyclic GMP levels induced by Aβ1-40 was completely blocked by MK-801 (inhibitor of NMDA receptor) and L-NAME (inhibitor of NOS) pre-treatment but changes in TBARS levels were only partially blocked by both compounds. The Aβ treatment also decreased Na,K-ATPase activity which was reverted by N-nitro-L-arginine methyl ester hydrochloride (L-NAME) but not by MK-801 pre-treatment. The decrease in enzyme activity induced by Aβ was isoform-specific since only α1-Na,K-ATPase was affected. These findings suggest that the activation of NMDA-NOS signaling cascade linked to α2,3-Na,K-ATPase activity may mediate an adaptive, neuroprotective response to Aβ in rat hippocampus.
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37
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Suresh V, Reddy A. Dysregulation of nitric oxide synthases during early and late pathophysiological conditions of diabetes mellitus leads to amassing of microvascular impedement. J Diabetes Metab Disord 2021; 20:989-1002. [PMID: 34178871 PMCID: PMC8212285 DOI: 10.1007/s40200-021-00799-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 04/11/2021] [Indexed: 12/20/2022]
Abstract
Diabetes is a major killer worldwide and its unprecedented rise poses a serious threat to mankind. According to recent estimation, 387 million people worldwide are affected from the disease with a prevalence rate of 8.3 and 46.3 % still remains undiagnosed. Important characteristics of diabetes are abnormalities of the physiological signalling functions of reactive oxygen species and reactive nitrogen species. Increased oxidative stress contributes to the activation of stress-sensitive intracellular signalling pathways and the development of gene products that trigger cellular damage and contribute to the vascular complications of diabetes. Growing evidence from studies into many diseases suggests that the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart failure are correlated with oxidative stress. This leads to cell metabolism and cell-cell homeostasis to be complexly dysregulated. This review focuses to investigate the status of oxidative stress, nitric oxide and reactive species in early and diabetes. Significance of nitric oxide synthases Evidences has accumulated indicating that the generation of reactive oxygen species (oxidative stress) may play an important role in the etiology of diabetic complications thus attention was given on the reactive oxygen and reactive nitrogen species and their potential role in pathogenesis. Additionally, the therapeutic advances in diabetes management are included. Nanotechnology, statins and stem cell technology are some techniques which can be considered to have a possible future in the treatment sector of diabetes.
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Affiliation(s)
- Varuna Suresh
- Animal Cell Culture Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kancheepuram District-603203, Kattankulathur, Tamil Nadu India
| | - Amala Reddy
- Animal Cell Culture Laboratory, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kancheepuram District-603203, Kattankulathur, Tamil Nadu India
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38
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Galloway JD, Sarabia C, Fettinger JC, Hratchian HP, Baxter RD. Versatile New Reagent for Nitrosation under Mild Conditions. Org Lett 2021; 23:3253-3258. [PMID: 33844555 DOI: 10.1021/acs.orglett.1c00637] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Here we report a new chemical reagent for transnitrosation under mild experimental conditions. This new reagent is stable to air and moisture across a broad range of temperatures and is effective for transnitrosation in multiple solvents. Compared with traditional nitrosation methods, our reagent shows high functional group tolerance for substrates that are susceptible to oxidation or reversible transnitrosation. Several challenging nitroso compounds are accessed here for the first time, including 15N isotopologues. X-ray data confirm that two rotational isomers of the reagent are configurationally stable at room temperature, although only one isomer is effective for transnitrosation. Computational analysis describes the energetics of rotamer interconversion, including interesting geometry-dependent hybridization effects.
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Affiliation(s)
- Jordan D Galloway
- Department of Chemistry and Chemical Biology, University of California, Merced, Merced, California 95343, United States
| | - Cristian Sarabia
- Department of Chemistry and Chemical Biology, University of California, Merced, Merced, California 95343, United States
| | - James C Fettinger
- Department of Chemistry, University of California, Davis, Davis, California 95616, United States
| | - Hrant P Hratchian
- Department of Chemistry and Chemical Biology, University of California, Merced, Merced, California 95343, United States
| | - Ryan D Baxter
- Department of Chemistry and Chemical Biology, University of California, Merced, Merced, California 95343, United States
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39
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Shi Y, Michael MA, Zhang Y. HNO to NO Conversion Mechanism with Copper Zinc Superoxide Dismutase, Comparison with Heme Protein Mediated Conversions, and the Origin of Questionable Reversibility. Chemistry 2021; 27:5019-5027. [PMID: 33398888 DOI: 10.1002/chem.202100015] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Indexed: 11/08/2022]
Abstract
The interconversion of NO and HNO, via copper zinc superoxide dismutase (CuZnSOD), is important in biomedicine and for HNO detection. Many mechanistic questions, including the decades-long debate on reversibility, were resolved in this work. Calculations of various active-site and full-protein models show that the basic mechanism is proton-coupled electron transfer with a computed barrier of 10.98 kcal mol-1 , which is in excellent agreement with experimental results (10.62 kcal mol-1 ), and this nonheme protein-mediated reaction has many significant mechanistic differences compared with the conversions mediated by heme proteins due to geometric and electronic factors. The reasons for the irreversible nature of this conversion and models with the first thermodynamically favorable and kinetically feasible mechanism for the experimental reverse reaction were discovered. Such results are the first for nonheme enzyme mediated HNO to NO conversions, which shall facilitate other related studies and HNO probe development.
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Affiliation(s)
- Yelu Shi
- Department of Chemistry and Chemical Biology, Stevens Institute, of Technology, 1 Castle Point on Hudson, Hoboken, NJ, 07030, USA.,College of Science and Technology, Wenzhou-Kean University, 88 Daxue Rd, Wenzhou, Zhejiang, 325060, P.R. China
| | - Matthew A Michael
- Department of Chemistry and Chemical Biology, Stevens Institute, of Technology, 1 Castle Point on Hudson, Hoboken, NJ, 07030, USA
| | - Yong Zhang
- Department of Chemistry and Chemical Biology, Stevens Institute, of Technology, 1 Castle Point on Hudson, Hoboken, NJ, 07030, USA
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40
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Bae HW, Choi W, Hwang AR, Lee SY, Seong GJ, Kim CY. Effects of Hypoxic Preconditioning and Vascular Endothelial Growth Factor on the Survival of Isolated Primary Retinal Ganglion Cells. Biomolecules 2021; 11:biom11030391. [PMID: 33800918 PMCID: PMC8002095 DOI: 10.3390/biom11030391] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/01/2021] [Accepted: 03/04/2021] [Indexed: 11/16/2022] Open
Abstract
This study aimed to investigate the effect of hypoxic preconditioning (HPC) on primary retinal ganglion cell (RGC) survival and the associated mechanism, including the role of vascular endothelial growth factor (VEGF). Retinas were separated from the enucleated eyeballs of Sprague-Dawley rats on postnatal days 1-4. RGCs were harvested using an immunopanning-magnetic separation system and maintained for 24 h in a defined medium. Hypoxic damage (0.3% O2) was inflicted on the cells using a CO₂ chamber. Anti-VEGF antibody (bevacizumab) was administered to RGCs exposed to hypoxic conditions, and RGC survival rate was compared to that of non-anti-VEGF antibody-treated RGCs. HPC lasting 4 h significantly increased RGC survival rate. In the RGCs exposed to hypoxic conditions for 4 h, VEGF mRNA and protein levels were significantly increased. Treatment with high dose bevacizumab (>1 mg/mL) countered HPC-mediated RGC survival. Protein kinase B and focal adhesion kinase levels were significantly increased in 4-h hypoxia-treated RGCs. HPC showed beneficial effects on primary RGC survival. However, only specifically controlled exposure to hypoxic conditions rendered neuroprotective effects. Strong inhibition of VEGF inhibited HPC-mediated RGC survival. These results indicate that VEGF may play an essential role in promoting cell survival under hypoxic conditions.
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Affiliation(s)
| | | | | | | | | | - Chan Yun Kim
- Correspondence: ; Tel.: +82-2-2228-3570; Fax: +82-2-312-0541
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41
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Ledo A, Lourenço CF, Cadenas E, Barbosa RM, Laranjinha J. The bioactivity of neuronal-derived nitric oxide in aging and neurodegeneration: Switching signaling to degeneration. Free Radic Biol Med 2021; 162:500-513. [PMID: 33186742 DOI: 10.1016/j.freeradbiomed.2020.11.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/02/2020] [Accepted: 11/05/2020] [Indexed: 12/22/2022]
Abstract
The small and diffusible free radical nitric oxide (•NO) has fascinated biological and medical scientists since it was promoted from atmospheric air pollutant to biological ubiquitous signaling molecule. Its unique physical chemical properties expand beyond its radical nature to include fast diffusion in aqueous and lipid environments and selective reactivity in a biological setting determined by bioavailability and reaction rate constants with biomolecules. In the brain, •NO is recognized as a key player in numerous physiological processes ranging from neurotransmission/neuromodulation to neurovascular coupling and immune response. Furthermore, changes in its bioactivity are central to the molecular pathways associated with brain aging and neurodegeneration. The understanding of •NO bioactivity in the brain, however, requires the knowledge of its concentration dynamics with high spatial and temporal resolution upon stimulation of its synthesis. Here we revise our current understanding of the role of neuronal-derived •NO in brain physiology, aging and degeneration, focused on changes in the extracellular concentration dynamics of this free radical and the regulation of bioenergetic metabolism and neurovascular coupling.
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Affiliation(s)
- A Ledo
- Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504, Coimbra, Portugal; University of Coimbra, Faculty of Pharmacy, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
| | - C F Lourenço
- Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504, Coimbra, Portugal; University of Coimbra, Faculty of Pharmacy, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal
| | - E Cadenas
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, 90089, CA, USA
| | - R M Barbosa
- Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504, Coimbra, Portugal; University of Coimbra, Faculty of Pharmacy, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal
| | - J Laranjinha
- Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 3004-504, Coimbra, Portugal; University of Coimbra, Faculty of Pharmacy, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal
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Nitrate and nitrite exposure leads to mild anxiogenic-like behavior and alters brain metabolomic profile in zebrafish. PLoS One 2020; 15:e0240070. [PMID: 33382700 PMCID: PMC7774831 DOI: 10.1371/journal.pone.0240070] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Accepted: 12/11/2020] [Indexed: 02/06/2023] Open
Abstract
Dietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. We tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish (Danio rerio) model. We utilized targeted and untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to examine the extent to which treatment resulted in changes in nitrate or nitrite concentrations in the brain and altered the brain metabolome. Fish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2–4 weeks and free swim, startle response, and shuttle box assays were performed. Nitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment was associated with mild anxiogenic-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted metabolomics analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. Untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment. Overall, the depletion in brain metabolites is plausibly associated with the regulation of neuronal activity including statistically significant reductions in the inhibitory neurotransmitter γ-aminobutyric acid (GABA; 18–19%), and its precursor, glutamine (17–22%). Nitrate treatment caused significant depletion in the brain concentration of fatty acids including linoleic acid (LA) by 50% and arachidonic acid (ARA) by 80%; nitrite treatment caused depletion of LA by ~90% and ARA by 60%, change which could alter the function of dopaminergic neurons and affect behavior. Nitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health. It is plausible that indirect NO-mediated mechanisms may be responsible for the nitrate and nitrite-mediated effects on the brain metabolome and behavior in zebrafish.
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de Sousa GG, Barbosa MA, Barbosa CM, Lima TC, Souza Dos Santos RA, Campagnole-Santos MJ, Alzamora AC. Different reactive species modulate the hypotensive effect triggered by angiotensins at CVLM of 2K1C hypertensive rats. Peptides 2020; 134:170409. [PMID: 32950566 DOI: 10.1016/j.peptides.2020.170409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 08/20/2020] [Accepted: 09/15/2020] [Indexed: 11/18/2022]
Abstract
Hypertension is associated with increased central activity of the renin-angiotensin system (RAS) and oxidative stress. Here, we evaluated whether reactive species and neurotransmitters could contribute to the hypotensive effect induced by angiotensin (Ang) II and Ang-(1-7) at the caudal ventrolateral medulla (CVLM) in renovascular hypertensive rats (2K1C). Therefore, we investigated the effect of Ang II, Ang-(1-7), and the Ang-(1-7) antagonist A-779 microinjected before and after CVLM microinjection of the nitric oxide (NO)-synthase inhibitor, (L-NAME), vitamin C (Vit C), bicuculline, or kynurenic acid in 2K1C and SHAM rats. Baseline values of the mean arterial pressure (MAP) in 2K1C rats were higher than in SHAM rats. CVLM microinjection of Ang II, Ang-(1-7), l-NAME, or bicuculline induced decreases in the MAP in SHAM and 2K1C rats. In addition, Vit C and A-779 produced decreases in the MAP only in 2K1C rats. Kynurenic acid increased the MAP in both SHAM and 2K1C rats. Only the Ang-(1-7) effect was increased by l-NAME and reduced by bicuculline in SHAM rats. L-NAME also reduced the A-779 effect in 2K1C rats. Only the Ang II effect was abolished by CVLM Vit C and enhanced by CVLM kynurenic acid in SHAM and 2K1C rats. Overall, the superoxide anion and glutamate participated in the hypotensive effect of Ang II, while NO and GABA participated in the hypotensive effect of Ang-(1-7) in CVLM. The higher hypotensive response of A-779 in the CVLM of 2K1C rats suggests that Ang-(1-7) contributes to renovascular hypertension.
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Affiliation(s)
- Graziele Galdino de Sousa
- Núcleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil
| | - Maria Andréa Barbosa
- Núcleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil
| | - Claudiane Maria Barbosa
- Núcleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil
| | - Taynara Carolina Lima
- Núcleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil
| | - Robson Augusto Souza Dos Santos
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Maria José Campagnole-Santos
- Departamento de Fisiologia e Biofísica, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil
| | - Andréia Carvalho Alzamora
- Departamento de Ciências Biológicas, Instituto de Ciências Exatas e Biológicas, Brazil; Núcleo de Pesquisa em Ciências Biológicas, Universidade Federal de Ouro Preto, Ouro Preto, MG, Brazil.
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Ferreira-Junior NC, Crestani CC, Lagatta DC, Resstel LBM, Correa FMA, Alves FHF. Nitric oxide in the insular cortex modulates baroreflex responses in a cGMP-independent pathway. Brain Res 2020; 1747:147037. [PMID: 32738232 DOI: 10.1016/j.brainres.2020.147037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/01/2020] [Accepted: 07/27/2020] [Indexed: 10/23/2022]
Abstract
Insular cortex is a brain structure involved in the modulation of autonomic activity and cardiovascular function. The nitric oxide/cyclic guanosine-3',5'-monophosphate pathway is a prominent signaling mechanism in the central nervous system, controlling behavioral and physiological responses. Nevertheless, despite evidence regarding the presence of nitric oxide-synthesizing neurons in the insular cortex, its role in the control of autonomic and cardiovascular function has never been reported. Thus, the present study aimed to investigate the involvement of nitric oxide/cyclic guanosine-3',5'-monophosphate pathway mediated by neuronal nitric oxide synthase (nNOS) activation within the insular cortex in the modulation of baroreflex responses in unanesthetized rats. For this, we evaluated the effect of bilateral microinjection of either the nitric oxide scavenger carboxy-PTIO, the selective neuronal nitric oxide synthase inhibitor Nω-Propyl-l-arginine or the soluble guanylate cyclase inhibitor ODQ into the insular cortex on the bradycardia evoked by blood pressure increases in response to intravenous infusion of phenylephrine, and the tachycardia caused by blood pressure decreases evoked by intravenous infusion of sodium nitroprusside. Bilateral microinjection of either NPLA or carboxy-PTIO into the insular cortex increased the reflex bradycardic response, whereas the reflex tachycardia was decreased by these treatments. Bilateral microinjection of the soluble guanylate cyclase inhibitor into the insular cortex did not affect any parameter of baroreflex function evaluated. Overall, our findings provide evidence that insular cortex nitrergic signaling, acting via neuronal nitric oxide synthase, plays a prominent role in control of baroreflex function. However, control of reflex responses seems to be independent of soluble guanylate cyclase activation.
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Affiliation(s)
- Nilson C Ferreira-Junior
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Carlos C Crestani
- Laboratory of Pharmacology, School of Pharmaceutical Sciences, São Paulo State University (UNESP), Araraquara, SP, Brazil
| | - Davi C Lagatta
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Leonardo B M Resstel
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Fernando M A Correa
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Fernando H F Alves
- Department of Health Sciences, Faculty of Medicine - Federal University of Lavras, Lavras, MG, Brazil.
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Ghotbeddin Z, Basir Z, Jamshidian J, Delfi F. Modulation of behavioral responses and CA1 neuronal death by nitric oxide in the neonatal rat's hypoxia model. Brain Behav 2020; 10:e01841. [PMID: 32940009 PMCID: PMC7667332 DOI: 10.1002/brb3.1841] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 08/22/2020] [Accepted: 08/29/2020] [Indexed: 01/13/2023] Open
Abstract
INTRODUCTION Neonatal hypoxia leads to cognitive and movement impairments that might persist throughout life. Hypoxia impairs hippocampal blood circulation and metabolism. The exact mechanisms underlying hypoxia-induced memory impairment are not fully understood. Nitric oxide (NO) is a key neuromodulator that regulates cerebral blood flow. In this study, we aimed to evaluate the possible role of NO on behavioral and histomorphometric changes in the hippocampus following hypoxia in neonate rats. MATERIAL AND METHODS Neonate male rats (n = 28) were randomly divided into 4 groups: control, hypoxia, hypoxia plus L-NAME (20 mg/kg), and hypoxia plus L-arginine (200 mg/kg). Drugs were injected intraperitoneally for seven consecutive days. Hypoxia was induced by keeping rats in a hypoxic chamber (7% oxygen and 93% nitrogen intensity). Ten to 14 days after hypoxia, behavioral changes were measured using a shuttle box, a rotarod, and an open field test. The histological changes in the hippocampus were measured using H&E and Nissl staining methods. RESULTS Findings showed that hypoxia caused significant atrophy in the hippocampus. Furthermore, the administration of L-NAME decreased the atrophy of the hippocampus in comparison with the hypoxic group. Behavioral results showed that hypoxia impaired memory performance and motor activity responses. Additionally, the administration of L-NAME improved behavioral performance in a significant manner compared with the hypoxic group. CONCLUSIONS Hypoxia damaged the neurons of hippocampal CA1 region and induced memory impairment. The NOS inhibitor, L-NAME, significantly attenuated the negative effects of hypoxia on behavior and observed changes in the hippocampus.
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Affiliation(s)
- Zohreh Ghotbeddin
- Department of PhysiologyFaculty of Veterinary MedicineShahid Chamran University of AhvazAhvazIran
- Stem Cell and Transgenic Technology Research CenterShahid Chamran University of AhvazAhvazIran
| | - Zahra Basir
- Department of HistologyFaculty of Veterinary MedicineShahid Chamran University of AhvazAhvazIran
| | - Javad Jamshidian
- Department of PharmacologyFaculty of Veterinary MedicineShahid Chamran University of AhvazAhvazIran
| | - Farideh Delfi
- Department of PhysiologyFaculty of Veterinary MedicineShahid Chamran University of AhvazAhvazIran
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Kimura H. Hydrogen sulfide signalling in the CNS - Comparison with NO. Br J Pharmacol 2020; 177:5031-5045. [PMID: 32860641 DOI: 10.1111/bph.15246] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/19/2020] [Accepted: 08/24/2020] [Indexed: 12/13/2022] Open
Abstract
Hydrogen sulfide (H2 S) together with polysulfides (H2 Sn , n > 2) are signalling molecules like NO with various physiological roles including regulation of neuronal transmission, vascular tone, inflammation and oxygen sensing. H2 S and H2 Sn diffuse to the target proteins for S-sulfurating their cysteine residues that induces the conformational changes to alter the activity. On the other hand, 3-mercaptopyruvate sulfurtransferase transfers sulfur from a substrate 3-mercaptopyruvate to the cysteine residues of acceptor proteins. A similar mechanism has also been identified in S-nitrosylation. S-sulfuration and S-nitrosylation by enzymes proceed only inside the cell, while reactions induced by H2 S, H2 Sn and NO even extend to the surrounding cells. Disturbance of signalling by these molecules as well as S-sulfuration and S-nitrosylation causes many nervous system diseases. This review focuses on the signalling by H2 S and H2 Sn with S-sulfuration comparing to that of NO with S-nitrosylation and discusses on their roles in physiology and pathophysiology.
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Affiliation(s)
- Hideo Kimura
- Department of Pharmacology, Faculty of Pharmaceutical Sciences, Sanyo-Onoda City University, Sanyo-Onoda, Japan
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Ammar A, Trabelsi K, Boukhris O, Bouaziz B, Müller P, Glenn JM, Chamari K, Müller N, Chtourou H, Driss T, Hökelmann A. Moderators of the Impact of (Poly)Phenols Interventions on Psychomotor Functions and BDNF: Insights from Subgroup Analysis and Meta-Regression. Nutrients 2020; 12:nu12092872. [PMID: 32961777 PMCID: PMC7551086 DOI: 10.3390/nu12092872] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 09/11/2020] [Accepted: 09/17/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Recent anti-aging interventions have shown contradictory impacts of (poly)phenols regarding the prevention of cognitive decline and maintenance of brain function. These discrepancies have been linked to between-study differences in supplementation protocols. This subgroup analysis and meta-regression aimed to (i) examine differential effects of moderator variables related to participant characteristics and supplementation protocols and (ii) identify practical recommendations to design effective (poly)phenol supplementation protocols for future anti-aging interventions. METHODS Multiple electronic databases (Web of Science; PubMed) searched for relevant intervention published from inception to July 2019. Using the PICOS criteria, a total of 4303 records were screened. Only high-quality studies (n = 15) were included in the final analyses. Random-effects meta-analysis was used, and we calculated standard differences in means (SDM), effect size (ES), and 95% confidence intervals (CI) for two sufficiently comparable items (i.e., psychomotor function and brain-derived neurotrophic factor (BDNF)). When significant heterogeneity was computed (I2 > 50%), a subgroup and meta-regression analysis were performed to examine the moderation effects of participant characteristics and supplementation protocols. RESULTS The reviewed studies support the beneficial effect of (poly)phenols-rich supplementation on psychomotor functions (ES = -0.677, p = 0.001) and brain plasticity (ES = 1.168, p = 0.028). Subgroup analysis revealed higher beneficial impacts of (poly)phenols (i) in younger populations compared to older (SDM = -0.89 vs. -0.47 for psychomotor performance, and 2.41 vs. 0.07 for BDNF, respectively), (ii) following an acute compared to chronic supplementation (SDM = -1.02 vs. -0.43 for psychomotor performance), and (iii) using a phenolic compound with medium compared to low bioavailability rates (SDM = -0.76 vs. -0.68 for psychomotor performance and 3.57 vs. 0.07 for DBNF, respectively). Meta-regressions revealed greater improvement in BDNF levels with lower percentages of female participants (Q = 40.15, df = 6, p < 0.001) and a skewed scatter plot toward a greater impact using higher (poly)phenols doses. CONCLUSION This review suggests that age group, gender, the used phenolic compounds, their human bioavailability rate, and the supplementation dose as the primary moderator variables relating to the beneficial effects of (poly)phenol consumption on cognitive and brain function in humans. Therefore, it seems more advantageous to start anti-aging (poly)phenol interventions in adults earlier in life using medium (≈500 mg) to high doses (≈1000 mg) of phenolic compounds, with at least medium bioavailability rate (≥9%).
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Affiliation(s)
- Achraf Ammar
- Institute of Sport Sciences, Otto-von-Guericke University, 39104 Magdeburg, Germany;
- Correspondence: ; Tel.: +49-391-67-57395
| | - Khaled Trabelsi
- High Institute of Sport and Physical Education, University of Sfax, Sfax 3000, Tunisia; (K.T.); (O.B.); (H.C.)
- Research Laboratory: Education, Motricité, Sport et Santé, EM2S, LR19JS01, High Institute of Sport and Physical Education of Sfax, University of Sfax, Sfax 3000, Tunisia
| | - Omar Boukhris
- High Institute of Sport and Physical Education, University of Sfax, Sfax 3000, Tunisia; (K.T.); (O.B.); (H.C.)
- Activité Physique, Sport et Santé, UR18JS01, Observatoire National du Sport, Tunis 1003, Tunisia
| | - Bassem Bouaziz
- Higher Institute of Computer Science and Multimedia of Sfax, University of Sfax, Sfax 3000, Tunisia;
| | - Patrick Müller
- German Center for Neurodegenerative Diseases (DZNE), 39104 Magdeburg, Germany; (P.M.); (N.M.)
- Department of Neurology, Medical Faculty, Otto von Guericke University, 39104 Magdeburg, Germany
| | - Jordan M. Glenn
- Department of Health, Exercise Science Research Center, Human Performance and Recreation, University of Arkansas, Fayetteville, AR 72701, USA;
- Neurotrack Technologies, 399 Bradford St, Redwood City, CA 94063, USA
| | - Karim Chamari
- ASPETAR, Qatar Orthopaedic and Sports Medicine Hospital, Doha PoBox 29222, Qatar;
- Laboratory “Sport Performance Optimization”, (CNMSS), ISSEP Ksar-Said, Manouba University, Manouba 1004, Tunisia
| | - Notger Müller
- German Center for Neurodegenerative Diseases (DZNE), 39104 Magdeburg, Germany; (P.M.); (N.M.)
| | - Hamdi Chtourou
- High Institute of Sport and Physical Education, University of Sfax, Sfax 3000, Tunisia; (K.T.); (O.B.); (H.C.)
- Activité Physique, Sport et Santé, UR18JS01, Observatoire National du Sport, Tunis 1003, Tunisia
| | - Tarak Driss
- Interdisciplinary Laboratory in Neurosciences, Physiology and Psychology: Physical Activity, Health and Learning (LINP2-2APS), UFR STAPS, UPL, Paris Nanterre University, 92000 Nanterre, France;
| | - Anita Hökelmann
- Institute of Sport Sciences, Otto-von-Guericke University, 39104 Magdeburg, Germany;
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Bhat A, Ray B, Mahalakshmi AM, Tuladhar S, Nandakumar DN, Srinivasan M, Essa MM, Chidambaram SB, Guillemin GJ, Sakharkar MK. Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders. Pharmacol Res 2020; 160:105078. [PMID: 32673703 DOI: 10.1016/j.phrs.2020.105078] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 07/09/2020] [Accepted: 07/10/2020] [Indexed: 02/08/2023]
Abstract
Phosphodiesterases (PDE) are a diverse family of enzymes (11 isoforms so far identified) responsible for the degradation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which are involved in several cellular and biochemical functions. Phosphodiesterase 4 (PDE4) is the major isoform within this group and is highly expressed in the mammalian brain. An inverse association between PDE4 and cAMP levels is the key mechanism in various pathophysiological conditions like airway inflammatory diseases-chronic obstruction pulmonary disease (COPD), asthma, psoriasis, rheumatoid arthritis, and neurological disorders etc. In 2011, roflumilast, a PDE4 inhibitor (PDE4I) was approved for the treatment of COPD. Subsequently, other PDE4 inhibitors (PDE4Is) like apremilast and crisaborole were approved by the Food and Drug Administration (FDA) for psoriasis, atopic dermatitis etc. Due to the adverse effects like unbearable nausea and vomiting, dose intolerance and diarrhoea, PDE4 inhibitors have very less clinical compliance. Efforts are being made to develop allosteric modulation with high specificity to PDE4 isoforms having better efficacy and lesser adverse effects. Interestingly, repositioning PDE4Is towards neurological disorders including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS) and sleep disorders, is gaining attention. This review is an attempt to summarize the data on the effects of PDE4 overexpression in neurological disorders and the use of PDE4Is and newer allosteric modulators as therapeutic options. We have also compiled a list of on-going clinical trials on PDE4 inhibitors in neurological disorders.
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Affiliation(s)
- Abid Bhat
- Dept. of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, India
| | - Bipul Ray
- Dept. of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, India
| | | | - Sunanda Tuladhar
- Dept. of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, India
| | - D N Nandakumar
- Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, 560029, India
| | - Malathi Srinivasan
- Department of Lipid Science, CSIR - Central Food Technological Research Institute (CFTRI), CFTRI Campus, Mysuru, 570020, India
| | - Musthafa Mohamed Essa
- Ageing and Dementia Research Group, Sultan Qaboos University, Muscat, Oman; Department of Food Science and Nutrition, CAMS, Sultan Qaboos University, Muscat, Oman.
| | - Saravana Babu Chidambaram
- Dept. of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru, India; Centre for Experimental Pharmacology and Toxicology, Central Animal Facility, JSS Academy of Higher Education & Research, Mysuru, India.
| | - Gilles J Guillemin
- Neuroinflammation group, Faculty of Medicine and Health Sciences, Macquarie University, NSW, 2109, Australia.
| | - Meena Kishore Sakharkar
- College of Pharmacy and Nutrition, University of Saskatchewan, 107, Wiggins Road, Saskatoon, SK, S7N 5C9, Canada
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Effects of Polyphenol-Rich Interventions on Cognition and Brain Health in Healthy Young and Middle-Aged Adults: Systematic Review and Meta-Analysis. J Clin Med 2020; 9:jcm9051598. [PMID: 32466148 PMCID: PMC7290428 DOI: 10.3390/jcm9051598] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 05/13/2020] [Accepted: 05/22/2020] [Indexed: 02/08/2023] Open
Abstract
Context: Affecting older and even some younger adults, neurodegenerative disease represents a global public health concern and has been identified as a research priority. To date, most anti-aging interventions have examined older adults, but little is known about the effects of polyphenol interventions on brain-related aging processes in healthy young and middle-aged adults. Objective: This systematic review and meta-analysis aimed to evaluate the acute and chronic effects of (poly)phenol-rich diet supplementation on cognitive function and brain health in young and middle-aged adults. In July 2019, two electronic databases (PubMed and Web of Science) were used to search for relevant trials examining the effect of acute or chronic (poly)phenol-rich supplementation on cognitive function and neuroprotective measures in young and middle-aged adults (<60 years old). A total of 4303 records were screened by two researchers using the PICOS criteria. Fifteen high quality (mean PEDro score = 8.8 ± 0.58) trials with 401 total participants were included in the final analyses. Information on treatment, study design, characteristics of participants, outcomes and used tools were extracted following PRISMA guidelines. When items were shown to be sufficiently comparable, a random-effects meta-analysis was used to pool estimates across studies. Effect size (ES) and its 95% confidence interval (CI) was calculated. The meta-analysis indicated that (poly)phenol supplementation significantly increased brain-derived neurotrophic factor (ES = 3.259, p = 0.033), which was accompanied by higher performance in serial (7s) subtraction (ES = 1.467, p = 0.001) and decreases in simple reaction time (ES = −0.926, p = 0.015) and mental fatigue (ES = −3.521, p = 0.010). Data related to cognitive function were skewed towards an effect from acute compared to chronic polyphenol intervention; data related to BDNF were skewed toward an effect from higher bioavailability phenolic components. Conclusion: This meta-analysis provides promising findings regarding the usefulness of polyphenol-rich intervention as an inexpensive approach for enhancing circulation of pro-cognitive neurotrophic factors. These beneficial effects appear to depend on the supplementation protocols. An early acute and/or chronic application of low- to high-dose phenolic components with high bioavailability rates (≥30%) at a younger age appear to provide more promising effects.
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Ploetz E, Zimpel A, Cauda V, Bauer D, Lamb DC, Haisch C, Zahler S, Vollmar AM, Wuttke S, Engelke H. Metal-Organic Framework Nanoparticles Induce Pyroptosis in Cells Controlled by the Extracellular pH. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2020; 32:e1907267. [PMID: 32182391 DOI: 10.1002/adfm.201909062] [Citation(s) in RCA: 139] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Revised: 03/01/2020] [Accepted: 03/02/2020] [Indexed: 05/23/2023]
Abstract
Ion homeostasis is essential for cellular survival, and elevated concentrations of specific ions are used to start distinct forms of programmed cell death. However, investigating the influence of certain ions on cells in a controlled way has been hampered due to the tight regulation of ion import by cells. Here, it is shown that lipid-coated iron-based metal-organic framework nanoparticles are able to deliver and release high amounts of iron ions into cells. While high concentrations of iron often trigger ferroptosis, here, the released iron induces pyroptosis, a form of cell death involving the immune system. The iron release occurs only in slightly acidic extracellular environments restricting cell death to cells in acidic microenvironments and allowing for external control. The release mechanism is based on endocytosis facilitated by the lipid-coating followed by degradation of the nanoparticle in the lysosome via cysteine-mediated reduction, which is enhanced in slightly acidic extracellular environment. Thus, a new functionality of hybrid nanoparticles is demonstrated, which uses their nanoarchitecture to facilitate controlled ion delivery into cells. Based on the selectivity for acidic microenvironments, the described nanoparticles may also be used for immunotherapy: the nanoparticles may directly affect the primary tumor and the induced pyroptosis activates the immune system.
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Affiliation(s)
- Evelyn Ploetz
- Department of Chemistry and Center for NanoScience (CeNS), LMU Munich, Munich, 81377, Germany
- Nanosystems Initiative Munich (NIM), LMU Munich, Munich, 81377, Germany
- Center for Integrated Protein Science Munich (CiPSM), LMU Munich, Munich, 81377, Germany
| | - Andreas Zimpel
- Department of Chemistry and Center for NanoScience (CeNS), LMU Munich, Munich, 81377, Germany
| | - Valentina Cauda
- Department of Applied Science and Technology, Politecnico di Torino, Torino, 10129, Italy
| | - David Bauer
- Department of Chemistry, TU Munich, Munich, 81377, Germany
| | - Don C Lamb
- Department of Chemistry and Center for NanoScience (CeNS), LMU Munich, Munich, 81377, Germany
- Nanosystems Initiative Munich (NIM), LMU Munich, Munich, 81377, Germany
- Center for Integrated Protein Science Munich (CiPSM), LMU Munich, Munich, 81377, Germany
| | | | - Stefan Zahler
- Department of Pharmacy, LMU Munich, Munich, 81377, Germany
| | | | - Stefan Wuttke
- BCMaterials, Basque Center for Materials, UPV/EHU Science Park, Leioa, 48940, Spain
- Ikerbasque, Basque Foundation for Science, Bilbao, 48013, Spain
| | - Hanna Engelke
- Department of Chemistry and Center for NanoScience (CeNS), LMU Munich, Munich, 81377, Germany
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