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Javaid S, Alqahtani F, Parveen A, Ashraf W, Rehman Z, Anjum SMM, Ahmad T, Imran I. Polypharmacy with tiagabine, levetiracetam, and perampanel in status epilepticus: Insights from EEG, biochemical, and histopathological studies in rats. Epilepsia Open 2025; 10:669-681. [PMID: 40198515 PMCID: PMC12163519 DOI: 10.1002/epi4.13141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 01/10/2025] [Accepted: 01/16/2025] [Indexed: 04/10/2025] Open
Abstract
OBJECTIVE Status epilepticus (SE) is a condition of neurological emergency, which precipitates various functional and morphological changes in the brain. Due to the risk of drug resistance associated with SE, this study aimed to evaluate a multitargeted approach to treat SE by combining clinically used antiseizure drugs. METHODS In this study, we intraperitoneally administered tiagabine (TGB), levetiracetam (LEV), and perampanel (PER) alone and in combination as a duo and trio therapy after 30 min of SE in electrode-implanted male Sprague-Dawley rats subjected to lithium-pilocarpine-induced convulsive SE. The rats were monitored for SE-associated behavioral and electroencephalographic (EEG) changes. Moreover, at the end of the experiment, rats were sacrificed and brains were excised for biochemical and histopathological evaluation. RESULTS The control rats showed behavioral progression to the seizure of Stages 4-5 with 30-40 min of pilocarpine administration along with the appearance of uninterrupted fully blown epileptic spikes on EEG noted up to 2 h. The rats treated with TGB, LEV, and PER alone failed to provide behavioral and ictal attenuation. However, when combinations were tested, there was an improvement in seizure presentation while TGB + PER and LEV + PER also reversed SE-associated electrographic changes. However, the most prominent seizure attenuation was noted in rats receiving trio therapy with TGB, LEV, and PER. Moreover, the trio-treated rats demonstrated marked protection from SE-induced oxidative stress and morphological alterations in different regions of the brains. SIGNIFICANCE We observed that intraperitoneal administration of TGB, LEV, and PER alone did not significantly alter the ictal activity recorded by EEG but pharmacological manipulation of acutely coadministered drugs caused a reduction of electrographic, biochemical, and histopathological eruptions providing preclinical evidence of a novel multitargeted combination treatment to ameliorate the acute SE. PLAIN LANGUAGE SUMMARY This study investigates and compares the efficacy of mono- and polytherapy approach to counter the behavioral, electrographic, and histopathlogical manifestations of status epilepticus. The tiagabine as monotherapy was administered after 30 min of uninterrupted SE, and the outcomes were compared with levetiracetam and perampanel alone as well as their duo and trio combinations. We noted that combining the low doses of tiagabine, levetiracetam, and perampanel notably interrupted the seizure progression through distinct mechanism in rat model of status epilepticus. Thus, we conclude that this novel combination may be a promising multitargeted approach for management of status epilepticus.
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Affiliation(s)
- Sana Javaid
- Department of Pharmacology, Faculty of PharmacyBahauddin Zakariya UniversityMultanPakistan
- Department of PharmacyThe Women UniversityMultanPakistan
| | - Faleh Alqahtani
- Department of Pharmacology and ToxicologyCollege of Pharmacy, King Saud UniversityRiyadhSaudi Arabia
| | - Abida Parveen
- Department of Pharmacology, Faculty of PharmacyBahauddin Zakariya UniversityMultanPakistan
| | - Waseem Ashraf
- Department of Pharmacology, Faculty of PharmacyBahauddin Zakariya UniversityMultanPakistan
| | - Zohabia Rehman
- Department of Pharmacology, Faculty of PharmacyBahauddin Zakariya UniversityMultanPakistan
| | | | - Tanveer Ahmad
- Institut Pour l'Avancée des Biosciences, Centre de Recherche UGA/INSERM U1209/CNRS 5309Université Grenoble AlpesGrenobleFrance
| | - Imran Imran
- Department of Pharmacology, Faculty of PharmacyBahauddin Zakariya UniversityMultanPakistan
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Anthwal T, Pant S, Rana P, Nain S. Design, synthesis, and in vitro, in vivo, and in silico evaluation of novel substituted 1,3,4-thiadiazole derivatives as anticonvulsant agents. Front Chem 2025; 12:1515866. [PMID: 40012830 PMCID: PMC11861159 DOI: 10.3389/fchem.2024.1515866] [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: 10/23/2024] [Accepted: 12/31/2024] [Indexed: 02/28/2025] Open
Abstract
In the present study, a library of ten novel substituted 1,3,4-thiadiazole derivatives were designed and synthesized using an appropriate synthetic route. The characterization of the synthesized compounds was performed by FT-IR and NMR (1H and 13C) spectroscopy. The synthesized compounds were assayed for in vitro human carbonic anhydrase (CA) inhibition against two isoforms II and IX. The neurotoxicity of the synthesized derivatives was also evaluated using the rotarod test, along with their in vivo anticonvulsant activity, which was determined using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (sc-PTZ) methods. Although all the compounds showed good CA inhibition and anticonvulsant activity, two compounds 6d and 7d showed the highest CA inhibition and anticonvulsant activity in both the isoforms and tested methods compared to the standard drugs (sodium valproate and acetazolamide), without any sign of neurotoxicity observed at the highest dose (300 mg/kg). Similarly, the standard drugs also displayed no neurotoxicity at the highest dose (300 mg/kg). Furthermore, the potent compounds (6d and 7d) were evaluated for the biochemical parameters, such as lipid peroxidation, nitrite oxide, reduced glutathione, superoxide dismutase, and total antioxidant capacity, and the GABA level was also determined. Finally, compound 6d was docked against CA-II and CA-IX (PDB-ID-5SZ5 and 5AML) receptors. The study concluded that the compounds 6d and 7d can be considered potent anticonvulsant agents for future research.
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Affiliation(s)
- Tulika Anthwal
- Department of Pharmacy, Banasthali Vidyapith, Banasthali, Rajasthan, India
| | - Swati Pant
- Department of Pharmacy, Banasthali Vidyapith, Banasthali, Rajasthan, India
| | - Preeti Rana
- National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India
| | - Sumitra Nain
- Department of Pharmacy, Banasthali Vidyapith, Banasthali, Rajasthan, India
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Mambou HMAY, Pale S, Bopda OSM, Jugha VT, Musa NSO, Ojongnkpot TA, Wanyu BY, Bila RB, Herqash RN, Shahat AA, Taiwe GS. Mimosa pudica L. aqueous extract protects mice against pilocarpine-picrotoxin kindling-induced temporal lobe epilepsy, oxidative stress, and alteration in GABAergic/cholinergic pathways and BDNF expression. Front Pharmacol 2025; 15:1301002. [PMID: 39996118 PMCID: PMC11848678 DOI: 10.3389/fphar.2024.1301002] [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: 09/23/2023] [Accepted: 12/19/2024] [Indexed: 02/26/2025] Open
Abstract
Ethnopharmacological studies revealed that the leaves and stems of Mimosa pudica L. (Fabaceae) are widely used for the treatment of epilepsy. This study sought to investigate the effects of the aqueous extract of Mimosa pudica leaves and stems against pilocarpine-picrotoxin kindling-induced temporal lobe epilepsy in mice and its implication on oxidative/nitrosative stress, GABAergic/cholinergic signalling, and brain-derived neurotrophic factor (BDNF) expression. The animals were treated for seven consecutive days as follows: one normal group and one negative control group that received orally distilled water; four test groups that received orally four doses of Mimosa pudica (20, 40, 80, and 160 mg/kg), respectively; and one positive control group that received 300 mg/kg sodium valproate intraperitoneally. One hour after the first treatment (first day), status epilepticus was induced by intraperitoneal injection of a single dose of pilocarpine (360 mg/kg). Then, 23 hours after the injection of pilocarpine to the mice, once again, they received their different treatments. Sixty minutes later, they were injected with a sub-convulsive dose of picrotoxin (1 mg/kg), and the anticonvulsant property of the extract was determined. On day 7, open-field, rotarod, and catalepsy tests were performed. Finally, the mice were sacrificed, and the hippocampi were isolated to quantify some biochemical markers of oxidative/nitrosative stress, GABAergic/cholinergic signalling, and BDNF levels in the hippocampus. Mimosa pudica extracts (160 mg/kg) significantly increased the latency time to status epilepticus by 70.91%. It significantly decreased the number of clonic and tonic seizures to 9.33 ± 1.03 and 5.00 ± 0.89, and their duration to 11.50 ± 2.07 and 6.83 ± 0.75 s, respectively. Exploratory behaviour, motor coordination, and catalepsy were significantly ameliorated, respectively, in the open-field, rotarod, and catalepsy tests. Pilocarpine-picrotoxin-induced alteration of oxidant-antioxidant balance, GABA-transaminase stability, acetylcholinesterase/butyrylcholinesterase activity, and neurogenesis were attenuated by the extract (80-160 mg/kg). This study showed that the aqueous extract of Mimosa pudica leaves and stems ameliorated epileptogenesis of temporal lobe epilepsy and could be used for the treatment of temporal lobe epilepsy.
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Affiliation(s)
| | - Simon Pale
- Department of Animal Biology and Conservation, Faculty of Science, University of Buea, Buea, Cameroon
| | | | - Vanessa Tita Jugha
- Department of Animal Biology and Conservation, Faculty of Science, University of Buea, Buea, Cameroon
| | - Nji Seraphin Ombel Musa
- Department of Animal Biology and Conservation, Faculty of Science, University of Buea, Buea, Cameroon
| | - Tambong Ako Ojongnkpot
- Department of Animal Biology and Conservation, Faculty of Science, University of Buea, Buea, Cameroon
| | - Bertrand Yuwong Wanyu
- Department of Animal Biology and Conservation, Faculty of Science, University of Buea, Buea, Cameroon
| | - Raymond Bess Bila
- Department of Animal Biology and Conservation, Faculty of Science, University of Buea, Buea, Cameroon
| | - Rashed N. Herqash
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Abdelaaty A. Shahat
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Germain Sotoing Taiwe
- Department of Animal Biology and Conservation, Faculty of Science, University of Buea, Buea, Cameroon
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Khatoon S, Kalam N. Mechanistic insight of curcumin: a potential pharmacological candidate for epilepsy. Front Pharmacol 2025; 15:1531288. [PMID: 39845785 PMCID: PMC11752882 DOI: 10.3389/fphar.2024.1531288] [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: 11/20/2024] [Accepted: 12/16/2024] [Indexed: 01/24/2025] Open
Abstract
Recurrent spontaneous seizures with an extended epileptic discharge are the hallmarks of epilepsy. At present, there are several available anti-epileptic drugs (AEDs) in the market. Still no adequate treatment for epilepsy treatment is available. The main disadvantages of AEDs are their associated adverse effects. It is a challenge to develop new therapies that can reduce seizures by modulating the underlying mechanisms with no adverse effects. In the last decade, the neuromodulatory potential of phytoconstituents has sparked their usage in the treatment of central nervous system disorders. Curcumin is an active polyphenolic component that interacts at cellular and molecular levels. Curcumin's neuroprotective properties have been discovered in recent preclinical and clinical studies due to its immunomodulatory effects. Curcumin has the propensity to modulate signaling pathways involved in cell survival and manage oxidative stress, apoptosis, and inflammatory mechanisms. Further, curcumin can persuade epigenetic alterations, including histone modifications (acetylation/deacetylation), which are the changes responsible for the altered expression of genes facilitating the process of epileptogenesis. The bioavailability of curcumin in the brain is a concern that needs to be tackled. Therefore, nanonization has emerged as a novel drug delivery system to enhance the pharmacokinetics of curcumin. In the present review, we reviewed curcumin's modulatory effects on potential biomarkers involved in epileptogenesis including dendritic cells, T cell subsets, cytokines, chemokines, apoptosis mediators, antioxidant mechanisms, and cognition impairment. Also, we have discussed the nanocarrier systems for encapsulating curcumin, offering a promising approach to enhance bioavailability of curcumin.
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Affiliation(s)
- Saima Khatoon
- Department of Obstetrics, Gynecology and Reproductive Sciences, School of Medicine, University of Maryland, Baltimore, MD, United States
| | - Nida Kalam
- Infection and Immunity Research Strength, Jeffrey Cheah School of Medicine and Health Sciences, Monash University, Bandar Sunway, Malaysia
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Antar A, Abdel-Rehiem ES, Al-Khalaf AA, Abuelsaad ASA, Abdel-Gabbar M, Shehab GMG, Abdel-Aziz AM. Therapeutic Efficacy of Lavandula dentata's Oil and Ethanol Extract in Regulation of the Neuroinflammation, Histopathological Alterations, Oxidative Stress, and Restoring Balance Treg Cells Expressing FoxP3+ in a Rat Model of Epilepsy. Pharmaceuticals (Basel) 2024; 18:35. [PMID: 39861097 PMCID: PMC11768170 DOI: 10.3390/ph18010035] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2024] [Revised: 12/26/2024] [Accepted: 12/27/2024] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Despite the availability of antiepileptic drugs (AEDs) that can manage seizures, they often come with cognitive side effects. Furthermore, the role of oxidative stress and neuroinflammatory responses in epilepsy and the limitations of current AEDs necessitate exploring alternative therapeutic options. Medicinal plants, e.g., Lavandula dentata L., are rich in phenolic compounds and may provide neuroprotective and anti-inflammatory benefits. However, limited research evaluates their effectiveness in modulating neuroinflammation and histopathological changes in epilepsy models. Therefore, the current study hypothesized that treating Lavandula dentata L. extract or essential oils may reduce neuroinflammatory responses and mitigate histopathological changes in the brain, providing a natural alternative or adjunct therapy for epilepsy management. Methods: Five groups of male Wistar rats were used: control, pilocarpine-treated epileptic, valproic acid (VPA-treated epileptic), L. dentata extract, and essential oils. Numerous electrolyte levels, monoamine levels, neurotransmitter levels, and the mRNA expression of specific gate channel subtypes were evaluated in homogenate brain tissue. Additionally, histological changes in various brain regions were investigated. Results: The investigation revealed that the extract and essential oils obtained from L. dentata L. exhibited the ability to improve the modulation of electrolytes and ions across voltage- and ligand-gated ion channels. Furthermore, it was revealed that they could decrease neuronal excitability by facilitating repolarization. Moreover, L. dentata's oil and ethanol extract re-balances T-reg/Th-17 cytokines, restoring the pro/anti-inflammatory cytokines and Treg markers, e.g., FOXP3 and CTLA-4, to their normal level. Conclusions: The present work confirms that the extract and essential oils of L. dentata L. have different activities to ameliorate the progression of histopathological alterations. Therefore, when used in conjunction with other AEDs, the extract and essential oils of L. dentata can slow the progression of epileptogenesis.
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Affiliation(s)
- Aziza Antar
- Biochemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt; (A.A.); (M.A.-G.)
| | - Eman S. Abdel-Rehiem
- Molecular Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt;
| | - Areej A. Al-Khalaf
- Biology Department, College of Science, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia;
| | - Abdelaziz S. A. Abuelsaad
- Immunology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt
| | - Mohamed Abdel-Gabbar
- Biochemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62521, Egypt; (A.A.); (M.A.-G.)
| | - Gaber M. G. Shehab
- Department of Biochemistry, College of Medicine, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;
| | - Ayman M. Abdel-Aziz
- Zoology Department, Faculty of Science, Fayoum University, Fayoum 63514, Egypt;
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Antmen FM, Fedaioglu Z, Acar D, Sayar AK, Yavuz IE, Ada E, Karakose B, Rzayeva L, Demircan S, Kardouh F, Senay S, Kolgazi M, Suyen G, Oz-Arslan D. Exploring Liraglutide in Lithium-Pilocarpine-Induced Temporal Lobe Epilepsy Model in Rats: Impact on Inflammation, Mitochondrial Function, and Behavior. Biomedicines 2024; 12:2205. [PMID: 39457518 PMCID: PMC11505538 DOI: 10.3390/biomedicines12102205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 09/12/2024] [Accepted: 09/19/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: Glucagon-like peptide-1 receptor agonists such as liraglutide are known for their neuroprotective effects in neurodegenerative disorders, but their role in temporal lobe epilepsy (TLE) remains unclear. We aimed to investigate the effects of liraglutide on several biological processes, including inflammation, antioxidant defense mechanisms, mitochondrial dynamics, and function, as well as cognitive and behavioral changes in the TLE model. Methods: Low-dose, repeated intraperitoneal injections of lithium chloride-pilocarpine hydrochloride were used to induce status epilepticus (SE) in order to develop TLE in rats. Fifty-six male Sprague Dawley rats were subjected and allocated to the groups. The effects of liraglutide on inflammatory markers (NLRP3, Caspase-1, and IL-1β), antioxidant pathways (Nrf-2 and p-Nrf-2), and mitochondrial dynamics proteins (Pink1, Mfn2, and Drp1) were evaluated in hippocampal tissues via a Western blot. Mitochondrial function in peripheral blood mononuclear cells (PBMCs) was examined using flow cytometry. Cognitive-behavioral outcomes were assessed using the open-field, elevated plus maze, and Morris water maze tests. Results: Our results showed that liraglutide modulates NLRP3-mediated inflammation, reduces oxidative stress, and triggers antioxidative pathways through Nrf2 in SE-induced rats. Moreover, liraglutide treatment restored Pink1, Mfn2, and Drp1 levels in SE-induced rats. Liraglutide treatment also altered the mitochondrial function of PBMCs in both healthy and epileptic rats. This suggests that treatment can modulate mitochondrial dynamics and functions in the brain and periphery. Furthermore, in the behavioral aspect, liraglutide reversed the movement-enhancing effect of epilepsy. Conclusions: This research underscores the potential of GLP-1RAs as a possibly promising therapeutic strategy for TLE.
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Affiliation(s)
- Fatma Merve Antmen
- Department of Physiology, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye; (F.M.A.)
- Biobank Unit, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
| | - Zeynep Fedaioglu
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
| | - Dilan Acar
- Department of Physiology, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye; (F.M.A.)
| | - Ahmed Kerem Sayar
- School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
| | - Ilayda Esma Yavuz
- School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
| | - Ece Ada
- School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
| | - Bengisu Karakose
- School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
| | - Lale Rzayeva
- School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
| | - Sevcan Demircan
- School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
| | - Farah Kardouh
- School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
| | - Simge Senay
- Department of Medical Biotechnology, Graduate School of Health Sciences, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
| | - Meltem Kolgazi
- Department of Physiology, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
| | - Guldal Suyen
- Department of Physiology, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
| | - Devrim Oz-Arslan
- Department of Biophysics, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Türkiye
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Duailibe JBB, Viau CM, Saffi J, Fernandes SA, Porawski M. Protective effect of long-chain polyunsaturated fatty acids on hepatorenal syndrome in rats. World J Nephrol 2024; 13:95627. [PMID: 39351184 PMCID: PMC11439093 DOI: 10.5527/wjn.v13.i3.95627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Revised: 06/07/2024] [Accepted: 07/25/2024] [Indexed: 09/19/2024] Open
Abstract
BACKGROUND Hepatorenal syndrome (HRS) is the most prevalent form of acute kidney injury in cirrhotic patients. It is characterized by reduced renal blood flow and represents the most severe complication in cirrhotic patients with advanced disease. Previous research has indicated that antioxidants can delay the onset of a hyperdynamic circulatory state in cirrhosis and improve renal function in HRS patients. Regular omega-3 supplementation has significantly reduced the risk of liver disease. This supplementation could represent an additional therapy for individuals with HRS. AIM To evaluated the antioxidant effect of omega-3 polyunsaturated fatty acid supplementation on the kidneys of cirrhotic rats. METHODS Secondary biliary cirrhosis was induced in rats by biliary duct ligation (BDL) for 28 d. We used 24 male Wistar rats divided into the following groups: I (control); II (treated with omega-3, 1 g/kg of body weight); III (BDL treated with omega-3, 1 g/kg of body weight); and IV (BDL without treatment). The animals were killed by overdose of anesthetic; the kidneys were dissected, removed, frozen in liquid nitrogen, and stored in a freezer at -80℃ for later analysis. We evaluated oxidative stress, nitric oxide (NO) metabolites, DNA damage by the comet assay, cell viability test, and apoptosis in the kidneys. Data were analyzed by one-way analysis of variance, and means were compared using the Tukey test, with P ≤ 0.05. RESULTS Omega-3 significantly decreased the production of reactive oxygen species (P < 0.001) and lipoperoxidation in the kidneys of cirrhotic rats treated with omega-3 (P < 0.001). The activity of the antioxidant enzymes superoxide dismutase and catalase increased in the BDL+omega-3 group compared to the BDL group (P < 0.01). NO production, DNA damage, and caspase-9 cleavage decreased significantly in the omega-3-treated BDL group. There was an increase in mitochondrial electrochemical potential (P < 0.001) in BDL treated with omega-3 compared to BDL. No changes in the cell survival index in HRS with omega-3 compared to the control group (P > 0.05) were observed. CONCLUSION The study demonstrates that omega-3 can protect cellular integrity and function by increasing antioxidant enzymes, inhibiting the formation of free radicals, and reducing apoptosis.
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Affiliation(s)
- João Bruno Beretta Duailibe
- Department of Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Cassiana Macagnan Viau
- Department of Basic Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Jenifer Saffi
- Department of Basic Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Sabrina Alves Fernandes
- Department of Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
| | - Marilene Porawski
- Department of Hepatology and Basic Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil
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Ignacio-Mejía I, Contreras-García IJ, Pichardo-Macías LA, García-Cruz ME, Ramírez Mendiola BA, Bandala C, Medina-Campos ON, Pedraza-Chaverri J, Cárdenas-Rodríguez N, Mendoza-Torreblanca JG. Effect of Levetiracetam on Oxidant-Antioxidant Activity during Long-Term Temporal Lobe Epilepsy in Rats. Int J Mol Sci 2024; 25:9313. [PMID: 39273262 PMCID: PMC11395009 DOI: 10.3390/ijms25179313] [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: 07/25/2024] [Revised: 08/20/2024] [Accepted: 08/26/2024] [Indexed: 09/15/2024] Open
Abstract
Epilepsy is a disorder characterized by a predisposition to generate seizures. Levetiracetam (LEV) is an antiseizure drug that has demonstrated oxidant-antioxidant effects during the early stages of epilepsy in several animal models. However, the effect of LEV on oxidant-antioxidant activity during long-term epilepsy has not been studied. Therefore, the objective of the present study was to determine the effects of LEV on the concentrations of five antioxidant enzymes and on the levels of four oxidant stress markers in the hippocampus of rats with temporal lobe epilepsy at 5.7 months after status epilepticus (SE). The results revealed that superoxide dismutase (SOD) activity was significantly greater in the epileptic group (EPI) than in the control (CTRL), CTRL + LEV and EPI + LEV groups. No significant differences were found among the groups' oxidant markers. However, the ratios of SOD/hydrogen peroxide (H2O2), SOD/glutathione peroxidase (GPx) and SOD/GPx + catalase (CAT) were greater in the EPI group than in the CTRL and EPI + LEV groups. Additionally, there was a positive correlation between SOD activity and GPx activity in the EPI + LEV group. LEV-mediated modulation of the antioxidant system appears to be time dependent; at 5.7 months after SE, the role of LEV may be as a stabilizer of the redox state.
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Affiliation(s)
- Iván Ignacio-Mejía
- Laboratorio de Medicina Traslacional, Escuela Militar de Graduados de Sanidad, UDEFA, Mexico City 11200, Mexico
| | - Itzel Jatziri Contreras-García
- Laboratorio de Medicina Traslacional, Escuela Militar de Graduados de Sanidad, UDEFA, Mexico City 11200, Mexico
- Laboratorio de Biología de la Reproducción, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico
| | - Luz Adriana Pichardo-Macías
- Departamento de Fisiología, Instituto Politécnico Nacional, Escuela Nacional de Ciencias Biológicas, Mexico City 07738, Mexico
| | - Mercedes Edna García-Cruz
- Laboratorio de Neurociencias, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico
| | | | - Cindy Bandala
- Laboratorio de Neurociencia Traslacional Enfermedades Crónicas y Emergentes, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City 11410, Mexico
| | - Omar Noel Medina-Campos
- Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - José Pedraza-Chaverri
- Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Noemí Cárdenas-Rodríguez
- Laboratorio de Neurociencias, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico
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de Melo Bastos Cavalcante C, Bruno Oliveira K, Maria Araújo de Souza F, Maria Jatobá Hasten Reiter M, Rodrigues Melo da Silva B, Lavínia da Silva Oliveira K, Vinicius Dos Santos Sales M, Larissa Dias Pacheco A, Santos Siqueira E, de Araújo Costa M, Gomes Dos Santos Neto J, Gabriely Duarte Torres R, Catarina R Leite A, Santana de Melo I, Salgueiro Machado S, Duzzioni M, Leite Góes Gitaí D, Wagner de Castro O. Crack cocaine inhalation increases seizure susceptibility by reducing acetylcholinesterase activity. Epilepsy Behav 2024; 156:109832. [PMID: 38761450 DOI: 10.1016/j.yebeh.2024.109832] [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: 11/27/2023] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 05/20/2024]
Abstract
Crack cocaine is a highly addictive and potent stimulant drug. Animal studies have shown that the cholinergic system plays a role in neurotoxicity induced by cocaine or its active metabolites inhalation. Behavioral alterations associated with crack cocaine use include hyperactivity, depressed mood, and decreased seizure threshold. Here we evaluate the acetylcholinesterase (AChE) and reactive oxygen species (ROS) activity, behavioral profile, and the threshold for epileptic seizures in rats that received intrahippocampal pilocarpine (H-PILO) followed by exposure to crack cocaine (H-PILO + CRACK). Animals exposed to H-PILO + CRACK demonstrated increased severity and frequency of limbic seizures. The AChE activity was reduced in the groups exposed to crack cocaine alone (CRACK) and H-PILO + CRACK, whereas levels of ROS remained unchanged. In addition, crack cocaine exposure increased vertical locomotor activity, without changing water and sucrose intake. Short-term memory consolidation remained unchanged after H-PILO, H-PILO + CRACK, and CRACK administration. Overall, our data suggest that crack cocaine inhalation reduced the threshold for epileptic seizures in rats submitted to low doses of pilocarpine through the inhibition of AChE. Taken together, our findings can be useful in the development of effective strategies for preventing and treating the harmful effects of cocaine and crack cocaine on the central nervous system.
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Affiliation(s)
| | - Kellysson Bruno Oliveira
- Department of Physiology, Institute of Biological Science and Health of Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Fernanda Maria Araújo de Souza
- Department of Physiology, Institute of Biological Science and Health of Federal University of Alagoas, Maceió, Alagoas, Brazil
| | | | - Bianca Rodrigues Melo da Silva
- Department of Physiology, Institute of Biological Science and Health of Federal University of Alagoas, Maceió, Alagoas, Brazil
| | | | | | - Amanda Larissa Dias Pacheco
- Department of Physiology, Institute of Biological Science and Health of Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Edite Santos Siqueira
- Department of Physiology, Institute of Biological Science and Health of Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Maisa de Araújo Costa
- Department of Physiology, Institute of Biological Science and Health of Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - José Gomes Dos Santos Neto
- Department of Physiology, Institute of Biological Science and Health of Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Rayssa Gabriely Duarte Torres
- Department of Physiology, Institute of Biological Science and Health of Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Ana Catarina R Leite
- Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Igor Santana de Melo
- Department of Physiology, Institute of Biological Science and Health of Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Sônia Salgueiro Machado
- Institute of Chemistry and Biotechnology, Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Marcelo Duzzioni
- Department of Physiology, Institute of Biological Science and Health of Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Daniel Leite Góes Gitaí
- Department of Physiology, Institute of Biological Science and Health of Federal University of Alagoas, Maceió, Alagoas, Brazil
| | - Olagide Wagner de Castro
- Department of Physiology, Institute of Biological Science and Health of Federal University of Alagoas, Maceió, Alagoas, Brazil.
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Armstrong OJ, Neal ES, Vidovic D, Xu W, Borges K. Transient anticonvulsant effects of time-restricted feeding in the 6-Hz mouse model. Epilepsy Behav 2024; 151:109618. [PMID: 38184948 DOI: 10.1016/j.yebeh.2023.109618] [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: 11/09/2023] [Revised: 12/23/2023] [Accepted: 12/27/2023] [Indexed: 01/09/2024]
Abstract
INTRODUCTION Intermittent fasting enhances neural bioenergetics, is neuroprotective, and elicits antioxidant effects in various animal models. There are conflicting findings on seizure protection, where intermittent fasting regimens often cause severe weight loss resembling starvation which is unsustainable long-term. Therefore, we tested whether a less intensive intermittent fasting regimen such as time-restricted feeding (TRF) may confer seizure protection. METHODS Male CD1 mice were assigned to either ad libitum-fed control, continuous 8 h TRF, or 8 h TRF with weekend ad libitum food access (2:5 TRF) for one month. Body weight, food intake, and blood glucose levels were measured. Seizure thresholds were determined at various time points using 6-Hz and maximal electroshock seizure threshold (MEST) tests. Protein levels and mRNA expression of genes, enzyme activity related to glucose metabolism, as well as mitochondrial dynamics were assessed in the cortex and hippocampus. Markers of antioxidant defence were evaluated in the plasma, cortex, and liver. RESULTS Body weight gain was similar in the ad libitum-fed and TRF mouse groups. In both TRF regimens, blood glucose levels did not change between the fed and fasted state and were higher during fasting than in the ad libitum-fed groups. Mice in the TRF group had increased seizure thresholds in the 6-Hz test on day 15 and on day 19 in a second cohort of 2:5 TRF mice, but similar seizure thresholds at other time points compared to ad libitum-fed mice. Continuous TRF did not alter MEST seizure thresholds on day 28. Mice in the TRF group showed increased maximal activity of pyruvate dehydrogenase in the cortex, which was accompanied by increased protein levels of mitochondrial pyruvate carrier 1 in the cortex and hippocampus. There were no other major changes in protein or mRNA levels associated with energy metabolism and mitochondrial dynamics in the brain, nor markers of antioxidant defence in the brain, liver, or plasma. CONCLUSIONS Both continuous and 2:5 TRF regimens transiently increased seizure thresholds in the 6-Hz model at around 2 weeks, which coincided with stability of blood glucose levels during the fed and fasted periods. Our findings suggest that the lack of prolonged anticonvulsant effects in the acute electrical seizure models employed may be attributed to only modest metabolic and antioxidant adaptations found in the brain and liver. Our findings underscore the potential therapeutic value of TRF in managing seizure-related conditions.
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Affiliation(s)
- Oliver J Armstrong
- School of Biomedical Sciences, Skerman Building 65, The University of Queensland, St. Lucia, QLD 4072, Australia
| | - Elliott S Neal
- School of Biomedical Sciences, Skerman Building 65, The University of Queensland, St. Lucia, QLD 4072, Australia
| | - Diana Vidovic
- School of Biomedical Sciences, Medical Building 181, The University of Melbourne, Parkville, VIC 3010, Australia
| | - Weizhi Xu
- School of Biomedical Sciences, Skerman Building 65, The University of Queensland, St. Lucia, QLD 4072, Australia
| | - Karin Borges
- School of Biomedical Sciences, Skerman Building 65, The University of Queensland, St. Lucia, QLD 4072, Australia.
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Akash MSH, Akbar M, Rehman K, Shah MA, Panichayupakaranant P, Imran M, Assiri MA. Biochemical profiling of berberine-enriched extract in aluminum chloride induced oxidative damage and neuroinflammation. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:85263-85275. [PMID: 37380861 DOI: 10.1007/s11356-023-28392-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 06/19/2023] [Indexed: 06/30/2023]
Abstract
Despite the numerous treatment strategies used for Alzheimer's disease (AD), only a few cholinesterase inhibitor drugs, such as memantine, are effective in symptomatically relieving the hallmarks of AD, providing momentary recovery of memory and cognitive decline. These available drugs do not treat the underlying causes of AD, and their chronic use is associated with serious adverse effects and disease progression. Berberine is an isoquinoline alkaloid that has been reported to possess therapeutic potential against AD. Therefore, its activity was evaluated against an aluminum chloride (AlCl3)-induced AD rat model, and a berberine-enriched extract (BEE) was used to determine if its activity is equivalent to pure berberine (PB). The rats were administered 300 mg/kg of oral AlCl3 to induce AD and were then treated with oral PB at a dosage of 50 mg/kg, BEE at a dosage of 50 mg/kg, and rivastigmine at a dosage of 1 mg/kg as a standard drug for 21 days. In this study, various parameters were assessed to evaluate cognitive functions, such as behavioral analysis, antioxidant enzyme levels, acetylcholinesterase (AChE) activity, proinflammatory cytokine levels, real-time polymerase chain reaction (RT-PCR) analysis of different biomarkers (AChE, IL-1α, IL-1β, BACE-1, TNF-α) linked to AD, and histopathological changes in the rats' brains. After 21 days, the disease control group showed a significant decline in cognitive function, decreased levels of antioxidant enzymes, upregulated activity of the AChE enzyme, increased levels of proinflammatory cytokines, and marked elevation in mRNA expression of AD-associated biomarkers. On the other hand, the treatment groups showed significant improvements in memory deficits, elevated levels of antioxidant enzymes, reduced levels of proinflammatory cytokines, decreased AChE activity, and significant downregulation of the expression of predefined biomarkers. Histological examination of the treatment groups showed less neuroinflammation and fewer amyloid plaques compared to the disease control group. In conclusion, both PB and BEE have comparable neuroprotective potential to mitigate the pathological hallmarks of AD. However, controlled clinical trials are needed to assess their efficacy and safety.
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Affiliation(s)
| | - Moazzama Akbar
- Department of Pharmacy, The University of Faisalabad, Faisalabad, Pakistan
| | - Kanwal Rehman
- Department of Pharmacy, The Women University, Multan, Pakistan.
| | | | - Pharkphoom Panichayupakaranant
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Thailand
| | - Muhammad Imran
- Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, 62413, Saudi Arabia
- Department of Chemistry, Faculty of Science, King Khalid University, Abha, 62413, Saudi Arabia
| | - Mohammed A Assiri
- Research Center for Advanced Materials Science (RCAMS), King Khalid University, Abha, 62413, Saudi Arabia
- Department of Chemistry, Faculty of Science, King Khalid University, Abha, 62413, Saudi Arabia
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kamruzzaman S, Bulbul L, Alam MZ, Rahman MM. GABA content and an antioxidant profile positively correlated with the anticonvulsive activity of Microcos paniculata in acute seizure mice. Heliyon 2023; 9:e18295. [PMID: 37539232 PMCID: PMC10395524 DOI: 10.1016/j.heliyon.2023.e18295] [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: 02/22/2023] [Revised: 07/06/2023] [Accepted: 07/13/2023] [Indexed: 08/05/2023] Open
Abstract
This study evaluated the effects of different parts of M. paniculata (MP) extracts on convulsions and antioxidant activities in mice. Six polyphenolic compounds were identified, where epicatechin and quercetin have been identified in the highest amounts (23.01 and 32.23 mg/100 g of dry MP extract, respectively) in MP leaf and stem extracts, using Ultra Performance Liquid Chromatography. 7-day oral administration of MP at doses of 100, 200, and 400 mg/kg body weight (BW) significantly reduced convulsions and reduced mortality rates compared with seizure inducer groups. Antioxidant potentials were measured by superoxide dismutase (SOD), catalase (CAT), thiobarbituric acid reactive substances (TBARS), and reduced glutathione (GSH) content in whole-brain homogenates. Gamma-aminobutyric acid (GABA) levels significantly increased in leaves and stem-treated groups, suggesting that MP leaves and stems have potent antioxidant properties that can attenuate convulsions by modulating the GABAergic system and antioxidant activities.
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Affiliation(s)
- S.M. kamruzzaman
- Department of Horticulture, Sher-e-Bangla Agricultural University, Dhaka, Bangladesh
| | - Latifa Bulbul
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Md Zahir Alam
- Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh
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Łukawski K, Czuczwar SJ. Oxidative Stress and Neurodegeneration in Animal Models of Seizures and Epilepsy. Antioxidants (Basel) 2023; 12:antiox12051049. [PMID: 37237916 DOI: 10.3390/antiox12051049] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/25/2023] [Accepted: 05/02/2023] [Indexed: 05/28/2023] Open
Abstract
Free radicals are generated in the brain, as well as in other organs, and their production is proportional to the brain activity. Due to its low antioxidant capacity, the brain is particularly sensitive to free radical damage, which may affect lipids, nucleic acids, and proteins. The available evidence clearly points to a role for oxidative stress in neuronal death and pathophysiology of epileptogenesis and epilepsy. The present review is devoted to the generation of free radicals in some animal models of seizures and epilepsy and the consequences of oxidative stress, such as DNA or mitochondrial damage leading to neurodegeneration. Additionally, antioxidant properties of antiepileptic (antiseizure) drugs and a possible use of antioxidant drugs or compounds in patients with epilepsy are reviewed. In numerous seizure models, the brain concentration of free radicals was significantly elevated. Some antiepileptic drugs may inhibit these effects; for example, valproate reduced the increase in brain malondialdehyde (a marker of lipid peroxidation) concentration induced by electroconvulsions. In the pentylenetetrazol model, valproate prevented the reduced glutathione concentration and an increase in brain lipid peroxidation products. The scarce clinical data indicate that some antioxidants (melatonin, selenium, vitamin E) may be recommended as adjuvants for patients with drug-resistant epilepsy.
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Affiliation(s)
- Krzysztof Łukawski
- Department of Physiopathology, Institute of Rural Health, Jaczewskiego 2, 20-090 Lublin, Poland
| | - Stanisław J Czuczwar
- Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland
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Vizuete AFK, Leal MB, Moreira AP, Seady M, Taday J, Gonçalves CA. Arundic acid (ONO-2506) downregulates neuroinflammation and astrocyte dysfunction after status epilepticus in young rats induced by Li-pilocarpine. Prog Neuropsychopharmacol Biol Psychiatry 2023; 123:110704. [PMID: 36565981 DOI: 10.1016/j.pnpbp.2022.110704] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 08/08/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Astrocytes, the most abundant glial cells, have several metabolic functions, including ionic, neurotransmitter and energetic homeostasis for neuronal activity. Reactive astrocytes and their dysfunction have been associated with several brain disorders, including the epileptogenic process. Glial Fibrillary Acidic Protein (GFAP) and S100 calcium-binding protein B (S100B) are astrocyte biomarkers associated with brain injury. We hypothesize that arundic acid (ONO-2506), which is known as an inhibitor of S100B synthesis and secretion, protects the hippocampal tissue from neuroinflammation and astrocyte dysfunction after status epileptics (SE) induction by Li-pilocarpine in young rats. Herein, we investigated the effects of arundic acid treatment, at time points of 6 or 24 h after the induction of SE by Li-pilocarpine, in young rats. In SE animals, arundic acid was able to prevent the damage induced by Li-pilocarpine in the hippocampus, decreasing neuroinflammatory signaling (reducing IL-1β, COX2, TLR4 and RAGE contents), astrogliosis (decreasing GFAP and S100B) and astrocytic dysfunction (recovering levels of GSH, glutamine synthetase and connexin-43). Furthermore, arundic acid improved glucose metabolism and reduced the glutamate excitotoxicity found in epilepsy. Our data reinforce the role of astrocytes in epileptogenesis development and the neuroprotective role of arundic acid, which modulates astrocyte function and neuroinflammation in SE animals.
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Affiliation(s)
- Adriana Fernanda K Vizuete
- Laboratory of Calcium-Binding Proteins in CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil.
| | - Miriara B Leal
- Laboratory of Calcium-Binding Proteins in CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Ana Paula Moreira
- Laboratory of Calcium-Binding Proteins in CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Marina Seady
- Laboratory of Calcium-Binding Proteins in CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Jéssica Taday
- Laboratory of Calcium-Binding Proteins in CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
| | - Carlos-Alberto Gonçalves
- Laboratory of Calcium-Binding Proteins in CNS, Department of Biochemistry, Institute of Basic Health Sciences, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil; Pos Graduate Program in Biochemistry, Institute of Basic Health Sciences, UFRGS, Porto Alegre, RS, Brazil
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Akyüz E, Saleem QH, Sari Ç, Auzmendi J, Lazarowski A. Enlightening the mechanism of ferroptosis in epileptic heart. Curr Med Chem 2023; 31:CMC-EPUB-129729. [PMID: 36815654 DOI: 10.2174/0929867330666230223103524] [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: 05/31/2022] [Revised: 11/29/2022] [Accepted: 12/13/2022] [Indexed: 02/24/2023]
Abstract
Epilepsy is a chronic neurological degenerative disease with a high incidence, affecting all age groups. Refractory Epilepsy (RE) occurs in approximately 30-40% of cases with a higher risk of sudden unexpected death in epilepsy (SUDEP). Recent studies have shown that spontaneous seizures developed in epilepsy can be related to an increase in oxidative stress and reactive oxygen derivatives (ROS) production. Increasing ROS concentration causes lipid peroxidation, protein oxidation, destruction of nuclear genetic material, enzyme inhibition, and cell death by a mechanism known as "ferroptosis" (Fts). Inactivation of glutathione peroxidase 4 (GPX4) induces Fts, while oxidative stress is linked with increased intracellular free iron (Fe+2) concentration. Fts is also a non-apoptotic programmed cell death mechanism, where a hypoxia-inducible factor 1 alpha (HIF-141) dependent hypoxic stress-like condition appears to occur with accumulation of iron and cytotoxic ROS in affected cells. Assuming convulsive crises as hypoxic stress, repetitive convulsive/hypoxic stress can be an effective inducer of the "epileptic heart" (EH), which is characterized by altered autonomic function and a high risk of malignant or fatal bradycardia. We previously reported that experimental recurrent seizures induce cardiomyocyte Fts associated with SUDEP. Furthermore, several genes related to Fts and hypoxia have recently been identified in acute myocardial infarction. An emerging theme from recent studies indicates that inhibition of GPX4 through modulating expression or activities of the xCT antiporter system (SLC7A11) governs cell sensitivity to oxidative stress from ferroptosis. Furthermore, during hypoxia, an increased expression of stress transcriptional factor ATF3 can promote Fts induced by erastin in a HIF-141-dependent manner. We propose that inhibition of Fts with ROS scavengers, iron chelators, antioxidants, and transaminase inhibitors could provide a therapeutic effect in epilepsy and improve the prognosis of SUDEP risk by protecting the heart from ferroptosis.
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Affiliation(s)
- Enes Akyüz
- University of Health Sciences, Faculty of International Medicine, Department of Biophysics, Istanbul, Turkey
| | - Qamar Hakeem Saleem
- University of Health Sciences, Faculty of International Medicine, Istanbul, Turkey
| | - Çiğdem Sari
- Istanbul University, Faculty of Medicine, Istanbul, Turkey
| | - Jerónimo Auzmendi
- National Council for Scientific and Technical Research (CONICET), Buenos Aires, Argentina
- Institute for Research in Physiopathology and Clinical Biochemistry (INFIBIOC), Clinical Biochemistry Department, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
| | - Alberto Lazarowski
- Institute for Research in Physiopathology and Clinical Biochemistry (INFIBIOC), Clinical Biochemistry Department, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
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Onishi K, Kamida T, Fujiki M, Momii Y, Sugita K. Anticonvulsant and antioxidant effects of lamotrigine on pilocarpine-induced status epilepticus in mice. Neuroreport 2023; 34:61-66. [PMID: 36484279 PMCID: PMC11115457 DOI: 10.1097/wnr.0000000000001859] [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] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 10/24/2022] [Indexed: 12/13/2022]
Abstract
OBJECTIVES The anticonvulsant and antioxidant effects of lamotrigine on status epilepticus (SE) are incompletely understood. We assessed these effects of lamotrigine on pilocarpine (Pilo)-induced SE in mice. METHODS Male C57BL/J6 mice were assigned to three groups: the control group, Pilo (400 mg/kg, s.c.)-induced SE (Pilo group) and lamotrigine (20 mg/kg, i.p.) treated (Pilo/lamotrigine group). The latency to SE of Racine's stage 3 or higher, the mortality rate within 2 h of Pilo administration, and the duration of SE until sacrifice were examined. Nitric oxide (NO), malondialdehyde and glutathione of oxidative stress biomarkers were detected in the hippocampus of the sacrificed animals in the above groups. NO was also detected in the cultured rat hippocampal neurons treated with 4 μM Pilo, Pilo+100 μM lamotrigine (Pilo/lamotrigine) and Pilo/lamotrigine+ N-methyl-D-aspartic acid (NMDA) receptor antagonist (10 μM MK-801, 3 μM ifenprodil) to examine the antioxidant effects of lamotrigine via non-NMDA-related pathways. RESULTS lamotrigine prolonged the latency to SE, the SE duration until sacrifice, and decreased the mortality rate in mice with Pilo-induced SE. Lamotrigine also decreased hippocampal concentrations of NO and malondialdehyde and increased the concentrations of glutathione in the SE model. Furthermore, there were significant differences in NO concentrations between groups of cultured rat hippocampal neurons treated with Pilo and Pilo/lamotrigine, and with Pilo/lamotrigine and Pilo/lamotrigine+MK-801. CONCLUSION Our findings suggest that lamotrigine exerts anticonvulsant and antioxidant effects on SE, but its antioxidant activity may not be fully exerted via NMDA-related pathways.
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Affiliation(s)
- Kouhei Onishi
- Department of Neurosurgery, School of Medicine, Oita University, Hasama-machi, Oita, Japan
| | - Tohru Kamida
- Department of Neurosurgery, School of Medicine, Oita University, Hasama-machi, Oita, Japan
| | - Minoru Fujiki
- Department of Neurosurgery, School of Medicine, Oita University, Hasama-machi, Oita, Japan
| | - Yasutomo Momii
- Department of Neurosurgery, School of Medicine, Oita University, Hasama-machi, Oita, Japan
| | - Kenji Sugita
- Department of Neurosurgery, School of Medicine, Oita University, Hasama-machi, Oita, Japan
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Ramos-Riera KP, Pérez-Severiano F, López-Meraz ML. Oxidative stress: a common imbalance in diabetes and epilepsy. Metab Brain Dis 2023; 38:767-782. [PMID: 36598703 DOI: 10.1007/s11011-022-01154-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 12/23/2022] [Indexed: 01/05/2023]
Abstract
The brain requires a large amount of energy. Its function can be altered when energy demand exceeds supply or during metabolic disturbances such as diabetes mellitus. Diabetes, a chronic disease with a high incidence worldwide, is characterized by high glucose levels (hyperglycemia); however, hypoglycemic states may also occur due to insulin treatment or poor control of the disease. These alterations in glucose levels affect the brain and could cause epileptic seizures and status epilepticus. In addition, it is known that oxidative stress states emerge as diabetes progresses, contributing to the development of diseases secondary to diabetes, including retinopathy, nephropathy, cardiovascular alterations, and alterations in the central nervous system, such as epileptic seizures. Seizures are a complex of transient signs and symptoms resulting from abnormal, simultaneous, and excessive activity of a population of neurons, and they can be both a cause and a consequence of oxidative stress. This review aims to outline studies linking diabetes mellitus and seizures to oxidative stress, a condition that may be relevant to the development of severe seizures in diabetes mellitus patients.
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Affiliation(s)
- Karen Paola Ramos-Riera
- Doctorado de Investigaciones Cerebrales, Instituto de Investigaciones Cerebrales, Universidad Veracruzana, Dr. Luis Castelazo Ayala s/n, Industrial Animas, 91190, Xalapa, Veracruz, México
| | - Francisca Pérez-Severiano
- Laboratorio de Neurofarmacología Molecular y Nanotecnología, Instituto Nacional de Neurología y Neurocirugía, "Manuel Velasco Suarez," Insurgentes Sur 3877, 14269, La Fama, CDMX, México
| | - María Leonor López-Meraz
- Instituto de Investigaciones Cerebrales, Universidad Veracruzana, Dr. Luis Castelazo Ayala s/n, Industrial Animas, 91190, Xalapa, Veracruz, México.
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Glyceryl triacetate feeding in mice increases plasma acetate levels but has no anticonvulsant effects in acute electrical seizure models. Epilepsy Behav 2022; 137:108964. [PMID: 36343532 DOI: 10.1016/j.yebeh.2022.108964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 10/13/2022] [Accepted: 10/17/2022] [Indexed: 11/06/2022]
Abstract
INTRODUCTION Acetate has been shown to have neuroprotective and anti-inflammatory effects. It is oxidized by astrocytes and can thus provide auxiliary energy to the brain in addition to glucose. Therefore, we hypothesized that it may protect against seizures, which is investigated here by feeding glyceryl triacetate (GTA), to provide high amounts of acetate without raising sodium or acid levels. METHOD CD1 male mice were fed controlled diets with or without GTA for up to three weeks. Body weights, blood glucose levels, plasma short-chain fatty acid levels, and other hematological parameters were monitored. Seizure thresholds were determined in 6 Hz and maximal electroshock seizure threshold (MEST) tests. Antioxidant capacities were evaluated in the cerebral cortex and plasma using a ferric reducing antioxidant power (FRAP) assay and Trolox equivalent antioxidant capacity assay. RESULTS Body weight gain was similar with both diets with and without GTA in two experiments. Glyceryl triacetate-fed groups showed 2-3- and 1.6-fold increased acetate and propionate levels in plasma, respectively. Glucose levels were unaltered in blood collected from the tail tip but increased in trunk blood. No differences were found in the activity of cerebral cortex acetyl-CoA synthetase. In the 6 Hz threshold test, seizure thresholds were lower by 3 mA and 2.4 mA after 8 and 14 days, respectively, in the GTA compared to the control diet-fed group, but showed no difference on day 16, showing that GTA has small, but inconsistent proconvulsant effects in this model. In MEST tests, a slightly increased seizure threshold (1 mA) was found on day 19 in the GTA-fed group, but not in another experiment on day 21. There were no differences in antioxidant capacity in plasma or cortex between the two groups. CONCLUSION Glyceryl triacetate feeding showed no antioxidant effects nor beneficial changes in acute electrical seizure threshold mouse models, despite its ability to increase plasma acetate levels.
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Ahmad M, Alshehry AS, Alharbi H. The Neuroprotective Effects of Natural Food Products Cinnamon and Curcumin in Lithium-Pilocarpine Induced Status Epilepticus Model. NEUROCHEM J+ 2022. [DOI: 10.1134/s1819712422020027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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20
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Abdelbasset WK, Jasim SA, Rudiansyah M, Huldani H, Margiana R, Jalil AT, Mohammad HJ, Ridha HS, Yasin G. Treatment of pilocarpine-induced epileptic seizures in adult male mice. BRAZ J BIOL 2022; 84:e260091. [PMID: 35584460 DOI: 10.1590/1519-6984.260091] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Accepted: 02/03/2022] [Indexed: 01/09/2023] Open
Abstract
Epilepsy is one of the most common neurological disorders affecting most social, economic and biological aspects of human life. Most patients with epilepsy have uncontrolled seizures and drug side effects despite the medications. Patients with epilepsy often have problems with attention, memory, and information processing speed, which may be due to seizures, underlying causes, or anticonvulsants. Therefore, improving seizure control and reducing or changing the anti-epileptic drugs can solve these problems, but these problems will not be solved in most cases. In this work, we looked at the effects of pioglitazone, a Peroxisome Proliferator-Activated Receptor agonist used to treat type 2 diabetes, on pilocarpine-induced seizures in mice. The Racine scale was used to classify pilocarpine-induced convulsions. After that, all of the animals were beheaded, and the brain and hippocampus were dissected. Finally, biochemical techniques were used to determine the levels of Malondialdehyde and Catalase activity, as well as Superoxide Dismutase and Glutathione Reductase in the hippocampus. The results of this investigation suggest that pioglitazone's antioxidant action may play a key role in its neuroprotective properties against pilocarpine-induced seizure neuronal damage.
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Affiliation(s)
- W K Abdelbasset
- Prince Sattam bin Abdulaziz University, College of Applied Medical Sciences, Department of Health and Rehabilitation Sciences, Al Kharj, Saudi Arabia.,Cairo University, Kasr Al-Aini Hospital, Department of Physical Therapy, Giza, Egypt
| | - S A Jasim
- Al-Maarif University College, Medical Laboratory Techniques Department, Al-anbar-Ramadi, Iraq
| | - M Rudiansyah
- Universitas Lambung Mangkurat, Faculty of Medicine, Department of Internal Medicine, Ulin Hospital, Banjarmasin, Indonesia
| | - H Huldani
- Lambung Mangkurat University, Department of Physiology, Magister Management, Magister Immunology, Banjarmasin, South Borneo, Indonesia
| | - R Margiana
- Universitas Indonesia, Faculty of Medicine, Department of Anatomy, Jakarta, Indonesia.,Universitas Indonesia, Faculty of Medicine, Master's Programme Biomedical Sciences, Jakarta, Indonesia
| | - A T Jalil
- Yanka Kupala State University of Grodno, Faculty of Biology and Ecology, Grodno, Belarus.,The Islamic University, College of Technical Engineering, Najaf, Iraq
| | - H J Mohammad
- Al-Manara College for Medical Sciences, Maysan, Iraq
| | - H Sh Ridha
- Al-Nisour University College, Baghdad, Iraq
| | - G Yasin
- Bahauddin Zakariya University, Department of Botany, Multan, Pakistan
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21
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Shehata NI, Abdelsamad MA, Amin HAA, Sadik NAH, Shaheen AA. Ameliorating effect of ketogenic diet on acute status epilepticus: Insights into biochemical and histological changes in rat hippocampus. J Food Biochem 2022; 46:e14217. [PMID: 35543175 DOI: 10.1111/jfbc.14217] [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: 07/17/2021] [Revised: 03/26/2022] [Accepted: 04/05/2022] [Indexed: 11/29/2022]
Abstract
This study aimed to evaluate the potential neuroprotective effects of ketogenic diet (KD) against the neuronal disruptions induced by SE in lithium-pilocarpine rat model of status epilepticus (SE). Four groups of female rats include; groups I and III received standard diet and groups II and IV received KD for 3 weeks. Groups I and II were left untreated, while groups III and IV were injected with LiCl (127 mg/kg, i.p.) followed by pilocarpine HCl (10 mg/kg, i.p.) 18-24 h later, repeatedly, till induction of SE. 72 h post-SE, KD effectively ameliorated the balance between excitatory (glutamate) and inhibitory (GABA) neurotransmitters and the oxidative stress indices, increased adenine nucleotides and decreased immunoreactivity of iNOS, TNFα, glial fibrillary acidic protein, and synaptophysin. Thiswas in association with improvement in inflammatory response and neuronal tissue characteristics in hippocampus of SE rats. Histological changes showed preservation of neuronal integrity. These findings highlight the protective effects of KD in the acute phase post-SE via ameliorating biochemical and histological changes involved. PRACTICAL APPLICATIONS: Epilepsy is the fourth most common neurological disorder that requires lifelong treatment. It stigmatizes patients and their families. The use of the ketogenic diet (KD) as a therapy for epilepsy developed from observations that fasting could reduce seizures. From 1920s, the KD was a common epilepsy treatment until it was gradually superseded by anticonvulsant drugs so that by the 1980s it was rarely used. However, there has been a resurgence of interest and usage of the KD for epilepsy since the turn of the century. Despite its long history, the mechanisms by which KD exhibits its anti-seizure action are not fully understood. Our study aims to identify the mechanism of KD which may help further studies to achieve the same benefits with a drug or supplement to overcome its unpalatability and gastrointestinal side effects.
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Affiliation(s)
- Nagwa I Shehata
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Mai A Abdelsamad
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Hebat Allah A Amin
- Pathology Department, Faculty of Medicine, Helwan University, Cairo, Egypt
| | - Nermin A H Sadik
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Amira A Shaheen
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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22
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Abd Allah HN, Abdul-Hamid M, Mahmoud AM, Abdel-Reheim ES. Melissa officinalis L. ameliorates oxidative stress and inflammation and upregulates Nrf2/HO-1 signaling in the hippocampus of pilocarpine-induced rats. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:2214-2226. [PMID: 34363578 DOI: 10.1007/s11356-021-15825-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 08/01/2021] [Indexed: 06/13/2023]
Abstract
Epilepsy is characterized by recurrent epileptic seizures, and its effective management continues to be a therapeutic challenge. Oxidative stress and local inflammatory response accompany the status epilepticus (SE). This study evaluated the effect of Melissa officinalis extract (MOE) on oxidative stress, inflammation, and neurotransmitters in the hippocampus of pilocarpine (PILO)-administered rats, pointing to the involvement of Nrf2/HO-1 signaling. Rats received PILO via intraperitoneal administration and were treated with MOE for 2 weeks. MOE prevented neuronal loss; decreased lipid peroxidation, Cox-2, PGE2, and BDNF; and downregulated glial fibrillary acidic protein in the hippocampus of PILO-treated rats. In addition, MOE enhanced GSH and antioxidant enzymes, upregulated Nrf2 and HO-1 mRNA abundance, and increased the nuclear translocation of Nrf2 in the hippocampus of epileptic rats. Na+/K+-ATPase activity and GABA were increased, and glutamate and acetylcholine were decreased in the hippocampus of epileptic rats treated with MOE. In conclusion, MOE attenuated neuronal loss, oxidative stress, and inflammation; activated Nrf2/HO-1 signaling; and modulated neurotransmitters, GFAP, and Na+/K+-ATPase in the hippocampus of epileptic rats. These findings suggest that M. officinalis can mitigate epileptogenesis, pending further studies to explore the exact underlying mechanisms.
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Affiliation(s)
- Hagar N Abd Allah
- Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Manal Abdul-Hamid
- Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Ayman M Mahmoud
- Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt.
- Biotechnology Department, Research Institute of Medicinal & Aromatic Plants, Beni-Suef University, Beni-Suef, Egypt.
| | - Eman S Abdel-Reheim
- Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
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23
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Upaganlawar AB, Wankhede NL, Kale MB, Umare MD, Sehgal A, Singh S, Bhatia S, Al-Harrasi A, Najda A, Nurzyńska-Wierdak R, Bungau S, Behl T. Interweaving epilepsy and neurodegeneration: Vitamin E as a treatment approach. Biomed Pharmacother 2021; 143:112146. [PMID: 34507113 DOI: 10.1016/j.biopha.2021.112146] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 08/31/2021] [Accepted: 08/31/2021] [Indexed: 12/29/2022] Open
Abstract
Epilepsy is the most common neurological disorder, affecting nearly 50 million people worldwide. The condition can be manifested either due to genetic predisposition or acquired from acute insult which leads to alteration of cellular and molecular mechanisms. Evaluating the latest and the current knowledge in regard to the mechanisms underlying molecular and cellular alteration, hyperexcitability is a consequence of an imbalanced state wherein enhance excitatory glutamatergic and reduced inhibitory GABAergic signaling is considered to be accountable for seizures associated damage. However, neurodegeneration contributing to epileptogenesis has become increasingly appreciated. The components at the helm of neurodegenerative alterations during epileptogenesis include GABAergic neuronal and receptor changes, neuroinflammation, alteration in axonal transport, oxidative stress, excitotoxicity, and other cellular as well as functional changes. Targeting neurodegeneration with vitamin E as an antioxidant, anti-inflammatory and neuroprotective may prove to be one of the therapeutic approaches useful in managing epilepsy. In this review, we discuss and converse about the seizure-induced episodes as a link for the development of neurodegenerative and pathological consequences of epilepsy. We also put forth a summary of the potential intervention with vitamin E therapy in the management of epilepsy.
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Affiliation(s)
- Aman B Upaganlawar
- SNJB's Shriman Sureshdada Jain College of Pharmacy, Neminagar, Chandwad, Nashik, Maharashtra, India
| | - Nitu L Wankhede
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India
| | - Mayur B Kale
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India
| | - Mohit D Umare
- Smt. Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Saurabh Bhatia
- Natural & Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
| | - Ahmed Al-Harrasi
- Natural & Medical Sciences Research Centre, University of Nizwa, Nizwa, Oman
| | - Agnieszka Najda
- Department of Vegetable Crops and Medicinal Plants, University of Life Sciences, Lublin, Poland.
| | | | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Romania
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
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24
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Sluter MN, Hou R, Li L, Yasmen N, Yu Y, Liu J, Jiang J. EP2 Antagonists (2011-2021): A Decade's Journey from Discovery to Therapeutics. J Med Chem 2021; 64:11816-11836. [PMID: 34352171 PMCID: PMC8455147 DOI: 10.1021/acs.jmedchem.1c00816] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
In the wake of health disasters associated with the chronic use of cyclooxygenase-2 (COX-2) inhibitor drugs, it has been widely proposed that modulation of downstream prostanoid synthases or receptors might provide more specificity than simply shutting down the entire COX cascade for anti-inflammatory benefits. The pathogenic actions of COX-2 have long been thought attributable to the prostaglandin E2 (PGE2) signaling through its Gαs-coupled EP2 receptor subtype; however, the truly selective EP2 antagonists did not emerge until 2011. These small molecules provide game-changing tools to better understand the EP2 receptor in inflammation-associated conditions. Their applications in preclinical models also reshape our knowledge of PGE2/EP2 signaling as a node of inflammation in health and disease. As we celebrate the 10-year anniversary of this breakthrough, the exploration of their potential as drug candidates for next-generation anti-inflammatory therapies has just begun. The first decade of EP2 antagonists passes, while their future looks brighter than ever.
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Affiliation(s)
- Madison N Sluter
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Ruida Hou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Lexiao Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Nelufar Yasmen
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Ying Yu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Jiawang Liu
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
- Medicinal Chemistry Core, Office of Research, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
| | - Jianxiong Jiang
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States
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25
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Manouze H, Ghestem A, Bennis M, Sokar Z, Benoliel JJ, Becker C, Ba-M'hamed S, Bernard C. Antiseizure effects of Anacyclus pyrethrum in socially isolated rats with and without a positive handling strategy. Epilepsia 2021; 62:2551-2564. [PMID: 34347880 DOI: 10.1111/epi.17028] [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: 03/22/2021] [Revised: 07/18/2021] [Accepted: 07/19/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVE Aqueous extract of Anacyclus pyrethrum (AEAPR) is used in traditional medicine to treat epilepsy, but whether it has antiseizure properties has not been established. Because extracts of the plant have antioxidant properties, we hypothesized that it may be particularly potent in conditions associated with oxidative stress, in particular social isolation. METHODS We addressed these objectives in the pilocarpine experimental model of epilepsy using socially isolated rats maintaining contacts with (handled) and without (unhandled) positive handling strategy. Both groups were further divided into treated (AEAPR was added to the drinking water) and untreated groups. Continuous (24/7) electroencephalography (EEG) recordings started in the sixth week after status epilepticus (SE) with a predrug control period of 3 weeks, followed by 3 weeks of daily treatment with AEAPR or water, and finally a postdrug control period of 3 weeks. At the end of the experimental procedure, we measured lipid peroxidation, superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase activities in the hippocampus to assess oxidative stress. RESULTS A. pyrethrum treatment significantly reduced seizure frequency by 51% and 57%, duration by 30% and 33%, and severity by 31% and 26% in isolated handled and unhandled rats, respectively. The beneficial effects on seizures were still present 3 weeks after the end of the treatment. The treatment reduced lipid peroxidation as well as SOD, GPx, and catalase activities. SIGNIFICANCE We conclude that A. pyrethrum has antiseizure and antioxidant properties, even in social isolation conditions.
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Affiliation(s)
- Houria Manouze
- Inserm, INS, Institut de Neurosciences des Systèmes, Aix Marseille Univ, Marseille, France.,Lab of Pharmacology, Neurobiology, Anthropology & Environment, Cadi Ayyad University, Marrakesh, Morocco
| | - Antoine Ghestem
- Inserm, INS, Institut de Neurosciences des Systèmes, Aix Marseille Univ, Marseille, France
| | - Mohamed Bennis
- Lab of Pharmacology, Neurobiology, Anthropology & Environment, Cadi Ayyad University, Marrakesh, Morocco
| | - Zahra Sokar
- Lab of Pharmacology, Neurobiology, Anthropology & Environment, Cadi Ayyad University, Marrakesh, Morocco
| | - Jean-Jacques Benoliel
- Service de Biochimie Endocrinienne et Oncologique, AP-HP, Hôpital de la Pitié-Salpêtrière, Sorbonne Université, Paris, France.,INSERM UMRS 1124, Faculté des Sciences Fondamentales et Biomédicales, Université de Paris, Paris, France
| | - Chrystel Becker
- INSERM UMRS 1124, Faculté des Sciences Fondamentales et Biomédicales, Université de Paris, Paris, France
| | - Saadia Ba-M'hamed
- Lab of Pharmacology, Neurobiology, Anthropology & Environment, Cadi Ayyad University, Marrakesh, Morocco
| | - Christophe Bernard
- Inserm, INS, Institut de Neurosciences des Systèmes, Aix Marseille Univ, Marseille, France
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26
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The protective effect of hydroxylated fullerene pretreatment on pilocarpine-induced status epilepticus. Brain Res 2021; 1764:147468. [PMID: 33831409 DOI: 10.1016/j.brainres.2021.147468] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/26/2021] [Accepted: 04/02/2021] [Indexed: 12/30/2022]
Abstract
Status epilepticus (SE) is a neurological emergency. The pathological hallmark of neuronal damage after epileptic seizures could be the chain reaction of oxygen free radicals. Hydroxylated fullerenes (HFs) are novel and effective free radical scavengers, which play an important role in various neurological diseases. However, whether they have a protective effect against epileptic seizures remains elusive. Our study explores the effect of pretreatment with HFs in different doses (0.5, 5, and 10 mg/kg) on SEmodels induced by pilocarpine (PILO). The results suggest that HFs have a protective effect on SE in a dose-dependent manner. HFs significantly reduce the incidence of SE, prolong the latency to SE, reduce the malondialdehyde (MDA) levels, and increase the glutathione (GSH) and superoxide dismutase (SOD) levels. In addition, HFs significantly raise the expression of B-cell lymphoma-2 (Bcl-2) and reduce the expression of Bcl-2-associated X protein (Bax). We found that expressions of nuclear NF-E2-related factor 2 (nNrf2), heme oxygenase-1 (HO-1) and NADPH: quinone oxidoreductase-1 (NQO1) were upregulated 24 h after the onset of SE, but the increase was not enough to combat oxidative stress damage, nor to attenuate lipid peroxidation and apoptosis. The expressions of these proteins in HFs pretreatment groups increased more significantly than those in the epilepsy (EP) group, which effectively reduced lipid peroxidation and apoptosis in the hippocampus. In summary, these findings highlight that HFs pretreatment has a protective effect against PILO-induced SE in rats. It may relieve oxidative stress damage by activating the Nrf2-ARE signaling pathway. It provides evidence that fullerene derivatives may have therapeutic potential for epileptic seizures.
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27
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Sumbul O, Aygun H. Chronic effects of different quercetin doses in penicillin-induced focal seizure model. Neurosci Lett 2021; 753:135848. [PMID: 33812925 DOI: 10.1016/j.neulet.2021.135848] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 02/27/2021] [Accepted: 03/22/2021] [Indexed: 11/25/2022]
Abstract
AIM The aim of the present study was to examine the effects of different quercetin pretreatment doses on focal epileptiform activity induced by penicillin in adult male rat cortex. METHOD Twenty-eight male Wistar rats weighing 200-235 g were randomly divided into four groups: control (only penicillin-injected group) and penicillin + 25, 50 or 100 mg/kg quercetin doses. All quercetin-treated rats had a daily single dose of 25, 50 or 100 mg/kg intraperitoneally administered quercetin for 21 days, and the last dose was given 30 min before the penicillin injection. Epileptiform activity was induced by a single intracortical (i.c.) microinjection of penicillin (500 units/2.5 μl) into left motor cortex. After penicillin injection ECoG was recorded for the following 180 min. RESULTS Quercetin pretreatments of 25, 50 and 100 mg/kg significantly increased the duration of latency (initial spike activity) and decreased spike frequency of the epileptiform activity compared to the control group (p < 0.05). Duration of latency was significantly longer in 25 mg/kg quercetin pretreatment group compared to 100 mg/kg group (p < 0.05). Spike amplitude of epileptiform activity was not different in the study groups (p > 0.05). CONCLUSION Quercetin had an anticonvulsant activity in penicillin-induced focal seizure model in the present study. In addition, lower quercetin doses had highest anticonvulsant effect in this model.
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Affiliation(s)
- Orhan Sumbul
- Department of Neurology, Faculty of Medicine, Tokat Gaziosmanpasa University, Tokat, Turkey
| | - Hatice Aygun
- Department of Physiology, Faculty of Medicine, Tokat Gaziosmanpasa University, Tokat, Turkey.
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28
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Mohammed HS, Khadrawy YA. Electrophysiological and neurochemical evaluation of the adverse effects of REM sleep deprivation and epileptic seizures on rat's brain. Life Sci 2021; 273:119303. [PMID: 33667518 DOI: 10.1016/j.lfs.2021.119303] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 02/09/2021] [Accepted: 02/22/2021] [Indexed: 11/25/2022]
Abstract
AIM The current study aims to investigate the impact of paradoxical (REM) sleep deprivation and/or epileptic seizures on rat's cortical brain tissues. MAIN METHODS Animals were divided into four groups; control, epileptic, REM sleep deprived and epileptic subjected to REM sleep deprivation. Electrocorticogram (ECoG) signals were recorded and quantitatively analyzed for each group. Concentrations of amino acid neurotransmitters; proinflammatory cytokines; and oxidative stress parameters; and acetylcholinesterase activity were determined in the cortex of the animals in different groups. KEY FINDINGS Results showed significant variations in the spectral distribution of ECoG waves in the epilepsy model, 24- and 48-hours of REM sleep deprivation and their combined effects indicating a state of cortical hyperexcitability. Significant increases in NO and taurine and significant decrement in glutamine, GABA and glycine were determined. In REM sleep deprived rats significant elevation in glutamate, aspartate, glycine and taurine and a significant lowering in GABA were obtained. This was accompanied by significant reduction in AchE and IL-β. In the cortical tissue of epileptic rats deprived from REM sleep significant increases in lipid peroxidation, TNF-α, IL-1β, IL-6 and aspartate and a significant reduction in AchE were observed. SIGNIFICANCE The present data indicate that REM sleep deprivation induces an increase in lipid peroxidation and storming in proinflammatory cytokines in the cortex of rat model of epilepsy during SRS. These changes are associated with a decreased seizure threshold as inferred from the increase in alpha and Beta waves and a decrease in Delta waves of ECoG.
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Affiliation(s)
- Haitham S Mohammed
- Biophysics Department, Faculty of Science, Cairo University, Giza, Egypt.
| | - Yasser A Khadrawy
- Medical Physiology Department, National Research Center, Giza, Egypt
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29
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Shishmanova-Doseva M, Peychev L, Yoanidu L, Uzunova Y, Atanasova M, Georgieva K, Tchekalarova J. Anticonvulsant Effects of Topiramate and Lacosamide on Pilocarpine-Induced Status Epilepticus in Rats: A Role of Reactive Oxygen Species and Inflammation. Int J Mol Sci 2021; 22:2264. [PMID: 33668718 PMCID: PMC7956388 DOI: 10.3390/ijms22052264] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 02/03/2021] [Accepted: 02/22/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Status epilepticus (SE) is a neurological disorder characterized by a prolonged epileptic activity followed by subsequent epileptogenic processes. The aim of the present study was to evaluate the early effects of topiramate (TPM) and lacosamide (LCM) treatment on oxidative stress and inflammatory damage in a model of pilocarpine-induced SE. METHODS Male Wistar rats were randomly divided into six groups and the two antiepileptic drugs (AEDs), TPM (40 and 80 mg/kg, i.p.) and LCM (10 and 30 mg/kg, i.p.), were injected three times repeatedly after pilocarpine administration. Rats were sacrificed 24 h post-SE and several parameters of oxidative stress and inflammatory response have been explored in the hippocampus. RESULTS The two drugs TPM and LCM, in both doses used, succeeded in attenuating the number of motor seizures compared to the SE-veh group 30 min after administration. Pilocarpine-induced SE decreased the superoxide dismutase (SOD) activity and reduced glutathione (GSH) levels while increasing the catalase (CAT) activity, malondialdehyde (MDA), and IL-1β levels compared to the control group. Groups with SE did not affect the TNF-α levels. The treatment with a higher dose of 30 mg/kg LCM restored to control level the SOD activity in the SE group. The two AEDs, in both doses applied, also normalized the CAT activity and MDA levels to control values. In conclusion, we suggest that the antioxidant effect of TPM and LCM might contribute to their anticonvulsant effect against pilocarpine-induced SE, whereas their weak anti-inflammatory effect in the hippocampus is a consequence of reduced SE severity.
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Affiliation(s)
| | - Lyudmil Peychev
- Department of Pharmacology and Drug Toxicology, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Lyubka Yoanidu
- Department of Bioorganic Chemistry, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria; (L.Y.); (Y.U.)
| | - Yordanka Uzunova
- Department of Bioorganic Chemistry, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria; (L.Y.); (Y.U.)
| | - Milena Atanasova
- Department of Biology, Medical University of Pleven, 5800 Pleven, Bulgaria;
| | - Katerina Georgieva
- Department of Physiology, Medical University-Plovdiv, 4002 Plovdiv, Bulgaria;
| | - Jana Tchekalarova
- Institute of Neurobiology, Bulgarian Academy of Sciences (BAS), 1113 Sofia, Bulgaria
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30
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Hosny EN, Elhadidy ME, Sawie HG, Kilany A, Khadrawy YA. Effect of frankincense oil on the neurochemical changes induced in rat model of status epilepticus. CLINICAL PHYTOSCIENCE 2020. [DOI: 10.1186/s40816-019-0139-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The current objective is to evaluate the effect of frankincense oil on the convulsions and the associated neurochemical alterations produced in pilocarpine-induced status epilepticus rat model.
Methods
Rats were divided randomly into: control, status epilepticus rat model and rat model of status epilepticus pretreated with frankincense oil daily for 5 days before pilocarpine treatment. On the fifth day, after pilocarpine injection, rats were observed to evaluate the severity of seizures for 2 h. The oxidative stress parameters malondialdehyde, reduced glutathione and nitric oxide, the proinflammatory cytokines interleukin-6 and interleukin-1β and acetylcholinesterase were determined in the cortex, hippocampus and striatum. Dopamine, norepinephrine and serotonin were measured in the cortex and striatum.
Results
The status epilepticus model exhibited repetitive seizures in the form of generalized tonic- clonic convulsions after 30 min. of pilocarpine injection. This was associated with a significant increase in the levels of malondialdehyde and nitric oxide and a significant decrease in reduced glutathione in the three regions. A significant increase was also observed in interleukin-1β, interleukin-6 and acetylcholinesterase. In the cortex and striatum, a significant decrease was recorded in monoamine levels. Pretreatment of rat model of status epilepticus with frankincense oil decreased the severity of seizures that appeared in the form of tremors and facial automatisms and prevented the increase in malondialdehyde, nitric oxide, interleukin-1β, interleukin-6 and acetylcholinesterase and the decrease in reduced glutathione induced by pilocarpine in the studied brain regions. Frankincense oil failed to restore the decreased level of cortical serotonin and dopamine. In the striatum, frankincense oil improved the levels of serotonin and norepinephrine but failed to restore the decreased dopamine levels.
Conclusion
It is clear from the present results that frankincense oil reduced the severity of seizures induced by pilocarpine. This could be mediated by its potent antioxidant and anti-inflammatory effects.
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ELMostafi H, Bahbiti Y, Elhessni A, Bousalham R, Doumar H, Ouichou A, Benmhammed H, Touil T, Mesfioui A. Neuroprotective potential of Argan oil in neuropsychiatric disorders in rats: A review. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104233] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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Olowe R, Sandouka S, Saadi A, Shekh-Ahmad T. Approaches for Reactive Oxygen Species and Oxidative Stress Quantification in Epilepsy. Antioxidants (Basel) 2020; 9:E990. [PMID: 33066477 PMCID: PMC7602129 DOI: 10.3390/antiox9100990] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 10/01/2020] [Accepted: 10/07/2020] [Indexed: 12/27/2022] Open
Abstract
Oxidative stress (OS) and excessive reactive oxygen species (ROS) production have been implicated in many neurological pathologies, including acute seizures and epilepsy. Seizure-induced damage has been demonstrated both in vitro and in several in vivo seizure and epilepsy models by direct determination of ROS, and by measuring indirect markers of OS. In this manuscript, we review the current reliable methods for quantifying ROS-related and OS-related markers in pre-clinical and clinical epilepsy studies. We first provide pieces of evidence for the involvement of different sources of ROS in epilepsy. We then discuss general methods and assays used for the ROS measurements, mainly superoxide anion, hydrogen peroxide, peroxynitrite, and hydroxyl radical in in vitro and in vivo studies. In addition, we discuss the role of these ROS and markers of oxidative injury in acute seizures and epilepsy pre-clinical studies. The indirect detection of secondary products of ROS such as measurements of DNA damage, lipid peroxidation, and protein oxidation will also be discussed. This review also discusses reliable methods for the assessment of ROS, OS markers, and their by-products in epilepsy clinical studies.
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Affiliation(s)
| | | | | | - Tawfeeq Shekh-Ahmad
- The Institute for Drug Research, The School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel; (R.O.); (S.S.); (A.S.)
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Mukhtar I. Inflammatory and immune mechanisms underlying epileptogenesis and epilepsy: From pathogenesis to treatment target. Seizure 2020; 82:65-79. [PMID: 33011590 DOI: 10.1016/j.seizure.2020.09.015] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Revised: 09/15/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Epilepsy is a brain disease associated with epileptic seizures as well as with neurobehavioral outcomes of this condition. In the last century, inflammation emerged as a crucial factor in epilepsy etiology. Various brain insults through activation of neuronal and non-neuronal brain cells initiate a series of inflammatory events. Growing observations strongly suggest that abnormal activation of critical inflammatory processes contributes to epileptogenesis, a gradual process by which a normal brain transforms into the epileptic brain. Increased knowledge of inflammatory pathways in epileptogenesis has unveiled mechanistic targets for novel antiepileptic therapies. Molecules specifically targeting the pivotal inflammatory pathways may serve as promising candidates to halt the development of epilepsy. The present paper reviews the pieces of evidence conceptually supporting the potential role of inflammatory mechanisms and the relevant blood-brain barrier (BBB) disruption in epileptogenesis. Also, it discusses the mechanisms underlying inflammation-induced neuronal-glial network impairment and highlights innovative neuroregulatory actions of typical inflammatory molecules. Finally, it presents a brief analysis of observations supporting the therapeutic role of inflammation-targeting tiny molecules in epileptic seizures.
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Affiliation(s)
- Iqra Mukhtar
- H.E.J Research Institute of Chemistry, International Center For Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan; Department of Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences, University of Karachi, Karachi, 75270, Pakistan.
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Sumbul O, Aygun H. The effect of vitamin D 3 and paricalcitol on penicillin-induced epileptiform activity in rats. Epilepsy Res 2019; 159:106262. [PMID: 31887643 DOI: 10.1016/j.eplepsyres.2019.106262] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 12/11/2019] [Accepted: 12/21/2019] [Indexed: 12/17/2022]
Abstract
AIM Epilepsy is a disease characterized by seizures which impair human life considerably. Vitamin D is of different systemic effects on metabolism and its deficiency is known to have a high prevalence among epilepsy patients. Paricalcitol, a vitamin D receptor agonist, has relatively fewer side effects. This study aimed to investigate the anticonvulsant effect of vitamin D3 (cholecalciferol) and paricalcitol on penicillin-induced epileptiform activity. METHOD 21 male Wistar rat weighing 180-240 g were used. After anesthetized by 1.25 g/kg urethane intraperitoneally (i.p.), rats were placed in the stereotaxic frame and tripolar electrodes were placed on the skull. The single microinjection of penicillin (2.5 μl, 500 IU, i.c.) into left sensorimotor cortex induced epileptiform activity. A single dose of 60.000 IU/kg (i.p.) vitamin D3 was administered 14 days before intracortical penicillin (500 IU) injection. Paricalcitol (10 μg/kg, i.p.) was administered 30 min before intracortical penicillin (500 IU) administration and recorded for the following 180 min. RESULTS Vitamin D3 pretreatment and paricalcitol diminished the frequency of epileptiform activity (p < 0.001) without changing the amplitude (p > 0.05) compared to the penicillin-injected group. Vitamin D3 pretreatment and paricalcitol led to an important delay in the onset of penicillin-induced epileptiform activity (p < 0.001 and p < 0.05, respectively). Vitamin D3 increased the latency of penicillin-induced epileptic activity compared to paricalcitol group (p < 0.001). CONCLUSION Results indicate that vitamin D3 and paricalcitol decreased the frequency and increased the latency of the penicillin-induced epileptic activity. Vitamin D3 was more effective than paricalcitol.
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Affiliation(s)
- Orhan Sumbul
- Department of Neurology, Faculty of Medicine, Tokat Gaziosmanpasa University, Tokat, Turkey
| | - Hatice Aygun
- Department of Physiology, Faculty of Medicine, Tokat Gaziosmanpasa University, Tokat, Turkey.
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Alachkar A, Azimullah S, Ojha SK, Beiram R, Łażewska D, Kieć-Kononowicz K, Sadek B. The Neuroprotective Effects of Histamine H3 Receptor Antagonist E177 on Pilocarpine-Induced Status Epilepticus in Rats. Molecules 2019; 24:E4106. [PMID: 31739417 PMCID: PMC6891424 DOI: 10.3390/molecules24224106] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 11/05/2019] [Accepted: 11/11/2019] [Indexed: 12/14/2022] Open
Abstract
Epilepsy is a multifaceted neurological disorder which severely affects neuronal function. Some patients may experience status epilepticus (SE), a life-threatening state of ongoing seizure activity linked to cognitive dysfunction, necessitating an immediate intervention. The potential of histamine H3 receptors in several neuropsychiatric diseases including epilepsy is well recognized. In the current study, we aimed to explore the effect of H3R antagonist E177 on prevention and termination of pilocarpine (PLC)-induced SE in rats as well as evaluating the effects of E177 on the levels of oxidative stress in hippocampus tissues. The results showed that the survival rate of animals pretreated with E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) was significantly increased during the first hour of observation, and animals were protected from SE incidence and showed a prolonged average of latency to the first seizure when compared with animals pretreated with PLC (400 mg/kg, i.p.). Moreover, the protective effect of E177 (10 mg/kg) on SE was partially reversed when rats were co- administered with H3R agonist R-(α)-methylhistamine (RAM) and with the H2R antagonist zolantidine (ZOL), but not with the H1R antagonist pyrilamine (PYR). Furthermore, pretreatment with E177 (5 and 10 mg/kg) significantly decreased the abnormal levels of malondialdehyde (MDA), and increased levels of glutathione (GSH) in the hippocampal tissues of the treated rats. However, E177 failed to modulate the levels of catalase (CAT), superoxide dismutase (SOD), or acetylcholine esterase activity (AChE). Our findings suggest that the newly developed H3R antagonist E177 provides neuroprotection in a preclinical PLC-induced SE in rats, highlighting the histaminergic system as a potential therapeutic target for the therapeutic management of SE.
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Affiliation(s)
- Alaa Alachkar
- Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE
| | - Sheikh Azimullah
- Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE
| | - Shreesh K. Ojha
- Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE
| | - Rami Beiram
- Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE
| | - Dorota Łażewska
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Kraków, Poland
| | - Katarzyna Kieć-Kononowicz
- Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9 St., 30-688 Kraków, Poland
| | - Bassem Sadek
- Department of Pharmacology & Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain 17666, UAE
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Ebrahimi F, Sadr SS, Roghani M, Khamse S, Mohammadian Haftcheshmeh S, Navid Hamidi M, Mohseni-Moghaddam P, Zamani E. Assessment of the protective effect of KN-93 drug in systemic epilepsy disorders induced by pilocarpine in male rat. J Cell Biochem 2019; 120:15906-15914. [PMID: 31074121 DOI: 10.1002/jcb.28864] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 02/05/2019] [Accepted: 02/14/2019] [Indexed: 01/02/2023]
Abstract
BACKGROUND AND AIMS Epileptic seizures occur as a consequence of a sudden imbalance between the stimuli and inhibitors within the network of cortical neurons in favor of the stimulus. One of the drugs that induce epilepsy is pilocarpine. Systemic injection of pilocarpine affects on muscarinic receptors. Increasing evidence has addressed the implication of KN-93 by blocking Ca2+ /calmodulin-dependent protein kinase II (CaMKII), suppressing oxidative stress and inflammation, and also reducing neuron decay. So, we aimed to evaluate the potential preventive effects of KN-93 in systemic epilepsy disorders induced by pilocarpine. MATERIALS AND METHODS In this animal study, male rats were divided into five groups including treatment group (KN-93 with the dose of 5 mM/10 µL dimethyl sulfoxide (DMSO) before inducing epilepsy by 380 mg/kg pilocarpine) KN-93 group (received 5 mM KN-93), control group, epilepsy group (received 380 mg/kg pilocarpine Intraperitoneal), and sham group (received 10 µL DMSO). Oxidative stress was assessed by measuring its indicators including the concentration of malondialdehyde (MDA), nitrite, glutathione (GSH), as well as the antioxidant activity of catalase. In addition, serum levels of proinflammatory mediators including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were determined. RESULTS Pretreatment with KN-93 significantly reduced oxidative stress index by reducing the concentration of MDA, nitrite, and increasing the level of GSH. In addition, low concentrations of TNF-α and IL-1β were observed in hippocampus supernatant of KN-93 pretreated rats in comparison with the pilocarpine groups. Moreover, administration of KN-93 improved neuronal density and attenuated the seizure activity and behavior. CONCLUSIONS Overall, our findings suggest that KN-93 can effectively suppress oxidative stress and inflammation. Furthermore, KN-93 is able to attenuate seizure behaviors by preventing its effects on neuron loss, so, it is valuable for the treatment of epileptic seizures.
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Affiliation(s)
- Fatemeh Ebrahimi
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.,Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Shahabeddin Sadr
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.,Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Roghani
- Department of Physiology, School of Medicine, Shahed University and Medicinal Plant Research Center, Tehran, Iran
| | - Safoura Khamse
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.,Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Saeed Mohammadian Haftcheshmeh
- Department of Medical Immunology, Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mojdeh Navid Hamidi
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Elham Zamani
- Department of Physiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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de Carvalho MAJ, Chaves-Filho A, de Souza AG, de Carvalho Lima CN, de Lima KA, Rios Vasconcelos ER, Feitosa ML, Souza Oliveira JV, de Souza DAA, Macedo DS, de Souza FCF, de França Fonteles MM. Proconvulsant effects of sildenafil citrate on pilocarpine-induced seizures: Involvement of cholinergic, nitrergic and pro-oxidant mechanisms. Brain Res Bull 2019; 149:60-74. [PMID: 31004733 DOI: 10.1016/j.brainresbull.2019.04.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2018] [Revised: 03/26/2019] [Accepted: 04/09/2019] [Indexed: 12/12/2022]
Abstract
Sildenafil is a phosphodiesterase 5 inhibitor used for the treatment of erectile dysfunction and pulmonary hypertension. Proconvulsant effect is a serious adverse event associated with sildenafil use. Here, we investigated the possible proconvulsant effects of sildenafil in pilocarpine (PILO)-induced seizures model, which mimics some aspects of temporal lobe epilepsy. We also evaluated sildenafil's effects on hippocampal markers related to PILO-induced seizure, for instance, acetylcholinesterase (AChE) activity, oxidative stress and nitric oxide (NO) markers, namely nitrite, inducible NO synthase (iNOS) and neuronal NOS (nNOS). The influences of muscarinic receptors blockade on sildenafil proconvulsant effects and brain nitrite levels were also evaluated. Male mice were submitted to single or repeated (7 days) sildenafil administration (2.5, 5, 10 and 20 mg/kg). Thirty minutes later, PILO was injected and mice were further evaluated for 1 h for seizure activity. Sildenafil induced a dose- and time-progressive proconvulsant effect in PILO-induced seizures. Sildenafil also potentiated the inhibitory effect of PILO in AChE activity and induced a further increase in nitrite levels and pro-oxidative markers, mainly in the hippocampus. Repeated sildenafil treatment also increased the hippocampal expression of iNOS and nNOS isoforms, while the blockade of muscarinic receptors attenuated both sildenafil-induced proconvulsant effect and brain nitrite changes. Our data firstly demonstrated the proconvulsant effect of sildenafil in PILO-model of seizures. This effect seems to be related to an increased cholinergic-nitrergic tone and pro-oxidative brain changes. Also, our findings advert to caution in using sildenafil for patients suffering from neurological conditions that reduces seizure threshold, such as epilepsy.
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Affiliation(s)
- Michele Albuquerque Jales de Carvalho
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Adriano Chaves-Filho
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Alana Gomes de Souza
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Camila Nayane de Carvalho Lima
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Klistenes Alves de Lima
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Emiliano Ricardo Rios Vasconcelos
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Mariana Lima Feitosa
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - João Victor Souza Oliveira
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Denia Alves Albuquerque de Souza
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Danielle S Macedo
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil; National Institute for Translational Medicine (INCT-TM, CNPq), Ribeirão Preto, Brazil
| | - Francisca Cléa Florenço de Souza
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil
| | - Marta Maria de França Fonteles
- Neuropsychopharmacology Laboratory, Drug Research and Development Center, Faculty of Medicine, Department of Physiology and Pharmacology, Universidade Federal do Ceará, Fortaleza, CE, Brazil; Pharmacy Department, Faculty of Dentistry, Nursing and Pharmacy, Universidade Federal do Ceará, Fortaleza, CE, Brazil.
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Immunohistochemical Study of Antioxidant Enzymes Regulated by Nrf2 in the Models of Epileptic Seizures (KA and PTZ). OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:1327986. [PMID: 31019649 PMCID: PMC6451808 DOI: 10.1155/2019/1327986] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 01/10/2019] [Accepted: 02/17/2019] [Indexed: 12/31/2022]
Abstract
Epilepsy is a neurological disorder characterized by recurrent spontaneous seizures due to an imbalance between cerebral excitability and inhibition, with a tendency towards uncontrolled excitability. Epilepsy has been associated with oxidative and nitrosative stress due to prolonged neuronal hyperexcitation and loss neurons during seizures. The experimental animal models report level of ATP diminished and increase in lipid peroxidation, catalase, and glutathione altered activity in the brain. We studied the immunohistochemical expression and localization of antioxidant enzymes GPx, SOD, and CAT in the rat brains treated with KA and PTZ. A significant decrease was observed in the number of immunoreactive cells to GPx, without significant changes for SOD and CAT in KA-treated rats, and decrease in the number of immunoreactive cells to SOD, without significant changes for GPx and only CAT in PTZ-treated rats. Evident immunoreactivity of GPx, SOD, and CAT was observed mainly in astrocytes and neurons of the hippocampal brain region in rats exposed at KA; similar results were observed in rats treated with PTZ at the first hours. These results provide evidence supporting the role of activation of the Nrf2 antioxidant system pathway against oxidative stress effects in the experimental models of epileptic seizures.
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Arslan G, Avci B, Kocacan SE, Rzayev E, Ayyildiz M, Agar E. The interaction between P2X7Rs and T-type calcium ion channels in penicillin-induced epileptiform activity. Neuropharmacology 2019; 149:1-12. [PMID: 30695710 DOI: 10.1016/j.neuropharm.2019.01.027] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 01/02/2019] [Accepted: 01/24/2019] [Indexed: 02/06/2023]
Abstract
Limited information exists on the link between purinergic class P2X7 receptors (P2X7Rs) and calcium ion channels in epilepsy; no data has been reported regarding the interaction between P2X7Rs and T-type calcium ion channels in epilepsy. Thus, this study is an evaluation of the role that T-type calcium ion channels play in the effect of P2X7Rs on penicillin-induced epileptiform activity. In the first set of experiments, P2X7R agonist BzATP (at 25-, 50-, 100- and 200-μg doses), P2X7R antagonist A-438079 (at 5-, 10-, 20- and 40-μg doses) and T-type calcium ion channel antagonist, NNC-550396 were administered for electrophysiological analyses 30 min after penicillin injection (2.5 μl, 500 IU). In the second set of experiments, the effective doses of these substances were used for biochemical analyses. Malondialdehyde (MDA), advanced oxidation protein product (AOPP), glutathione (GSH), glutathione reductase (GR), glutathione peroxide (GPx), catalase (CAT) and superoxide dismutase (SOD) levels were measured in the cerebrum, cerebellum and brainstem of rats. BzATP (100 μg, icv) increased the mean frequency of epileptiform activity, whereas A-438079 (40 μg, icv) and NNC-550396 (30 μg, ic) reduced it. Both A-438079 and NNC-550396 reversed BzATP's proconvulsant action. BzATP increased lipid peroxidation and protein oxidation; it also altered other antioxidant enzymes measured in this study, which were all then reversed via A-438079 and NNC-550396, at least in the cerebrum. The electrophysiological and biochemical analysis of present study suggest that P2X7Rs and its interaction with T-type calcium ion channels play an important role in the experimental model of epilepsy.
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Affiliation(s)
- Gokhan Arslan
- Department of Physiology, Medical School, University of Ondokuz Mayis, Samsun, Turkey
| | - Bahattin Avci
- Department of Biochemistry, Medical School, University of Ondokuz Mayis, Samsun, Turkey
| | - Süleyman Emre Kocacan
- Department of Physiology, Medical School, University of Ondokuz Mayis, Samsun, Turkey
| | - Emil Rzayev
- Department of Biochemistry, Medical School, University of Ondokuz Mayis, Samsun, Turkey
| | - Mustafa Ayyildiz
- Department of Physiology, Medical School, University of Ondokuz Mayis, Samsun, Turkey
| | - Erdal Agar
- Department of Physiology, Medical School, University of Ondokuz Mayis, Samsun, Turkey.
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Pansani AP, Cysneiros RM, Colugnati DB, Janjoppi L, Ferrari D, de Lima E, Ghazale PP, Sinigaglia-Coimbra R, Scorza FA. Long-term monotherapy treatment with vitamin E reduces oxidative stress, but not seizure frequency in rats submitted to the pilocarpine model of epilepsy. Epilepsy Behav 2018; 88:301-307. [PMID: 30342389 DOI: 10.1016/j.yebeh.2018.09.027] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2018] [Accepted: 09/20/2018] [Indexed: 01/29/2023]
Abstract
The imbalance between antioxidant system and reactive oxygen species (ROS) generation is related to epileptogenesis, neuronal death, and seizure frequency. Treatment with vitamin E has been associated with neuroprotection and control of seizures. In most experimental studies, vitamin E treatment has short duration. Therefore, the aim of this study was to verify the role of long-term treatment with vitamin E in rats submitted to the pilocarpine model of epilepsy. Rats were divided into two main groups: control (Ctr) and pilocarpine (Pilo). Each one was subdivided according to treatment: vehicle (Ctr V and Pilo V) or vitamin E at dosages of 6 IU/kg/day (Ctr E6 and Pilo E6) or 60 IU/kg/day (Ctr E60 and Pilo E60). Treatment lasted 120 days from status epilepticus (SE). There were no statistical differences concerning treatment in the Ctr group for all variables, so the data were grouped. Carbonyl content in the hippocampus of Pilo V and Pilo E6 was higher compared with that of the Ctr group (8 ± 1.5, 7.1 ± 1, and 3.1 ± 0.3 nmol carbonyl/mg protein, respectively for Pilo V, Pilo E6, and Ctr; p < 0.05). Carbonyl content was restored to control values in Pilo E60 rats (4.2 ± 1.1 and 3.1 ± 0.3 nmol carbonyl/mg protein, respectively for Pilo E60 and Ctr; p > 0.05). The volume of the hippocampal formation (6.5 ± 0.3, 6.6 ± 0.4, 6.3 ± 0.3, and 7.4 ± 0.2, respectively for Pilo V, Pilo E6, Pilo E60, and Ctr) and subfields CA1 (1.6 ± 0.1, 1.4 ± 0.2, 1.5 ± 0.1, and 2 ± 0.05, respectively for Pilo V, Pilo E6, Pilo E60, and Ctr) and CA3 (1.7 ± 0.1, 1.5 ± 0.2, 1.4 ± 0.1, and 2 ± 0.1, respectively for Pilo V, Pilo E6, Pilo E60, and Ctr) was reduced in the Pilo group regardless of treatment. Parvalbumin immunostaining was increased in the hilus of the Pilo E60 group compared with that in the Ctr group (26 ± 2 and 39.6 ± 8.3 neurons, respectively for Ctr and Pilo E60). No difference was found in seizure frequency and Neo-Timm staining. Therefore, long-term treatment with 60 IU/kg/day of vitamin E prevented oxidative damage in the hippocampus and increased hilar parvalbumin expression in rats with epilepsy without a reduction in seizure frequency.
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Affiliation(s)
- Aline Priscila Pansani
- Laboratório Integrado de Fisiopatologia Cardiovascular e Neurológica, Departamento de Ciências Fisiológicas, Universidade Federal de Goiás, Brazil.
| | - Roberta Monterazzo Cysneiros
- Programa de Pós-Graduação em Distúrbios do Desenvolvimento do Centro de Ciências Biológicas e da Saúde - Universidade Presbiteriana Mackenzie, São Paulo, Brazil
| | - Diego Basile Colugnati
- Laboratório Integrado de Fisiopatologia Cardiovascular e Neurológica, Departamento de Ciências Fisiológicas, Universidade Federal de Goiás, Brazil
| | - Luciana Janjoppi
- Laboratório de Neurologia Experimental - Universidade Federal de São Paulo (UNIFESP), Brazil
| | - Danuza Ferrari
- Laboratório de Neurologia Experimental - Universidade Federal de São Paulo (UNIFESP), Brazil
| | - Eliângela de Lima
- Laboratório de Fisiologia, Departamento de Ciências Básicas em Saúde - Universidade Federal de Mato Grosso (UFMT), Brazil
| | - Poliana Peres Ghazale
- Laboratório de Neurologia Experimental - Universidade Federal de São Paulo (UNIFESP), Brazil
| | | | - Fulvio Alexandre Scorza
- Laboratório de Neurologia Experimental - Universidade Federal de São Paulo (UNIFESP), Brazil
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Inhibition of NADPH Oxidase Activation by Apocynin Rescues Seizure-Induced Reduction of Adult Hippocampal Neurogenesis. Int J Mol Sci 2018; 19:ijms19103087. [PMID: 30304850 PMCID: PMC6212849 DOI: 10.3390/ijms19103087] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 09/28/2018] [Accepted: 10/02/2018] [Indexed: 12/19/2022] Open
Abstract
Apocynin, also known as acetovanillone, is a natural organic compound structurally related to vanillin. Apocynin is known to be an inhibitor of NADPH (Nicotinamide adenine dinucleotide phosphate) oxidase activity and is highly effective in suppressing the production of superoxide. The neuroprotective effects of apocynin have been investigated in numerous brain injury settings, such as stroke, traumatic brain injury (TBI), and epilepsy. Our lab has demonstrated that TBI or seizure-induced oxidative injury and neuronal death were reduced by apocynin treatment. Several studies have also demonstrated that neuroblast production is transiently increased in the hippocampus after seizures. Here, we provide evidence confirming the hypothesis that long-term treatment with apocynin may enhance newly generated hippocampal neuronal survival by reduction of superoxide production after seizures. A seizure was induced by pilocarpine [(25 mg/kg intraperitoneal (i.p.)] injection. Apocynin was continuously injected for 4 weeks after seizures (once per day) into the intraperitoneal space. We evaluated neuronal nuclear antigen (NeuN), bromodeoxyuridine (BrdU), and doublecortin (DCX) immunostaining to determine whether treatment with apocynin increased neuronal survival and neurogenesis in the hippocampus after seizures. The present study indicates that long-term treatment of apocynin increased the number of NeuN⁺ and DCX⁺ cells in the hippocampus after seizures. Therefore, this study suggests that apocynin treatment increased neuronal survival and neuroblast production by reduction of hippocampal oxidative injury after seizures.
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Gyurászová M, Kovalčíková A, Janšáková K, Šebeková K, Celec P, Tóthová Ľ. Markers of oxidative stress and antioxidant status in the plasma, urine and saliva of healthy mice. Physiol Res 2018; 67:921-934. [PMID: 30204460 DOI: 10.33549/physiolres.933866] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Oxidative stress markers are usually measured in plasma, a stable environment for biomarkers. Blood collection is invasive, but the use of alternative biofluids is limited, due to high variability. In this study, we aimed to establish reference values for oxidative stress markers in plasma, urine and saliva of adult, healthy mice and to identify some sources of variability. Samples were obtained from 41 female and 37 male adult, healthy mice of the CD-1 strain, aged 95-480 days, weighing 21-55 grams. Reference ranges of TBARS (thiobarbituric acid reactive substances), AOPP (advanced oxidation protein products), fructosamine, GSH/GSSG (reduced and oxidized glutathione) ratio, TAC (total antioxidant capacity), and FRAP (ferric reducing antioxidant power) were measured in plasma and urine, and TBARS, GSH/GSSG ratio, TAC and FRAP in saliva, using standard spectrophotometric and fluorometric methods. Salivary GSH/GSSG and urinary AOPP were higher in females. Urinary fructosamine, GSH/GSSG and FRAP were higher in males. Urinary TAC and FRAP negatively correlated with age, and urinary GSH/GSSG positively correlated with weight. We determined that urine and saliva can be obtained non-invasively from mice, in sufficient amounts for reliable oxidative status assessment. Further studies are needed to uncover whether these biofluids reflect systemic oxidative status in diseases.
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Affiliation(s)
- M Gyurászová
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
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Ali AE, Mahdy HM, Elsherbiny DM, Azab SS. Rifampicin ameliorates lithium-pilocarpine-induced seizures, consequent hippocampal damage and memory deficit in rats: Impact on oxidative, inflammatory and apoptotic machineries. Biochem Pharmacol 2018; 156:431-443. [PMID: 30195730 DOI: 10.1016/j.bcp.2018.09.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Accepted: 09/05/2018] [Indexed: 01/28/2023]
Abstract
Epilepsy is one of the serious neurological sequelae of bacterial meningitis. Rifampicin, the well-known broad spectrum antibiotic, is clinically used for chemoprophylaxis of meningitis. Besides its antibiotic effects, rifampicin has been proven to be an effective neuroprotective candidate in various experimental models of neurological diseases. In addition, rifampicin was found to have promising antioxidant, anti-inflammatory and anti-apoptotic effects. Herein, we investigated the anticonvulsant effect of rifampicin at experimental meningitis dose (20 mg/kg, i.p.) using lithium-pilocarpine model of status epilepticus (SE) in rats. Additionally, we studied the effect of rifampicin on seizure induced histopathological, neurochemical and behavioral abnormalities. Our study showed that rifampicin pretreatment attenuated seizure activity and the resulting hippocampal insults marked by hematoxylin and eosin. Markers of oxidative stress, neuroinflammation and apoptosis were evaluated, in the hippocampus, 24 h after SE induction. We found that rifampicin pretreatment suppressed oxidative stress as indicated by normalized malondialdehyde and glutathione levels. Rifampicin pretreatment attenuated SE-induced neuroinflammation and decreased the hippocampal expression of interleukin-1β, tumor necrosis factor-α, nuclear factor kappa-B, and cyclooxygenase-2. Moreover, rifampicin mitigated SE-induced neuronal apoptosis as indicated by fewer positive cytochrome c immunostained cells and lower caspase-3 activity in the hippocampus. Furthermore, Morris water maze testing at 7 days after SE induction showed that rifampicin pretreatment can improve cognitive dysfunction. Therefore, rifampicin, currently used in the management of meningitis, has a potential additional advantage of ameliorating its epileptic sequelae.
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Affiliation(s)
- Alaa E Ali
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Heba M Mahdy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Doaa M Elsherbiny
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Samar S Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
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Nirwan N, Siraj F, Vohora D. Inverted-U response of lacosamide on pilocarpine-induced status epilepticus and oxidative stress in C57BL/6 mice is independent of hippocampal collapsin response mediator protein-2. Epilepsy Res 2018; 145:93-101. [PMID: 29935443 DOI: 10.1016/j.eplepsyres.2018.06.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 06/09/2018] [Accepted: 06/15/2018] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Currently, lacosamide (LCM) is not approved for use in status epilepticus (SE) but several shreds of evidence are available to support its use. The present study was, therefore, undertaken to evaluate the effect of LCM on pilocarpine (PILO) induced SE and neurodegeneration in C57BL/6 mice and to ascertain the involvement of CRMP-2 in mediating above effect. METHODS Pilocarpine-induced SE model was developed to explore the effect of LCM 20, 40 and 80 mg/kg in mice. We assessed the seizure severity, seizure latency, spontaneous alternation behavior (SAB) and motor coordination by behavioral observation. Histopathological evaluation and measurement of the levels of CRMP-2, reduced glutathione (GSH) and malondialdehyde (MDA) were carried out in mice hippocampus. RESULTS LCM exhibited a biphasic effect i.e., protection against SE at 20 mg/kg and 40 mg/kg dose whilst aggravated seizure-like behavior and mortality at 80 mg/kg. Further, it increased percentage alternation (i.e., restored spatial memory) in SAB and elevated motor impairment with increasing dose. Histologically, LCM 20 mg/kg and 40 mg/kg (but not 80 mg/kg) reduced neurodegeneration. LCM 20 mg/kg and 40 mg/kg reversed the elevated MDA and GSH levels while 80 mg/kg showed a tendency to increase oxidative stress. In contrast, LCM (at all doses) reversed the pilocarpine-induced elevation of collapsin response mediator protein-2 (CRMP-2). CONCLUSION LCM protected against pilocarpine-induced SE, associated neurodegeneration and improved pilocarpine-associated impairment of spatial memory. The study reveals that CRMP-2 may not be mediating the inverted-U-response of LCM at least in pilocarpine model. Therefore, the anti-oxidant effect of LCM (and not its ability to modulate CRMP-2) was anticipated as the mechanism underlying neuroprotection.
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Affiliation(s)
- Nikita Nirwan
- Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India
| | - Fouzia Siraj
- National Institute of Pathology (ICMR), Safdarjang Hospital Campus, New Delhi 110029, India
| | - Divya Vohora
- Neurobehavioral Pharmacology Laboratory, Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi 110062, India.
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de Gois da Silva ML, da Silva Oliveira GL, de Oliveira Bezerra D, da Rocha Neto HJ, Feitosa MLT, Argôlo Neto NM, Rizzo MDS, de Carvalho MAM. Neurochemical properties of neurospheres infusion in experimental-induced seizures. Tissue Cell 2018; 54:47-54. [PMID: 30309509 DOI: 10.1016/j.tice.2018.08.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Revised: 08/03/2018] [Accepted: 08/06/2018] [Indexed: 02/07/2023]
Abstract
Cell replacement through neural stem cells has been a promising alternative therapy for neurodegenerative diseases. It was evaluated the possible protect and/or prevent role of neurospheres in experimental models of epilepsy by the use of biomarkers of oxidative stress and histopathological analysis. After 1 h of the epileptic inductions by pilocarpine, pentylenotetrazole and picrotoxin, rats were infused with a suspension of 2 × 106 cells/0.25 mL, marked with Qtracker® 655, via caudal vein. In the control group epilepsy was not induced, but received the cell infusion under the same conditions of other groups. After 30 days, the rats were euthanized, and the removal of the brain was proceeded to later perform the assays oxidative stress and histopathology analysis. Thiobarbituric acid and nitrite levels were elevated in epileptic groups treated with neurospheres, and the levels of reduced glutathione, superoxide dismutase and catalase were reduced when compared to non-treated groups. The performance of oxidative enzymes from pilocarpine group treated with neurospheres showed slight increase. Histopathological evaluation observed distribution of neurospheres throughout the brain tissue, with viable cells and in process of differentiation in the pilocarpine group, but with differentiation and regeneration compromised in epilepsy by picrotoxin and pentylenetetrazole due to a microenvironment of oxidative stress. Neural stem cell therapy has a promising potential for protection in the pilocarpine epilepsy model, suggesting that the antioxidant system of neurospheres could reduce oxidative damage generated by seizure.
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Affiliation(s)
| | - George Laylson da Silva Oliveira
- Postgraduate program in biotechnology-RENORBIO, Federal University of Piauí, Teresina, PI, Ininga Campus, Brazil; Department of Biology, Federal Institute of Mato Grosso, Guarantã do Norte - MT, Guarantã do Norte Campus, Brazil.
| | - Dayseanny de Oliveira Bezerra
- Integrated Nucleus of Morphology and Stem Cell Research, Agrarian Sciences Center, Federal University of Piauí, Teresina, PI, Ininga Campus, Brazil.
| | - Hermínio José da Rocha Neto
- Integrated Nucleus of Morphology and Stem Cell Research, Agrarian Sciences Center, Federal University of Piauí, Teresina, PI, Ininga Campus, Brazil.
| | - Matheus Levi Tajra Feitosa
- Integrated Nucleus of Morphology and Stem Cell Research, Agrarian Sciences Center, Federal University of Piauí, Teresina, PI, Ininga Campus, Brazil; State University of Maranhão, São Luis, MA, Brazil.
| | - Napoleão Martins Argôlo Neto
- Integrated Nucleus of Morphology and Stem Cell Research, Agrarian Sciences Center, Federal University of Piauí, Teresina, PI, Ininga Campus, Brazil.
| | - Marcia Dos Santos Rizzo
- Department of Morphology, Health Sciences Center, Federal University of Piauí, Teresina, PI, Ininga Campus, Brazil.
| | - Maria Acelina Martins de Carvalho
- Postgraduate program in biotechnology-RENORBIO, Federal University of Piauí, Teresina, PI, Ininga Campus, Brazil; Integrated Nucleus of Morphology and Stem Cell Research, Agrarian Sciences Center, Federal University of Piauí, Teresina, PI, Ininga Campus, Brazil.
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Increased Superoxide Dismutase 2 by Allopregnanolone Ameliorates ROS-Mediated Neuronal Death in Mice with Pilocarpine-Induced Status Epilepticus. Neurochem Res 2018; 43:1464-1475. [PMID: 29855848 DOI: 10.1007/s11064-018-2561-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 05/23/2018] [Accepted: 05/26/2018] [Indexed: 12/19/2022]
Abstract
Excessive production of reactive oxygen species (ROS), along with dysfunction of the antioxidant defense system, such as that involving superoxide dismutase (SOD), may play a major role in neuronal death following status epilepticus (SE). Neurosteroids, which are allosteric modulators of the GABAA receptor in cerebral metabolism, have been suggested as being neuroprotective in various animal models; however, their effect to preventing ROS has not been examined. Herein, we investigate the neuroprotective role of allopregnanolone, the prototypical neurosteroid in the brain, in relation to the ROS-mediated neuronal injury. Adult male C57BL/6 mice were subjected to SE and treated with allopregnanolone. Hippocampal cell death was assessed by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and ROS production was investigated by in situ detection of oxidized hydroethidine. SOD2 expression was analyzed by both western blot and immunofluorescent staining in the hippocampal subfields. In mice treated with allopregnanolone after SE, hippocampal cell death, DNA fragmentation, oxidative DNA damage, and ROS production were reduced significantly compared to mice subjected to vehicle treatment after SE. Hippocampal SOD2 expression was significantly increased by allopregnanolone. These finding suggest that allopregnanolone plays a neuroprotective role, with not only anticonvulsant but also antioxidant effects, by increasing SOD2 in pilocarpine-induced SE model.
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A novel online fluorescence method for in-vivo measurement of hydrogen peroxide during oxidative stress produced in a temporal lobe epilepsy model. Neuroreport 2018; 29:621-630. [DOI: 10.1097/wnr.0000000000001007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Khadrawy YA, Sawie HG, Hosny EN. Neuroprotective effect of curcumin nanoparticles against rat model of status epilepticus induced by pilocarpine. JOURNAL OF COMPLEMENTARY & INTEGRATIVE MEDICINE 2018; 15:jcim-2017-0117. [PMID: 29570450 DOI: 10.1515/jcim-2017-0117] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 02/20/2018] [Indexed: 11/15/2022]
Abstract
Abstract
Background
The present study aims to investigate the neuroprotective effect of curcumin nanoparticles (Cur-NP) on the rat model of status epilepticus (SE) induced by pilocarpine.
Methods
In the present study, animals were divided into three groups: control animals, rat model of SE induced by a single dose of pilocarpine (380 mg/kg) injected intraperitoneally, and rat model of SE that received a daily intraperitoneal injection of Cur-NP (50 mg/kg) for four consecutive days prior to pilocarpine administration.
Results
The present results revealed a state of oxidative stress in the cortex and hippocampus of rat model of SE as compared to control. This was evident from the significant increase in lipid peroxidation and the significant decrease in reduced glutathione and nitric oxide. In addition, a significant increase in the levels of tumor necrosis factor-alpha (TNF-α) and caspase-3 was detected in the two studied brain regions of rat model of SE. The activities of acetylcholinesterase (AchE) and Na+/K+-ATPase decreased significantly in the cortex and hippocampus of rat model of SE. Protection with Cur-NP prevented oxidative stress and improved the elevated level of caspase-3 in the hippocampus and cortex and the hippocampal TNF-α to nonsignificant changes. Although Cur-NP prevented the decrease in AchE activity in the two studied brain regions, it failed to return Na+/K+-ATPase activity to its normal value.
Conclusions
It is clear from the present findings that Cur-NP could prevent the oxidative stress and neuroinflammation and cell death that were induced during SE. This in turn may help in ameliorating the subsequent cascades of events that follow SE and its development into epileptogenesis.
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Affiliation(s)
- Yasser A Khadrawy
- Medical Physiology Department, Medical Division, National Research Center, El-Behouth St., Giza, Egypt
| | - Hussein G Sawie
- Medical Physiology Department, Medical Division, National Research Center, El-Behouth St., Giza, Egypt
| | - Eman N Hosny
- Medical Physiology Department, Medical Division, National Research Center, El-Behouth St., Giza, Egypt
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Vizuete AFK, Hansen F, Negri E, Leite MC, de Oliveira DL, Gonçalves CA. Effects of dexamethasone on the Li-pilocarpine model of epilepsy: protection against hippocampal inflammation and astrogliosis. J Neuroinflammation 2018; 15:68. [PMID: 29506554 PMCID: PMC5839012 DOI: 10.1186/s12974-018-1109-5] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 02/28/2018] [Indexed: 11/25/2022] Open
Abstract
Background Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy and is accompanied, in one third of cases, by resistance to antiepileptic drugs (AED). Most AED target neuronal activity modulated by ionic channels, and the steroid sensitivity of these channels has supported the use of corticosteroids as adjunctives to AED. Assuming the importance of astrocytes in neuronal activity, we investigated inflammatory and astroglial markers in the hippocampus, a key structure affected in TLE and in the Li-pilocarpine model of epilepsy. Methods Initially, hippocampal slices were obtained from sham rats and rats subjected to the Li-pilocarpine model of epilepsy, at 1, 14, and 56 days after status epilepticus (SE), which correspond to the acute, silent, and chronic phases. Dexamethasone was added to the incubation medium to evaluate the secretion of S100B, an astrocyte-derived protein widely used as a marker of brain injury. In the second set of experiments, we evaluated the in vivo effect of dexamethasone, administrated at 2 days after SE, on hippocampal inflammatory (COX-1/2, PGE2, and cytokines) and astroglial parameters: GFAP, S100B, glutamine synthetase (GS) and water (AQP-4), and K+ (Kir 4.1) channels. Results Basal S100B secretion and S100B secretion in high-K+ medium did not differ at 1, 14, and 56 days for the hippocampal slices from epileptic rats, in contrast to sham animal slices, where high-K+ medium decreased S100B secretion. Dexamethasone addition to the incubation medium per se induced a decrease in S100B secretion in sham and epileptic rats (1 and 56 days after SE induction). Following in vivo dexamethasone administration, inflammatory improvements were observed, astrogliosis was prevented (based on GFAP and S100B content), and astroglial dysfunction was partially abrogated (based on Kir 4.1 protein and GSH content). The GS decrease was not prevented by dexamethasone, and AQP-4 was not altered in this epileptic model. Conclusions Changes in astroglial parameters emphasize the importance of these cells for understanding alterations and mechanisms of epileptic disorders in this model. In vivo dexamethasone administration prevented most of the parameters analyzed, reinforcing the importance of anti-inflammatory steroid therapy in the Li-pilocarpine model and possibly in other epileptic conditions in which neuroinflammation is present. Electronic supplementary material The online version of this article (10.1186/s12974-018-1109-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Adriana Fernanda K Vizuete
- Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil.
| | - Fernanda Hansen
- Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Elisa Negri
- Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Marina Concli Leite
- Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Diogo Losch de Oliveira
- Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
| | - Carlos-Alberto Gonçalves
- Department of Biochemistry, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, 90035-003, Brazil
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Nkamguie Nkantchoua GC, Kameni Njapdounke JS, Jules Fifen J, Sotoing Taiwe G, Josiane Ojong L, Kavaye Kandeda A, Ngo Bum E. Anticonvulsant effects of Senna spectabilis on seizures induced by chemicals and maximal electroshock. JOURNAL OF ETHNOPHARMACOLOGY 2018; 212:18-28. [PMID: 28986332 DOI: 10.1016/j.jep.2017.09.042] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 09/26/2017] [Accepted: 09/29/2017] [Indexed: 06/07/2023]
Abstract
Senna spectabilis (Fabaceae) is one of the medicinal plants used in Cameroon by traditional healers to treat epilepsy, constipation, insomnia, anxiety. The present study aimed to investigate the anticonvulsant effects of Senna spectabilis decoction on seizures induced by maximal electroshock (MES), pentylenetetrazole (PTZ), pilocarpine (PC) and its possible action mechanisms in animal models using flumazenil (FLU), methyl-ß-carboline-3-carboxylate (BC) and bicuculline (BIC). Senna spectabilis decoction (106.5 and 213.0mg/kg) antagonized completely tonic-clonic hind limbs of mice induced by MES. The lowest plant dose (42.6mg/kg) provided 100% of protection against seizures induced by PTZ (70mg/kg). Administration of different doses of the plant decoction antagonized seizures induced by PC up to 75%, causing a dose dependent protection and reduced significantly the mortality rate induced by this convulsant. Both FLU and BC antagonize strongly the anticonvulsant effects of this plant and are unable to reverse totally diazepam or the plant decoction effects on inhibiting seizures. The animals did not present any sign of acute toxicity even at higher doses of the plant decoction. In conclusion, Senna spectabilis possesses an anticonvulsant activity. We showed that its decoction protects significantly mice against seizures induced by chemicals and MES, delays the onset time and reduces mortality rate in seizures-induced. It also appears that the oral administration of the decoction of S. spectabilis is more active than the intraperitoneal administration of the ethanolic extract on inhibiting seizures induced by MES and PTZ. Moreover, the plant decoction could interact with GABAA complex receptor probably on the GABA and benzodiazepines sites.
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Affiliation(s)
| | | | - Jean Jules Fifen
- Department of Physics, Faculty of Science, The University of Ngaoundere, Cameroon
| | - Germain Sotoing Taiwe
- Department of Zoology and Animal Physiology, Faculty of Science, University of Buea, Cameroon
| | - Lucie Josiane Ojong
- Department of Biological Sciences, Faculty of Science, The University of Ngaoundere, Cameroon
| | - Antoine Kavaye Kandeda
- Department of Animal Biology and Physiology, Faculty of Science, University of Yaounde 1, Cameroon
| | - Elisabeth Ngo Bum
- Department of Biological Sciences, Faculty of Science, The University of Ngaoundere, Cameroon
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