|
1
|
Upadhayay S, Uttam V, Kumar P. G-Protein-Coupled Estrogen Receptor 1 (GPER1) Activation Mitigates Haloperidol-Induced Neurotoxicity in SHSY-5Y Cells and Improves Motor Functions in Adult Zebrafish. Neurochem Res 2025; 50:119. [PMID: 40087195 DOI: 10.1007/s11064-025-04369-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2024] [Revised: 02/19/2025] [Accepted: 03/05/2025] [Indexed: 03/17/2025]
Abstract
Haloperidol (Halo) is a typical antipsychotic medication used to treat schizophrenia, but its long-term treatment causes neurotoxicity, leading to irregular involuntary movements called Tardive Dyskinesia. Raloxifene (Ralo) and fulvestrant (Fulve) are G-protein-coupled estrogen receptor 1 (GPER1) activators and show similar pharmacological properties as identified in 17β-estradiol. It is reported to have anti-oxidant, anti-inflammatory, and anti-apoptotic properties against neurological disorders. Our study aimed to investigate the neuroprotective effect of ralo and fulve against halo-induced neurotoxicity in SHSY-5Y cells and adult zebrafish. In this study, SHSY-5Y cell lines were treated with ralo (0.01 µM), fulve (0.01 µM), G-15 (1 µM), and G-1 (2 µM) 1 h before halo (100 µM) exposure. Moreover, cell viability was analyzed using MTT assay; apoptosis was done using a confocal microscope, and molecular mechanism investigated through Western Blot and qRT-PCR analysis. For in-vivo study, zebrafish were divided into six groups (n = 12). Treatment with ralo and fulve significantly improved the viability of halo-exposed cells, while it was reduced by G15 treatment. Moreover, ralo and fulve substantially reversed ROS generation, and apoptosis by enhancing the qRT-PCR expression of Nrf2/HO-1/Bcl2 and reduced Bax expression in halo-treated cells. In addition, ralo and fulve treatment enhanced GPER1 expression in halo-treated cells, while G15 treatment reduced it. Furthermore, ralo and fulve injections improved total distance travelled, mean speed, and catalepsy-like behaviour, restoring antioxidant activity in halo-treated zebrafish. Findings suggest that ralo and fulve can activate GPER1/Nrf2/HO-1 signaling pathways and show neuroprotection against halo-induced neurotoxicity. It could be used in the management of neurological disorders.
Collapse
Affiliation(s)
- Shubham Upadhayay
- Department of Pharmacology, Central University of Punjab, Ghudda, Bhatinda, 151401, Punjab, India
| | - Vivek Uttam
- Department of Zoology, Central University of Punjab, Ghudda, Bhatinda, Punjab, India
| | - Puneet Kumar
- Department of Pharmacology, Central University of Punjab, Ghudda, Bhatinda, 151401, Punjab, India.
| |
Collapse
|
|
2
|
Toro-Urrego N, Luaces JP, Kobiec T, Udovin L, Bordet S, Otero-Losada M, Capani F. Raloxifene Protects Oxygen-Glucose-Deprived Astrocyte Cells Used to Mimic Hypoxic-Ischemic Brain Injury. Int J Mol Sci 2024; 25:12121. [PMID: 39596189 PMCID: PMC11594051 DOI: 10.3390/ijms252212121] [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: 05/20/2024] [Revised: 08/11/2024] [Accepted: 08/23/2024] [Indexed: 11/28/2024] Open
Abstract
Perinatal asphyxia (PA) is a clinical condition characterized by oxygen supply suspension before, during, or immediately after birth, and it is an important risk factor for neurodevelopmental damage. Its estimated 1/1000 live births incidence in developed countries rises to 5-10-fold in developing countries. Schizophrenia, cerebral palsy, mental retardation, epilepsy, blindness, and others are among the highly disabling chronic pathologies associated with PA. However, so far, there is no effective therapy to neutralize or reduce PA-induced harm. Selective regulators of estrogen activity in tissues and selective estrogen receptor modulators like raloxifene have shown neuroprotective activity in different pathological scenarios. Their effect on PA is yet unknown. The purpose of this paper is to examine whether raloxifene showed neuroprotection in an oxygen-glucose deprivation/reoxygenation astrocyte cell model. To study this issue, T98G cells in culture were treated with a glucose-free DMEM medium and incubated at 37 °C in a hypoxia chamber with 1% O2 for 3, 6, 12, and 24 h. Cultures were supplemented with raloxifene 10, and 100 nM during both glucose and oxygen deprivation and reoxygenation periods. Raloxifene 100 nM and 10 nM improved cell survival-65.34% and 70.56%, respectively, compared with the control cell groups. Mitochondrial membrane potential was preserved by 58.9% 10 nM raloxifene and 81.57% 100 nM raloxifene cotreatment. Raloxifene co-treatment reduced superoxide production by 72.72% and peroxide production by 57%. Mitochondrial mass was preserved by 47.4%, 75.5%, and 89% in T98G cells exposed to 6-h oxygen-glucose deprivation followed by 3, 6, and 9 h of reoxygenation, respectively. Therefore, raloxifene improved cell survival and mitochondrial membrane potential and reduced lipid peroxidation and reactive oxygen species (ROS) production, suggesting a direct effect on mitochondria. In this study, raloxifene protected oxygen-glucose-deprived astrocyte cells, used to mimic hypoxic-ischemic brain injury. Two examiners performed the qualitative assessment in a double-blind fashion.
Collapse
Affiliation(s)
- Nicolás Toro-Urrego
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
| | - Juan P. Luaces
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
| | - Tamara Kobiec
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
- Centro de Investigaciones en Psicología y Psicopedagogía (CIPP), Facultad de Psicología y Psicopedagogía, Pontificia Universidad Católica Argentina (UCA), Buenos Aires C1107AFB, Argentina
| | - Lucas Udovin
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
| | - Sofía Bordet
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
- Centro de Investigaciones en Psicología y Psicopedagogía (CIPP), Facultad de Psicología y Psicopedagogía, Pontificia Universidad Católica Argentina (UCA), Buenos Aires C1107AFB, Argentina
| | - Matilde Otero-Losada
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
| | - Francisco Capani
- Centro de Altos Estudios en Ciencias Humanas y de la Salud, Universidad Abierta Interamericana, Consejo Nacional de Investigaciones Científicas y Técnicas, CAECIHS, UAI-CONICET, Buenos Aires C1270AAH, Argentina; (N.T.-U.); (J.P.L.); (T.K.); (L.U.); (S.B.)
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Santiago 7500912, Chile
| |
Collapse
|
|
3
|
Yang XM, Yu H, Li JX, Li N, Li C, Xu DH, Zhang H, Fang TH, Wang SJ, Yan PY, Han BB. Excitotoxic Storms of Ischemic Stroke: A Non-neuronal Perspective. Mol Neurobiol 2024; 61:9562-9581. [PMID: 38662299 DOI: 10.1007/s12035-024-04184-7] [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: 11/26/2023] [Accepted: 04/15/2024] [Indexed: 04/26/2024]
Abstract
Numerous neurological disorders share a fatal pathologic process known as glutamate excitotoxicity. Among which, ischemic stroke is the major cause of mortality and disability worldwide. For a long time, the main idea of developing anti-excitotoxic neuroprotective agents was to block glutamate receptors. Despite this, there has been little successful clinical translation to date. After decades of "neuron-centered" views, a growing number of studies have recently revealed the importance of non-neuronal cells. Glial cells, cerebral microvascular endothelial cells, blood cells, and so forth are extensively engaged in glutamate synthesis, release, reuptake, and metabolism. They also express functional glutamate receptors and can listen and respond for fast synaptic transmission. This broadens the thoughts of developing excitotoxicity antagonists. In this review, the critical contribution of non-neuronal cells in glutamate excitotoxicity during ischemic stroke will be emphasized in detail, and the latest research progress as well as corresponding therapeutic strategies will be updated at length, aiming to reconceptualize glutamate excitotoxicity in a non-neuronal perspective.
Collapse
Affiliation(s)
- Xiao-Man Yang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, People's Republic of China
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Hao Yu
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Jia-Xin Li
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, People's Republic of China
| | - Na Li
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Chong Li
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Dong-Han Xu
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, People's Republic of China
| | - Hao Zhang
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, People's Republic of China
| | - Tian-He Fang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China
| | - Shi-Jun Wang
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China.
| | - Pei-Yu Yan
- Faculty of Chinese Medicine, Macau University of Science and Technology, Macau, People's Republic of China.
- State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, People's Republic of China.
- Zhuhai MUST Science and Technology Research Institute, Macau University of Science and Technology, Macau, People's Republic of China.
| | - Bing-Bing Han
- College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, People's Republic of China.
| |
Collapse
|
|
4
|
Liu L, Tian X, Li W. Mechanistic study of the anti-excitatory amino acid toxicity of Bushen Zhichan decoction for Parkinson's disease based on the transcriptional regulation of EAAT1 by YY1. JOURNAL OF ETHNOPHARMACOLOGY 2024; 325:117857. [PMID: 38350506 DOI: 10.1016/j.jep.2024.117857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 01/25/2024] [Accepted: 02/02/2024] [Indexed: 02/15/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Bushen Zhichan decoction (BSZCF) is derived from Liuwei Dihuang Pill, a famous Chinese herbal formula recorded in the book Key to Therapeutics of Children's Diseases. It has been widely used as a basic prescription for nourishing and tonifying the liver and kidneys to treat Parkinson's disease (PD), but its mechanism remains to be explored. AIM OF THE STUDY BSZCF, a Chinese herbal formula comprising five herbs: Rehmannia glutinosa (Gaertn.) DC., Dioscorea oppositifolia L., Cornus officinalis Siebold & Zucc., Fallopia multiflora (Thunb.) Haraldson and Cistanche tubulosa (Schenk) Wight, is used clinically to treat PD. In vivo and in vitro experiments were designed to elucidate the mechanism of BSZCF in the protection of dopamine (DA) neurons and the treatment of PD. The toxicity of excitatory amino acids (EAA) may be attenuated by inhibiting the transcription factor Yin Yang 1 (YY1) and up-regulating the expression of excitatory amino acid transporter 1 (EAAT1). MATERIALS AND METHODS IN VIVO: After 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was intraperitoneally injected into specific pathogen free (SPF) C57BL/6J mice, model mice were intragastrically given adamantane hydrochloride tablets (AHT) or different doses of BSZCF for 14 days. Both open field and pole-climbing tests were conducted to assess behavioral changes. In vitro: 1-Methyl-4-phe-nylpyridiniumiodide (MPP+)-injured human neuroblastoma cells (SH-SY5Y) were utilized to construct PD cell models. Primary astrocytes were transfected with EAAT1 and YY1 lentiviruses for EAAT1 gene knockout and YY1 gene knockout astrocytes, respectively. The high performance liquid chromatography-mass spectrometry (HPLC-MS) analysis of BSZCF was performed to control the quality of blood drugs. The optimal concentration and time of PD cell models treated by BSZCF were determined by the use of Cell Counting Kit-8 (CCK8). Enzyme-linked immunosorbent assay (ELISA) was used for measuring glutamate (Glu) in the peripheral blood and cells of each group. Western blotting (WB) and real-time quantitative polymerase chain reaction (qPCR) were used to detect tyrosine hydroxylase (TH), dopamine transporters (DAT), EAAT1 and YY1 protein and mRNA. After the blockade of EAAT1, immunofluorescence (IF) assay was used to detect the TH protein in each group. RESULTS In vivo research showed that BSZCF improved the behavioral symptoms of PD mice, and reduced the death of DA neurons and the level of Glu. The mechanism may be related to the decrease of YY1 expression and the increase of EAAT1 levels. In vitro experiments showed that the anti-excitatory amino acid toxicity of BSZCF was achieved by inhibiting YY1 expression and regulating EAAT1. CONCLUSIONS By inhibiting YY1 to increase the expression of EAAT1 and attenuating the toxicity of Glu, BSZCF exerts the effect of protecting DA neurons and treating PD-like symptoms in mice.
Collapse
Affiliation(s)
- Leilei Liu
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, China.
| | - Xinyun Tian
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, China.
| | - Wentao Li
- Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, China.
| |
Collapse
|
|
5
|
Wang X, Zhang F, Niu L, Yan J, Liu H, Wang D, Hui J, Dai H, Song J, Zhang Z. High-frequency repetitive transcranial magnetic stimulation improves depressive-like behaviors in CUMS-induced rats by modulating astrocyte GLT-1 to reduce glutamate toxicity. J Affect Disord 2024; 348:265-274. [PMID: 38159655 DOI: 10.1016/j.jad.2023.12.068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 11/20/2023] [Accepted: 12/24/2023] [Indexed: 01/03/2024]
Abstract
Impaired glutamate recycling plays an important role in the pathophysiology of depression, and it has been demonstrated that glutamate transporter-1 (GLT-1) on astrocytes is involved in glutamate uptake. Studies have shown that repetitive transcranial magnetic stimulation (rTMS) is effective in treating depression, however, the exact mechanism of rTMS treatment remains unclear. Here, we used a chronic unpredictable mild stress (CUMS) protocol to induce depression-like behaviors in rats followed by rTMS treatment. Behavioral assessment was primarily through SPT, FST, OFT and body weight. Histological analysis focused on GFAP and GLT-1 expression, synaptic plasticity, apoptosis and PI3K/Akt/CREB pathway-related proteins. The results showed that rTMS treatment increased sucrose preference, improved locomotor activity, shortened immobility time as well as increased body weight. And rTMS intervention reversed the elevated glutamate concentration in the hippocampus of CUMS rats using an ELISA kit. Moreover, rTMS ameliorated the reduction in GFAP and GLT-1 expression, alleviated the decrease in BDNF, PSD95 and synapsin-1 expression, also reversed the expression levels of BAX and Bcl2 in the hippocampus of CUMS-induced rats. Moreover, rTMS also increased the protein phosphorylation level of PI3K/Akt/CREB pathway. These results suggest that rTMS treatment ameliorates depression-like behaviors in the rat model by reversing the reduction of GLT-1 on astrocytes and reducing glutamate accumulation in the synaptic cleft, which in turn ameliorates synaptic plasticity damage and neuronal apoptosis. The regulation of GLT-1 by rTMS may be through the PI3K/Akt/CREB pathway.
Collapse
Affiliation(s)
- Xiaonan Wang
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Henan Key Lab of Biological Psychiatry, Xinxiang, Henan 453002, China; Henan Engineering Research Center of Physical Diagnostics and Treatment Technology for the Mental and Neurological Diseases, Xinxiang, Henan 453002, China
| | - Fuping Zhang
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Henan Key Lab of Biological Psychiatry, Xinxiang, Henan 453002, China; Henan Engineering Research Center of Physical Diagnostics and Treatment Technology for the Mental and Neurological Diseases, Xinxiang, Henan 453002, China
| | - Le Niu
- The First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Neurorestoratology, Weihui, Henan 453100, China; The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Henan Key Lab of Biological Psychiatry, Xinxiang, Henan 453002, China
| | - Junni Yan
- Nanjing Brain Hospital, Nanjing, 210029, China
| | - Huanhuan Liu
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Henan Key Lab of Biological Psychiatry, Xinxiang, Henan 453002, China; Henan Engineering Research Center of Physical Diagnostics and Treatment Technology for the Mental and Neurological Diseases, Xinxiang, Henan 453002, China
| | - Di Wang
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Henan Key Lab of Biological Psychiatry, Xinxiang, Henan 453002, China; Henan Engineering Research Center of Physical Diagnostics and Treatment Technology for the Mental and Neurological Diseases, Xinxiang, Henan 453002, China
| | - Juan Hui
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Henan Key Lab of Biological Psychiatry, Xinxiang, Henan 453002, China
| | - Haiyue Dai
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Henan Key Lab of Biological Psychiatry, Xinxiang, Henan 453002, China
| | - Jinggui Song
- The Second Affiliated Hospital of Xinxiang Medical University (Henan Mental Hospital), Henan Key Lab of Biological Psychiatry, Xinxiang, Henan 453002, China; Henan Engineering Research Center of Physical Diagnostics and Treatment Technology for the Mental and Neurological Diseases, Xinxiang, Henan 453002, China.
| | - Zhaohui Zhang
- The First Affiliated Hospital of Xinxiang Medical University, Henan Key Laboratory of Neurorestoratology, Weihui, Henan 453100, China.
| |
Collapse
|
|
6
|
Bhatnagar A, Parmar V, Barbieri N, Bearoff F, Elefant F, Kortagere S. Novel EAAT2 activators improve motor and cognitive impairment in a transgenic model of Huntington's disease. Front Behav Neurosci 2023; 17:1176777. [PMID: 37351153 PMCID: PMC10282606 DOI: 10.3389/fnbeh.2023.1176777] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/19/2023] [Indexed: 06/24/2023] Open
Abstract
Introduction Glutamate excitotoxicity is causal in striatal neurodegeneration underlying motor dysfunction and cognitive deficits in Huntington's disease (HD). Excitatory amino acid transporter 2 (EAAT2), the predominant glutamate transporter accounting for >90% of glutamate transport, plays a key role in preventing excitotoxicity by clearing excess glutamate from the intrasynaptic cleft. Accordingly, EAAT2 has emerged as a promising therapeutic target for prevention of neuronal excitotoxicity underlying HD and other neurodegenerative diseases. Methods We have previously designed novel EAAT2 positive allosteric modulator GT951, GTS467, and GTS551, with low nanomolar efficacy in glutamate uptake and favorable pharmacokinetic properties. In this study, we test the neuroprotective abilities of these novel EAAT2 activators in vivo using the robust Drosophila HD transgenic model expressing human huntingtin gene with expanded repeats (Htt128Q). Results All three compounds significantly restored motor function impaired under HD pathology over a wide dose range. Additionally, treatment with all three compounds significantly improved HD-associated olfactory associative learning and short-term memory defects, while GT951 and GTS551 also improved middle-term memory in low-performing group. Similarly, treatment with GT951 and GTS551 partially protected against early mortality observed in our HD model. Further, treatment with all three EAAT2 activators induced epigenetic expression of EAAT2 Drosophila homolog and several cognition-associated genes. Conclusion Together, these results highlight the efficacy of GT951, GTS467 and GTS551 in treating motor and cognitive impairments under HD pathology and support their development for treatment of HD.
Collapse
Affiliation(s)
- Akanksha Bhatnagar
- Department of Biology, Papadakis Integrated Sciences Building, Drexel University, Philadelphia, PA, United States
| | - Visha Parmar
- Department of Biology, Papadakis Integrated Sciences Building, Drexel University, Philadelphia, PA, United States
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Nicholas Barbieri
- Department of Biology, Papadakis Integrated Sciences Building, Drexel University, Philadelphia, PA, United States
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Frank Bearoff
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, United States
| | - Felice Elefant
- Department of Biology, Papadakis Integrated Sciences Building, Drexel University, Philadelphia, PA, United States
| | - Sandhya Kortagere
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, United States
| |
Collapse
|
|
7
|
Fontana IC, Souza DG, Souza DO, Gee A, Zimmer ER, Bongarzone S. A Medicinal Chemistry Perspective on Excitatory Amino Acid Transporter 2 Dysfunction in Neurodegenerative Diseases. J Med Chem 2023; 66:2330-2346. [PMID: 36787643 PMCID: PMC9969404 DOI: 10.1021/acs.jmedchem.2c01572] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
The excitatory amino acid transporter 2 (EAAT2) plays a key role in the clearance and recycling of glutamate - the major excitatory neurotransmitter in the mammalian brain. EAAT2 loss/dysfunction triggers a cascade of neurodegenerative events, comprising glutamatergic excitotoxicity and neuronal death. Nevertheless, our current knowledge regarding EAAT2 in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), is restricted to post-mortem analysis of brain tissue and experimental models. Thus, detecting EAAT2 in the living human brain might be crucial to improve diagnosis/therapy for ALS and AD. This perspective article describes the role of EAAT2 in physio/pathological processes and provides a structure-activity relationship of EAAT2-binders, bringing two perspectives: therapy (activators) and diagnosis (molecular imaging tools).
Collapse
Affiliation(s)
- Igor C Fontana
- School of Biomedical Engineering and Imaging Sciences, St Thomas' Hospital, King's College London, London SE1 7EH, United Kingdom.,Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, 90035-003 Porto Alegre, Brazil.,Division of Clinical Geriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Blickagången 16 - Neo floor seventh, 141 83 Stockholm, Sweden
| | - Débora G Souza
- Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, 90035-003 Porto Alegre, Brazil.,Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul, Av. Ipiranga, 6681 Porto Alegre, Brazil
| | - Diogo O Souza
- Graduate Program in Biological Sciences: Biochemistry, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, 90035-003 Porto Alegre, Brazil.,Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, 90035-003 Porto Alegre, Brazil
| | - Antony Gee
- School of Biomedical Engineering and Imaging Sciences, St Thomas' Hospital, King's College London, London SE1 7EH, United Kingdom
| | - Eduardo R Zimmer
- Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, 90035-003 Porto Alegre, Brazil.,Department of Pharmacology, Universidade Federal do Rio Grande do Sul, Av. Sarmento Leite 500, sala, 90035-003 Porto Alegre, Brazil.,Graduate Program in Biological Sciences: Biochemistry (PPGBioq), and Pharmacology and Therapeutics (PPGFT), Universidade Federal do Rio Grande do Sul, Av. Sarmento Leite 500, sala, 305 Porto Alegre, Brazil.,Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul, Av. Ipiranga, 6681 Porto Alegre, Brazil.,McGill University Research Centre for Studies in Aging, McGill University, Montreal, Quebec H4H 1R3, Canada
| | - Salvatore Bongarzone
- School of Biomedical Engineering and Imaging Sciences, St Thomas' Hospital, King's College London, London SE1 7EH, United Kingdom
| |
Collapse
|
|
8
|
Yuan F, Li Y, Hu R, Gong M, Chai M, Ma X, Cha J, Guo P, Yang K, Li M, Xu M, Ma Q, Su Q, Zhang C, Sheng Z, Wu H, Wang Y, Yuan W, Bian S, Shao L, Zhang R, Li K, Shao Z, Zhang ZN, Li W. Modeling disrupted synapse formation in wolfram syndrome using hESCs-derived neural cells and cerebral organoids identifies Riluzole as a therapeutic molecule. Mol Psychiatry 2023; 28:1557-1570. [PMID: 36750736 DOI: 10.1038/s41380-023-01987-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/18/2023] [Accepted: 01/30/2023] [Indexed: 02/09/2023]
Abstract
Dysregulated neurite outgrowth and synapse formation underlie many psychiatric disorders, which are also manifested by wolfram syndrome (WS). Whether and how the causative gene WFS1 deficiency affects synapse formation remain elusive. By mirroring human brain development with cerebral organoids, WFS1-deficient cerebral organoids not only recapitulate the neuronal loss in WS patients, but also exhibit significantly impaired synapse formation and function associated with reduced astrocytes. WFS1 deficiency in neurons autonomously delays neuronal differentiation with altered expressions of genes associated with psychiatric disorders, and impairs neurite outgrowth and synapse formation with elevated cytosolic calcium. Intriguingly, WFS1 deficiency in astrocytes decreases the expression of glutamate transporter EAAT2 by NF-κB activation and induces excessive glutamate. When co-cultured with wildtype neurons, WFS1-deficient astrocytes lead to impaired neurite outgrowth and increased cytosolic calcium in neurons. Importantly, disrupted synapse formation and function in WFS1-deficient cerebral organoids and impaired neurite outgrowth affected by WFS1-deficient astrocytes are efficiently reversed with Riluzole treatment, by restoring EAAT2 expression in astrocytes. Furthermore, Riluzole rescues the depressive-like behavior in the forced swimming test and the impaired recognition and spatial memory in the novel object test and water maze test in Wfs1 conditional knockout mice. Altogether, our study provides novel insights into how WFS1 deficiency affects synapse formation and function, and offers a strategy to treat this disease.
Collapse
Affiliation(s)
- Fei Yuan
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.,Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266071, China
| | - Yana Li
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.,University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Rui Hu
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.,Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266071, China
| | - Mengting Gong
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.,Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266071, China
| | - Mengyao Chai
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.,Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266071, China
| | - Xuefei Ma
- QuietD Biotechnology, Ltd., Shanghai, 201210, China
| | - Jiaxue Cha
- Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Pan Guo
- Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Kaijiang Yang
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.,Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266071, China
| | - Mushan Li
- Department of Statistics, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Minglu Xu
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.,Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266071, China
| | - Qing Ma
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.,Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266071, China
| | - Qiang Su
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.,Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266071, China
| | - Chuan Zhang
- School of Medicine, Tongji University, Shanghai, 200092, China
| | - Zhejin Sheng
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.,Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266071, China
| | - Heng Wu
- Department of Psychosomatic Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, Shanghai, 200092, China
| | - Yuan Wang
- Department of Neurology and Department of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu, Sichuan, 610041, China
| | - Wen Yuan
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA
| | - Shan Bian
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.,Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266071, China
| | - Li Shao
- Department of VIP Clinic, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200092, China
| | - Ru Zhang
- Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Kaicheng Li
- QuietD Biotechnology, Ltd., Shanghai, 201210, China
| | - Zhen Shao
- CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China.
| | - Zhen-Ning Zhang
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. .,Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266071, China.
| | - Weida Li
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China. .,Tsingtao Advanced Research Institute, Tongji University, Qingdao, 266071, China. .,Reg-Verse Therapeutics (Shanghai) Co. Ltd., Shanghai, 200120, China.
| |
Collapse
|
|
9
|
Silva-Parra J, Sandu C, Felder-Schmittbuhl MP, Hernández-Kelly LC, Ortega A. Aryl Hydrocarbon Receptor in Glia Cells: A Plausible Glutamatergic Neurotransmission Orchestrator. Neurotox Res 2023; 41:103-117. [PMID: 36607593 DOI: 10.1007/s12640-022-00623-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 11/23/2022] [Accepted: 12/15/2022] [Indexed: 01/07/2023]
Abstract
Glutamate is the major excitatory amino acid in the vertebrate brain. Glutamatergic signaling is involved in most of the central nervous system functions. Its main components, namely receptors, ion channels, and transporters, are tightly regulated at the transcriptional, translational, and post-translational levels through a diverse array of extracellular signals, such as food, light, and neuroactive molecules. An exquisite and well-coordinated glial/neuronal bidirectional communication is required for proper excitatory amino acid signal transactions. Biochemical shuttles such as the glutamate/glutamine and the astrocyte-neuronal lactate represent the fundamental involvement of glial cells in glutamatergic transmission. In fact, the disruption of any of these coordinated biochemical intercellular cascades leads to an excitotoxic insult that underlies some aspects of most of the neurodegenerative diseases characterized thus far. In this contribution, we provide a comprehensive summary of the involvement of the Aryl hydrocarbon receptor, a ligand-dependent transcription factor in the gene expression regulation of glial glutamate transporters. These receptors might serve as potential targets for the development of novel strategies for the treatment of neurodegenerative diseases.
Collapse
Affiliation(s)
- Janisse Silva-Parra
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. IPN 2508, San Pedro Zacatenco, 07360, CDMX, México
| | - Cristina Sandu
- Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives, Université de Strasbourg, Strasbourg, France
| | - Marie-Paule Felder-Schmittbuhl
- Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives, Université de Strasbourg, Strasbourg, France
| | - Luisa C Hernández-Kelly
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. IPN 2508, San Pedro Zacatenco, 07360, CDMX, México
| | - Arturo Ortega
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Av. IPN 2508, San Pedro Zacatenco, 07360, CDMX, México.
| |
Collapse
|
|
10
|
Li M, Yu J, Deng H, Xie S, Li Q, Zhao Y, Yin S, Ji YF. Upregulation of glutamate transporter 1 by mTOR/Akt pathway in astrocyte culture during oxygen-glucose deprivation and reoxygenation. Exp Brain Res 2023; 241:201-209. [PMID: 36436003 DOI: 10.1007/s00221-022-06514-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 11/16/2022] [Indexed: 11/28/2022]
Abstract
Astrocyte-specific glutamate transporter subtype 1 (GLT-1) plays an important role in influencing glutamate excitatory toxicity and preventing the death of excitatory toxic neurons. Although the mammalian target of rapamycin (mTOR)/protein kinase B(Akt)/nuclear factor kappa B signaling cascade is involved in the upregulation of astrocytic GLT-1 in oxygen-glucose deprivation (OGD), it is unclear whether the mTOR/Akt pathway is involved in astrocytic GLT-1 upregulation in OGD and reoxygenation (OGD/R). In this study, we found that the treatment of cultured astrocytes with rapamycin and triciribine led to the decreased astrocytes' protrusions, smaller nuclei, and an increased apoptotic rate. The inhibitors of mTOR complex 1 significantly increased the expression levels of phosphorylated Akt-Ser473 (p-Akt), phosphorylated Akt-Thr308(p-Akt), and GLT-1, while Akt-specific inhibitors blocked GLT-1 expression, suggesting that the mTOR/Akt pathway is involved in GLT-1 upregulation. We further demonstrated that astrocytes under OGD/R adapted to environmental changes through the mTOR/Akt pathway, mainly by altering cell morphology and apoptosis and upregulating the expression levels of p-Akt and GLT-1. Our results suggested that astrocytes may adapt to short-term ischemic-reperfusion injury by regulating cell morphology, apoptosis and GLT-1 upregulation.
Collapse
Affiliation(s)
- Mi Li
- Department of Neurology, Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
- Department of Neurology, Yilong County People's Hospital, Nanchong, Sichuan, People's Republic of China
| | - Jingmei Yu
- Department of Neurology, Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Huan Deng
- Department of Neurology, Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Shansha Xie
- Department of Neurology, Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Qiuling Li
- Department of Neurology, Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Yuping Zhao
- Department of Neurology, Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Shubin Yin
- Department of Neurology, Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China
| | - Yi-Fei Ji
- Department of Neurology, Second Clinical College, North Sichuan Medical College, Nanchong, Sichuan, People's Republic of China.
| |
Collapse
|
|
11
|
Pajarillo E, Nyarko-Danquah I, Digman A, Multani HK, Kim S, Gaspard P, Aschner M, Lee E. Mechanisms of manganese-induced neurotoxicity and the pursuit of neurotherapeutic strategies. Front Pharmacol 2022; 13:1011947. [PMID: 36605395 PMCID: PMC9808094 DOI: 10.3389/fphar.2022.1011947] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 12/01/2022] [Indexed: 01/07/2023] Open
Abstract
Chronic exposure to elevated levels of manganese via occupational or environmental settings causes a neurological disorder known as manganism, resembling the symptoms of Parkinson's disease, such as motor deficits and cognitive impairment. Numerous studies have been conducted to characterize manganese's neurotoxicity mechanisms in search of effective therapeutics, including natural and synthetic compounds to treat manganese toxicity. Several potential molecular targets of manganese toxicity at the epigenetic and transcriptional levels have been identified recently, which may contribute to develop more precise and effective gene therapies. This review updates findings on manganese-induced neurotoxicity mechanisms on intracellular insults such as oxidative stress, inflammation, excitotoxicity, and mitophagy, as well as transcriptional dysregulations involving Yin Yang 1, RE1-silencing transcription factor, transcription factor EB, and nuclear factor erythroid 2-related factor 2 that could be targets of manganese neurotoxicity therapies. This review also features intracellular proteins such as PTEN-inducible kinase 1, parkin, sirtuins, leucine-rich repeat kinase 2, and α-synuclein, which are associated with manganese-induced dysregulation of autophagy/mitophagy. In addition, newer therapeutic approaches to treat manganese's neurotoxicity including natural and synthetic compounds modulating excitotoxicity, autophagy, and mitophagy, were reviewed. Taken together, in-depth mechanistic knowledge accompanied by advances in gene and drug delivery strategies will make significant progress in the development of reliable therapeutic interventions against manganese-induced neurotoxicity.
Collapse
Affiliation(s)
- Edward Pajarillo
- Department of Pharmaceutical Science, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, United States
| | - Ivan Nyarko-Danquah
- Department of Pharmaceutical Science, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, United States
| | - Alexis Digman
- Department of Pharmaceutical Science, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, United States
| | - Harpreet Kaur Multani
- Department of Biology, College of Science and Technology, Florida A&M University, Tallahassee, FL, United States
| | - Sanghoon Kim
- Department of Pharmaceutical Science, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, United States
| | - Patric Gaspard
- Department of Pharmaceutical Science, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, United States
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, NY, United States
| | - Eunsook Lee
- Department of Pharmaceutical Science, College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, United States
| |
Collapse
|
|
12
|
Tibolone Pre-Treatment Ameliorates the Dysregulation of Protein Translation and Transport Generated by Palmitic Acid-Induced Lipotoxicity in Human Astrocytes: A Label-Free MS-Based Proteomics and Network Analysis. Int J Mol Sci 2022; 23:ijms23126454. [PMID: 35742897 PMCID: PMC9223656 DOI: 10.3390/ijms23126454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/27/2022] [Accepted: 05/30/2022] [Indexed: 01/27/2023] Open
Abstract
Excessive accumulation and release of fatty acids (FAs) in adipose and non-adipose tissue are characteristic of obesity and are associated with the leading causes of death worldwide. Chronic exposure to high concentrations of FAs such as palmitic acid (pal) is a risk factor for developing different neurodegenerative diseases (NDs) through several mechanisms. In the brain, astrocytic dysregulation plays an essential role in detrimental processes like metabolic inflammatory state, oxidative stress, endoplasmic reticulum stress, and autophagy impairment. Evidence shows that tibolone, a synthetic steroid, induces neuroprotective effects, but its molecular mechanisms upon exposure to pal remain largely unknown. Due to the capacity of identifying changes in the whole data-set of proteins and their interaction allowing a deeper understanding, we used a proteomic approach on normal human astrocytes under supraphysiological levels of pal as a model to induce cytotoxicity, finding changes of expression in proteins related to translation, transport, autophagy, and apoptosis. Additionally, tibolone pre-treatment showed protective effects by restoring those same pal-altered processes and increasing the expression of proteins from cell survival processes. Interestingly, ARF3 and IPO7 were identified as relevant proteins, presenting a high weight in the protein-protein interaction network and significant differences in expression levels. These proteins are related to transport and translation processes, and their expression was restored by tibolone. This work suggests that the damage caused by pal in astrocytes simultaneously involves different mechanisms that the tibolone can partially revert, making tibolone interesting for further research to understand how to modulate these damages.
Collapse
|
|
13
|
High-fat diet induces depression-like phenotype via astrocyte-mediated hyperactivation of ventral hippocampal glutamatergic afferents to the nucleus accumbens. Mol Psychiatry 2022; 27:4372-4384. [PMID: 36180573 PMCID: PMC9734059 DOI: 10.1038/s41380-022-01787-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 09/05/2022] [Accepted: 09/09/2022] [Indexed: 12/14/2022]
Abstract
Comorbidity exists between metabolic disorders and depressive syndrome with unclear mechanisms. To characterize the causal relationship, we adopted a 12-week high-fat diet (HFD) to induce metabolic disorder and depressive phenotypes in mice. Initially, we identified an enhanced glutamatergic input in the nucleus accumbens of HFD mice. Retrograde tracing and chemogenetic inhibition showed that the hyperactive ventral hippocampal glutamatergic afferents to the nucleus accumbens determined the exhibition of depression-like behavior in HFD mice. Using lentiviral knockdown and overexpression approaches, we proved that HFD-induced downregulation of glial glutamate transporters, GLAST and GLT-1, contributed to the observed circuit maladaptations and subsequent depression-like behaviors. Finally, we identified a potential therapeutic agent, riluzole, which could mitigate the HFD-induced behavioral deficits by normalizing the expressions of GLAST and GLT-1 and ventral hippocampal glutamatergic afferents to the nucleus accumbens. Overall, astrocyte-mediated disturbance in glutamatergic transmission underlies the metabolic disorder-related depressive syndrome and represents a therapeutic target for this subtype of depressive mood disorders.
Collapse
|
|
14
|
Critical Involvement of Glial Cells in Manganese Neurotoxicity. BIOMED RESEARCH INTERNATIONAL 2021; 2021:1596185. [PMID: 34660781 PMCID: PMC8514895 DOI: 10.1155/2021/1596185] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 09/16/2021] [Accepted: 09/21/2021] [Indexed: 12/13/2022]
Abstract
Over the years, most of the research concerning manganese exposure was restricted to the toxicity of neuronal cells. Manganese is an essential trace element that in high doses exerts neurotoxic effects. However, in the last two decades, efforts have shifted toward a more comprehensive approach that takes into account the involvement of glial cells in the development of neurotoxicity as a brain insult. Glial cells provide structural, trophic, and metabolic support to neurons. Nevertheless, these cells play an active role in adult neurogenesis, regulation of synaptogenesis, and synaptic plasticity. Disturbances in glial cell function can lead to neurological disorders, including neurodegenerative diseases. This review highlights the pivotal role that glial cells have in manganese-induced neurotoxicity as well as the most sounding mechanisms involved in the development of this phenomenon.
Collapse
|
|
15
|
Sun YW, Zhang LY, Gong SJ, Hu YY, Zhang JG, Xian XH, Li WB, Zhang M. The p38 MAPK/NF-κB pathway mediates GLT-1 up-regulation during cerebral ischemic preconditioning-induced brain ischemic tolerance in rats. Brain Res Bull 2021; 175:224-233. [PMID: 34343641 DOI: 10.1016/j.brainresbull.2021.07.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 07/25/2021] [Accepted: 07/29/2021] [Indexed: 10/20/2022]
Abstract
Our previous finding suggests that p38 MAPK contributes to the GLT-1 upregulation during induction of brain ischemic tolerance by cerebral ischemic preconditioning (CIP), however, the underlying mechanism is still unclear. Here, we investigated the molecular mechanisms underlying the CIP-induced GLT-1 upregulation by using Western blotting, Co-immunoprecipitation (Co-IP), electrophoretic mobility shift assay (EMSA) and thionin staining in rat hippocampus CA1 subset. We found that application of BAY11-7082 (an inhibitor of NF-κB), or dihydrokainate (an inhibitor of GLT-1), or SB203580 (an inhibitor of p38 MAPK) could attenuate the CIP-induced neuronal protection in hippocampus CA1 region of rats. Moreover, CIP caused rapid activation of NF-κB, as evidenced by nuclear translocation of NF-κB p50 protein, which led to active p50/p65 dimer formation and increased DNA binding activity. GLT-1 was also increased after CIP. Pretreatment with BAY11-7082 blocked the CIP-induced GLT-1 upregulation. The above results suggest that NF-κB participates in GLT-1 up-regulation during the induction of brain ischemic tolerance by CIP. We also found that pretreatment with SB203580 caused significant reduction of NF-κB p50 protein in nucleus, NF-κB p50/p65 dimer nuclear translocation and DNA binding activity of NF-κB. Together, we conclude that p38 MAPK/NF-κB pathway participates in the mediation of GLT-1 up-regulation during the induction of brain ischemic tolerance induced by CIP.
Collapse
Affiliation(s)
- Ya-Wei Sun
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China; Xing Tai People's Hospital, 16 Hong Xing Road, Xing Tai, 054001, People's Republic of China
| | - Ling-Yan Zhang
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China; Hebei Key Laboratory of Critical Disease Mechanism and Intervention, People's Republic of China
| | - Shu-Juan Gong
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China
| | - Yu-Yan Hu
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China; Hebei Key Laboratory of Critical Disease Mechanism and Intervention, People's Republic of China
| | - Jing-Ge Zhang
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China; Hebei Key Laboratory of Critical Disease Mechanism and Intervention, People's Republic of China
| | - Xiao-Hui Xian
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China; Hebei Key Laboratory of Critical Disease Mechanism and Intervention, People's Republic of China
| | - Wen-Bin Li
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China; Hebei Key Laboratory of Critical Disease Mechanism and Intervention, People's Republic of China
| | - Min Zhang
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China; Hebei Key Laboratory of Critical Disease Mechanism and Intervention, People's Republic of China.
| |
Collapse
|
|
16
|
Rodríguez-Campuzano AG, Ortega A. Glutamate transporters: Critical components of glutamatergic transmission. Neuropharmacology 2021; 192:108602. [PMID: 33991564 DOI: 10.1016/j.neuropharm.2021.108602] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/09/2021] [Accepted: 04/27/2021] [Indexed: 02/06/2023]
Abstract
Glutamate is the major excitatory neurotransmitter in the vertebrate central nervous system. Once released, it binds to specific membrane receptors and transporters activating a wide variety of signal transduction cascades, as well as its removal from the synaptic cleft in order to avoid its extracellular accumulation and the overstimulation of extra-synaptic receptors that might result in neuronal death through a process known as excitotoxicity. Although neurodegenerative diseases are heterogenous in clinical phenotypes and genetic etiologies, a fundamental mechanism involved in neuronal degeneration is excitotoxicity. Glutamate homeostasis is critical for brain physiology and Glutamate transporters are key players in maintaining low extracellular Glutamate levels. Therefore, the characterization of Glutamate transporters has been an active area of glutamatergic research for the last 40 years. Transporter activity its regulated at different levels: transcriptional and translational control, transporter protein trafficking and membrane mobility, and through extensive post-translational modifications. The elucidation of these mechanisms has emerged as an important piece to shape our current understanding of glutamate actions in the nervous system.
Collapse
Affiliation(s)
- Ada G Rodríguez-Campuzano
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, Ciudad de México, 07000, Mexico
| | - Arturo Ortega
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, Ciudad de México, 07000, Mexico.
| |
Collapse
|
|
17
|
Yuan LJ, Zhang M, Chen S, Chen WF. Anti-inflammatory effect of IGF-1 is mediated by IGF-1R cross talk with GPER in MPTP/MPP +-induced astrocyte activation. Mol Cell Endocrinol 2021; 519:111053. [PMID: 33035625 DOI: 10.1016/j.mce.2020.111053] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 10/02/2020] [Accepted: 10/04/2020] [Indexed: 12/17/2022]
Abstract
Insulin-like growth factor-1 (IGF-1) is a potent neuroprotective polypeptide that exerts neuroprotective effects via the IGF-1 receptor (IGF-1R). Our previous study reported that G protein-coupled estrogen receptor (GPER) was involved in the anti-apoptotic effect of IGF-1. The present study was designed to investigate the anti-inflammatory effect of IGF-1 in association with astrocyte activation and the molecular details of the interaction between IGF-1R and GPER. We showed that IGF-1 could improve 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor deficits and attenuate the upregulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) both in vivo and in vitro. The IGF-1R antagonist JB-1 and the GPER antagonist G15 could antagonize the anti-inflammatory effect of IGF-1. Silencing GPER abrogated the inhibitory effect of IGF-1 on 1-methyl-4-phenylpyridinium (MPP+)-induced upregulation of COX-2 and iNOS in primary astrocytes. Moreover, the MPP + -induced inflammatory response was related to the activation of mitogen-activated protein kinases (MAPKs) and NF-κB signaling pathways. The inhibitory effects of IGF-1 on the phosphorylation of p38, JNK and IκB could be blocked by JB-1. G15 antagonized the inhibitory effects of IGF-1 on p-JNK and p-IκB, but not p-p38. Furthermore, IGF-1 treatment alone increased the expression of GPER, which was blocked by JB-1, the phosphatidylinositol 3-kinase (PI3-K) antagonist LY294002 and the MEK antagonist PD98059 in primary astrocytes. Overall, we show for the first time that GPER may contribute to the anti-inflammatory effect of IGF-1 against MPTP/MPP + -induced astrocyte activation. IGF-1 could regulate the expression of GPER via the IGF-1R/PI3-K/MAPK signaling pathway in primary astrocytes.
Collapse
MESH Headings
- 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
- 1-Methyl-4-phenylpyridinium/toxicity
- Animals
- Anti-Inflammatory Agents/pharmacology
- Astrocytes/drug effects
- Astrocytes/metabolism
- Behavior, Animal
- Benzodioxoles/pharmacology
- Cells, Cultured
- Cyclooxygenase 2/genetics
- Cyclooxygenase 2/metabolism
- Humans
- Insulin-Like Growth Factor I/pharmacology
- MAP Kinase Signaling System/drug effects
- Male
- Mice, Inbred C57BL
- NF-kappa B/metabolism
- Nitric Oxide Synthase Type II/genetics
- Nitric Oxide Synthase Type II/metabolism
- Phosphatidylinositol 3-Kinases/metabolism
- Phosphorylation/drug effects
- Quinolines/pharmacology
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Receptor, IGF Type 1/metabolism
- Receptors, Estrogen/metabolism
- Receptors, G-Protein-Coupled/metabolism
- Substantia Nigra/metabolism
- Up-Regulation/drug effects
- Mice
Collapse
Affiliation(s)
- Liang-Jie Yuan
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China; School of Basic Medicine, Shandong First Medical University & Shandong Academy of Medical Sciences, Taian, 271000, China
| | - Mei Zhang
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Su Chen
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Wen-Fang Chen
- Department of Physiology, Shandong Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, China.
| |
Collapse
|
|
18
|
Xian XH, Gao JX, Qi J, Fan SJ, Zhang M, Li WB. Activation of p38 MAPK participates in the sulbactam-induced cerebral ischemic tolerance mediated by glial glutamate transporter-1 upregulation in rats. Sci Rep 2020; 10:20601. [PMID: 33244020 PMCID: PMC7692545 DOI: 10.1038/s41598-020-77583-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Accepted: 11/12/2020] [Indexed: 12/13/2022] Open
Abstract
Our previous studies have shown that sulbactam can play a neuroprotection role in hippocampal neurons by upregulating the expression and function of glial glutamate transporter-1 (GLT-1) during ischemic insult. Here, using rat global cerebral ischemia model, we studied in vivo the role of p38 mitogen-activated protein kinases (MAPK) in the sulbactam-induced GLT-1 upregulation and neuroprotection against ischemia. The hippocampal CA1 field was selected as observing target. The expressions of phosphorylated-p38 MAPK and GLT-1 were assayed with western blot analysis and immunohistochemistry. The condition of delayed neuronal death (DND) was assayed with neuropathological evaluation under thionin staining. It was shown that administration of sulbactam protected CA1 hippocampal neurons against ischemic insult accompanied with significantly upregulation in the expressions of phosphorylated-p38 MAPK and GLT-1. The time course analysis showed that sulbactam activated p38 MAPK before the GLT-1 upregulation in either normal or global cerebral ischemic rats. Furthermore, inhibiting p38 MAPK activation by SB203580 blocked the GLT-1 upregulation and neuroprotection induced by sulbactam. The above results suggested that p38 MAPK, at least partly, participated in the sulbactam-induced brain tolerance to ischemia mediated by GLT-1 upregulation in rats.
Collapse
Affiliation(s)
- Xiao-Hui Xian
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China
| | - Jun-Xia Gao
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China
| | - Jie Qi
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China
| | - Shu-Juan Fan
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China
| | - Min Zhang
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China. .,Neuroscience Research Center of Hebei Medical University, Shijiazhuang, People's Republic of China.
| | - Wen-Bin Li
- Department of Pathophysiology, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang, 050017, People's Republic of China. .,Neuroscience Research Center of Hebei Medical University, Shijiazhuang, People's Republic of China.
| |
Collapse
|
|
19
|
Mehkari Z, Mohammed L, Javed M, Althwanay A, Ahsan F, Oliveri F, Goud HK, Rutkofsky IH. Manganese, a Likely Cause of 'Parkinson's in Cirrhosis', a Unique Clinical Entity of Acquired Hepatocerebral Degeneration. Cureus 2020; 12:e10448. [PMID: 33072457 PMCID: PMC7557798 DOI: 10.7759/cureus.10448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
With idiopathic Parkinson's disease being a common entity, parkinsonism in acquired hepatocerebral degeneration (AHD) in the context of Manganese (Mn) has gained importance in recent years. An insight into the pathomechanisms behind this disease has been put forth. How can Mn as a divalent metal exert its effect in leading to chronic neurodegenerative disorder? Secondary to decreased excretion in liver cirrhosis, Mn significantly alters the striatal dopaminergic system. Management of this debilitating disease also focuses on different aspects where Mn has been involved in the pathogenesis. We have put forth the details behind Mn effects in Parkinson’s, which will be a guide for better understanding and management of this disease. A literature search was performed using PubMed as a sole database, and all the articles were peer-reviewed. The author tried to follow the PRISMA guidelines. Inclusion criteria were set for 10 years, with most studies with in the last seven years. All types of study designs were included relevant to the topic, clearly delineating the pathomechanisms of Mn in the disease and also its management. After extensive research, through the PubMed database, we found that Parkinson's disease is one of the neurological complications in advanced liver cirrhosis. Mn is an essential element behind its pathogenesis; it works at different cellular levels to promote neurotoxicity. From its influx to its effects on dopamine transporters (DAT), where it disrupts dopamine homeostasis also altering postsynaptic dopamine (D2) receptors, it disrupts mitochondria and the endoplasmic reticulum (ER) promotes oxidative stress and neuroinflammation. Misfolding of alpha-synuclein (α-Syn) is promoted on chronic exposure to Mn where α-Syn from being neuroprotective becomes neurotoxic. It also alters glutaminergic and gabaergic neurotransmission. In a nutshell, the diversity of its effect on nigrostriatal denervation is challenging. The importance of neuroimaging and various approaches to management is also discussed. AHD, an uncommon entity in advanced liver cirrhosis, needs more awareness so that it can be diagnosed earlier and better therapeutic options can be sought. Our study highlighted Mn mechanisms behind this clinical entity, putting forth grounds for a better understanding of this disease. Advanced research targeting Mn for managing this disease will be revolutionary.
Collapse
Affiliation(s)
- Zainab Mehkari
- Internal Medicine, California Institute of Behavioral Neuroscience & Psychology, Fairfield, USA
| | - Lubna Mohammed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Moiz Javed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Aldanah Althwanay
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Farah Ahsan
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Federico Oliveri
- Cardiology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Harshit K Goud
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ian H Rutkofsky
- Psychiatry, Neuroscience, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| |
Collapse
|
|
20
|
Tibolone Ameliorates the Lipotoxic Effect of Palmitic Acid in Normal Human Astrocytes. Neurotox Res 2020; 38:585-595. [DOI: 10.1007/s12640-020-00247-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 06/13/2020] [Accepted: 06/17/2020] [Indexed: 02/06/2023]
|
|
21
|
Yang F, Wang H, Chen H, Ran D, Tang Q, Weng P, Sun Y, Jiang W. RAGE Signaling pathway in hippocampus dentate gyrus involved in GLT-1 decrease induced by chronic unpredictable stress in rats. Brain Res Bull 2020; 163:49-56. [PMID: 32621862 DOI: 10.1016/j.brainresbull.2020.06.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 06/17/2020] [Accepted: 06/28/2020] [Indexed: 11/26/2022]
Abstract
A pivotal role of glutamatergic neurotransmission in the pathophysiology of major depressive disorder (MDD) has been supported in preclinical and clinical studies. Glutamate transporters are responsible for rapid uptake of glutamate to maintain glutamate homeostasis. Down-regulation of glutamate transporters has been reported in MDD patients and animal models. However, the mechanism for stress-induced modulation of glutamate transporter expression is poorly understood. Receptor for advanced glycosylation end products (RAGE), a member of immunoglobulin family, is found expressed widely in brain and play important roles in neuronal development, neurite growth, neurogenesis and neuroinflammation. Our study showed chronic unpredictable stress (CUS) induced depressive-like behaviors and reduced RAGE expression in hippocampus DG, CA1 and CA3 areas. The protein levels of GLT-1, p-CREB and p-p65 decreased in hippocampus DG as well. Knockdown of RAGE expression in hippocampus DG with RAGE shRNA lentivirus particles induced depressive-like behaviors. Meanwhile, the protein and mRNA levels of GLT-1 were significantly decreased as well as phosphorylation of CREB and p65. Neither CUS nor RAGE knockdown altered GLAST protein and mRNA levels. These findings suggested that RAGE/CREB-NF-κB signaling pathway in hippocampus DG involved in modulation of GLT-1 expression, which possibly contributed to the depressive-like behavior induced by CUS.
Collapse
Affiliation(s)
- Fang Yang
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Hong Wang
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Huali Chen
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Dongzhi Ran
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Qiang Tang
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Ping Weng
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Yuzhuo Sun
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China
| | - Wengao Jiang
- Key Laboratory of Molecular and Biochemical Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing, China.
| |
Collapse
|
|
22
|
Neuroprotective Effects of Emodin against Ischemia/Reperfusion Injury through Activating ERK-1/2 Signaling Pathway. Int J Mol Sci 2020; 21:ijms21082899. [PMID: 32326191 PMCID: PMC7215870 DOI: 10.3390/ijms21082899] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 04/11/2020] [Accepted: 04/16/2020] [Indexed: 01/28/2023] Open
Abstract
Background: Stroke is one of the leading causes of death and disability worldwide and places a heavy burden on the economy in our society. Current treatments, such as the use of thrombolytic agents, are often limited by a narrow therapeutic time window. However, the regeneration of the brain after damage is still active days, even weeks, after stroke occurs, which might provide a second window for treatment. Emodin, a traditional Chinese medicinal herb widely used to treat acute hepatitis, has been reported to possess antioxidative capabilities and protective effects against myocardial ischemia/reperfusion injury. However, the underlying mechanisms and neuroprotective functions of Emodin in a rat middle cerebral artery occlusion (MCAO) model of ischemic stroke remain unknown. This study investigates neuroprotective effects of Emodin in ischemia both in vitro and in vivo. Methods: PC12 cells were exposed to oxygen-glucose deprivation to simulate hypoxic injury, and the involved signaling pathways and results of Emodin treatment were evaluated. The therapeutic effects of Emodin in ischemia animals were further investigated. Results: Emodin reduced infarct volume and cell death following focal cerebral ischemia injury. Emodin treatment restored PC12 cell viability and reduced reactive oxygen species (ROS) production and glutamate release under conditions of ischemia/hypoxia. Emodin increased Bcl-2 and glutamate transporter-1 (GLT-l) expression but suppressed activated-caspase 3 levels through activating the extracellular signal-regulated kinase (ERK)-1/2 signaling pathway. Conclusion: Emodin induced Bcl-2 and GLT-1 expression to inhibit neuronal apoptosis and ROS generation while reducing glutamate toxicity via the ERK-1/2 signaling pathway. Furthermore, Emodin alleviated nerve cell injury following ischemia/reperfusion in a rat MCAO model. Emodin has neuroprotective effects against ischemia/reperfusion injury both in vitro and in vivo, which may be through activating the ERK-1/2 signaling pathway.
Collapse
|
|
23
|
Adenosine Receptor A1-A2a Heteromers Regulate EAAT2 Expression and Glutamate Uptake via YY1-Induced Repression of PPAR γ Transcription. PPAR Res 2020; 2020:2410264. [PMID: 32206061 PMCID: PMC7079221 DOI: 10.1155/2020/2410264] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 01/23/2020] [Indexed: 12/29/2022] Open
Abstract
Adenosine receptors A1 (A1AR) and A2a (A2aAR) play an important role in regulating glutamate uptake to avoid glutamate accumulation that causes excitotoxicity in the brain; however, the precise mechanism of the effects of A1AR and A2aAR is unclear. Herein, we report that expression of the A1AR protein in the astrocyte membrane and the level of intracellular glutamate were decreased, while expression of the A2aR protein was elevated in cells exposed to oxygen-glucose deprivation (OGD) conditions. Coimmunoprecipitation (Co-IP) experiments showed that A1AR interacts with A2aAR under OGD conditions. The activation of A1AR and inactivation of A2aAR by 2-chloro-N6-cyclopentyladenosine (CCPA) and SCH58251, respectively, partly reversed OGD-mediated glutamate uptake dysfunction, elevated EAAT2, and PPARγ protein levels, and suppressed the expression of Ying Yang 1 (YY1). Both the silencing of YY1 and the activation of PPARγ upregulated EAAT2 expression. Moreover, YY1 silencing elevated the PPARγ level under both normal and OGD conditions. Histone deacetylase (HDAC)1 was found to interact with YY1, and HDAC1 silencing improved PPARγ promoter activity. Taken together, our findings suggest that A1AR-A2aAR heteromers regulate EAAT2 expression and glutamate uptake through the YY1-mediated recruitment of HDAC1 to the PPARγ promoter region.
Collapse
|
|
24
|
Pottoo FH, Tabassum N, Javed MN, Nigar S, Sharma S, Barkat MA, Alam MS, Ansari MA, Barreto GE, Ashraf GM. Raloxifene potentiates the effect of fluoxetine against maximal electroshock induced seizures in mice. Eur J Pharm Sci 2020; 146:105261. [PMID: 32061655 DOI: 10.1016/j.ejps.2020.105261] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 01/24/2020] [Accepted: 02/07/2020] [Indexed: 01/17/2023]
Abstract
The evidence to guide clinicians regarding rationale polytherapy with current antiepileptic drugs (AEDs) is lacking, and current practice recommendations are largely empirical. The excessive drug loading with combinatorial therapies of existing AEDs are associated with escalated neurotoxicity, and that emergence of pharmacoresistant seizures couldn't be averted. In pursuit of judicious selection of novel AEDs in combinatorial therapies with mechanism based evidences, standardized dose of raloxifene, fluoxetine, bromocriptine and their low dose combinations, were experimentally tested for their impact on maximal electroshock (MES) induced tonic hind limb extension (THLE) in mice. Hippocampal neuropeptide Y (NPY) levels, oxidative stress and histopathological studies were undertaken. The results suggest the potentiating effect of 4 mg/kg raloxifene on 14 mg/kg fluoxetine against MES induced THLE, as otherwise monotherapy with 4 mg/kg raloxifene was unable to produce an effect. The results also depicted better efficacy than carbamazepine (20 mg/kg), standard AED. Most profoundly, MES-induced significant (P < 0.001) reduction in hippocampal NPY levels, that were escalated insignificantly with the duo-drug combination, suggesting some other mechanism in mitigation of electroshock induced seizures. These results were later corroborated with assays to assess oxidative stress and neuronal damage. In conclusion, the results demonstrated the propitious therapeutic benefit of duo-drug low dose combination of drugs; raloxifene and fluoxetine, with diverse mode of actions fetching greater effectiveness in the management of generalized tonic clonic seizures (GTCS).
Collapse
Affiliation(s)
- Faheem Hyder Pottoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O.BOX 1982, Dammam, 31441 Saudi Arabia.
| | - Nahida Tabassum
- Department of Pharmaceutical Sciences, Faculty of Applied Sc. and Tech, University of Kashmir, Srinagar, India.
| | - Md Noushad Javed
- Department of Pharmaceutics, School of Pharmaceutical Sciences and Research, Jamia Hamdard University, New Delhi, India; School of Pharmaceutical Sciences, Apeejay Stya University, Gurugram, Haryana, India
| | - Shah Nigar
- Department of Pharmaceutical Sciences, Faculty of Applied Sc. and Tech, University of Kashmir, Srinagar, India
| | - Shrestha Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, K.R.Mangalam University, Gurgaon, India
| | - Md Abul Barkat
- Department of Pharmaceutics, College of Pharmacy, University of Hafr Al Batin, Al Jamiah, Hafr Al Batin 39524, Saudi Arabia
| | - Md Sabir Alam
- Department of Pharmacy, School of Medical and Allied Sciences, K.R.Mangalam University, Gurgaon, India
| | - Mohammad Azam Ansari
- Department of Epidemic Disease Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O.BOX 1982, Dammam, 31441 Saudi Arabia
| | - George E Barreto
- Department of Biological Sciences, University of Limerick, Limerick, Ireland; Health Research Institute, University of Limerick, Ireland.
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia.
| |
Collapse
|
|
25
|
Wang XS, Yue J, Hu LN, Tian Z, Zhang K, Yang L, Zhang HN, Guo YY, Feng B, Liu HY, Wu YM, Zhao MG, Liu SB. Activation of G protein-coupled receptor 30 protects neurons by regulating autophagy in astrocytes. Glia 2020; 68:27-43. [PMID: 31429156 DOI: 10.1002/glia.23697] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 07/23/2019] [Accepted: 07/24/2019] [Indexed: 12/24/2022]
Abstract
Ischemic stroke leads to neuronal damage induced by excitotoxicity, inflammation, and oxidative stress. Astrocytes play diverse roles in stroke and ischemia-induced inflammation, and autophagy is critical for maintaining astrocytic functions. Our previous studies showed that the activation of G protein-coupled receptor 30 (GPR30), an estrogen membrane receptor, protected neurons from excitotoxicity. However, the role of astrocytic GPR30 in maintaining autophagy and neuroprotection remained unclear. In this study, we found that the neuroprotection induced by G1 (GPR30 agonist) in wild-type mice after a middle cerebral artery occlusion was completely blocked in GPR30 conventional knockout (KO) mice but partially attenuated in astrocytic or neuronal GPR30 KO mice. In cultured primary astrocytes, glutamate exposure induced astrocyte proliferation and decreased astrocyte autophagy by activating mammalian target of rapamycin (mTOR) and c-Jun N-terminal kinase (JNK) and inhibiting p38 mitogen-activated protein kinase (MAPK) pathway. G1 treatment restored autophagy to its basal level by regulating the p38 pathway but not the mTOR and JNK signaling pathways. Our findings revealed a key role of GPR30 in neuroprotection via the regulation of astrocyte autophagy and support astrocytic GPR30 as a potential drug target against ischemic brain damage.
Collapse
Affiliation(s)
- Xin-Shang Wang
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.,Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Jiao Yue
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.,Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Li-Ning Hu
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.,Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhen Tian
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.,Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.,Department of Pharmacy, The 154th Central Hospital of PLA, Xinyang, China
| | - Kun Zhang
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.,Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Le Yang
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.,Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Hui-Nan Zhang
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.,Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Yan-Yan Guo
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.,Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Bin Feng
- State Key Laboratory of Military Stomatology, Department of pharmacy, School of Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, Xi'an, China
| | - Hai-Yan Liu
- State Key Laboratory of Military Stomatology, Department of pharmacy, School of Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Fourth Military Medical University, Xi'an, China
| | - Yu-Mei Wu
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.,Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Ming-Gao Zhao
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.,Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Shui-Bing Liu
- Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.,Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| |
Collapse
|
|
26
|
Pajarillo E, Rizor A, Lee J, Aschner M, Lee E. The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics. Neuropharmacology 2019; 161:107559. [PMID: 30851309 PMCID: PMC6731169 DOI: 10.1016/j.neuropharm.2019.03.002] [Citation(s) in RCA: 247] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 02/28/2019] [Accepted: 03/02/2019] [Indexed: 12/12/2022]
Abstract
Glutamate is the primary excitatory neurotransmitter in the central nervous system (CNS) which initiates rapid signal transmission in the synapse before its re-uptake into the surrounding glia, specifically astrocytes. The astrocytic glutamate transporters glutamate-aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) and their human homologs excitatory amino acid transporter 1 (EAAT1) and 2 (EAAT2), respectively, are the major transporters which take up synaptic glutamate to maintain optimal extracellular glutamic levels, thus preventing accumulation in the synaptic cleft and ensuing excitotoxicity. Growing evidence has shown that excitotoxicity is associated with various neurological disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), manganism, ischemia, schizophrenia, epilepsy, and autism. While the mechanisms of neurological disorders are not well understood, the dysregulation of GLAST/GLT-1 may play a significant role in excitotoxicity and associated neuropathogenesis. The expression and function of GLAST/GLT-1 may be dysregulated at the genetic, epigenetic, transcriptional or translational levels, leading to high levels of extracellular glutamate and excitotoxicity. Consequently, understanding the regulatory mechanisms of GLAST/GLT-1 has been an area of interest in developing therapeutics for the treatment of neurological disorders. Pharmacological agents including β-lactam antibiotics, estrogen/selective estrogen receptor modulators (SERMs), growth factors, histone deacetylase inhibitors (HDACi), and translational activators have shown significant efficacy in enhancing the expression and function of GLAST/GLT-1 and glutamate uptake both in vitro and in vivo. This comprehensive review will discuss the regulatory mechanisms of GLAST/GLT-1, their association with neurological disorders, and the pharmacological agents which mediate their expression and function. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
Collapse
Affiliation(s)
- Edward Pajarillo
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL, 32301, USA
| | - Asha Rizor
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL, 32301, USA
| | - Jayden Lee
- Department of Speech, Language & Hearing Sciences, Boston University, Boston, MA, 02215, USA
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Eunsook Lee
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL, 32301, USA.
| |
Collapse
|
|
27
|
Malik AR, Willnow TE. Excitatory Amino Acid Transporters in Physiology and Disorders of the Central Nervous System. Int J Mol Sci 2019; 20:ijms20225671. [PMID: 31726793 PMCID: PMC6888459 DOI: 10.3390/ijms20225671] [Citation(s) in RCA: 105] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 11/07/2019] [Accepted: 11/11/2019] [Indexed: 12/12/2022] Open
Abstract
Excitatory amino acid transporters (EAATs) encompass a class of five transporters with distinct expression in neurons and glia of the central nervous system (CNS). EAATs are mainly recognized for their role in uptake of the amino acid glutamate, the major excitatory neurotransmitter. EAATs-mediated clearance of glutamate released by neurons is vital to maintain proper glutamatergic signalling and to prevent toxic accumulation of this amino acid in the extracellular space. In addition, some EAATs also act as chloride channels or mediate the uptake of cysteine, required to produce the reactive oxygen speciesscavenger glutathione. Given their central role in glutamate homeostasis in the brain, as well as their additional activities, it comes as no surprise that EAAT dysfunctions have been implicated in numerous acute or chronic diseases of the CNS, including ischemic stroke and epilepsy, cerebellar ataxias, amyotrophic lateral sclerosis, Alzheimer’s disease and Huntington’s disease. Here we review the studies in cellular and animal models, as well as in humans that highlight the roles of EAATs in the pathogenesis of these devastating disorders. We also discuss the mechanisms regulating EAATs expression and intracellular trafficking and new exciting possibilities to modulate EAATs and to provide neuroprotection in course of pathologies affecting the CNS.
Collapse
Affiliation(s)
- Anna R. Malik
- Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland
- Correspondence:
| | | |
Collapse
|
|
28
|
Maleki N, Androulakis XM. Is There Any MRI Pattern That Discriminates Female From Male Migraine Patients? Front Neurol 2019; 10:961. [PMID: 31551917 PMCID: PMC6747047 DOI: 10.3389/fneur.2019.00961] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 08/21/2019] [Indexed: 12/27/2022] Open
Abstract
There has been accumulating evidence on sex disparity in incidence, prevalence, symptomology, and burden of migraine. Several neuroimaging studies on migraine patients attempted to unravel the mechanisms of the disease, yet very few of them examined the sex-related differences. Here, we will first discuss some of the reported neuroimaging patterns that discriminate females from males in migraine. We will then re-examine the salient neuroimaging findings in migraine and discuss them in relation to sex-related influences. Finally, we will discuss some of the intriguing recent data suggesting the presence of sex-specific traits in migraineurs. These findings may have potential implications for future neuroimaging studies to identify underlying correlating patterns in the brain to (1) explain the neural basis for higher prevalence of migraine in women, and (2) better understand migraine-specific changes during different stages of life in both men and women.
Collapse
Affiliation(s)
- Nasim Maleki
- Psychiatric Neuroimaging Division, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Xiao Michelle Androulakis
- Columbia VA Health Care System, Columbia, SC, United States.,Department of Neurology, School of Public Health, University of South Carolina, Columbia, SC, United States
| |
Collapse
|
|
29
|
Tominna R, Chokr S, Feri M, Chuon T, Sinchak K. Plasma membrane G protein-coupled estrogen receptor 1 (GPER) mediates rapid estradiol facilitation of sexual receptivity through the orphanin-FQ-ORL-1 system in estradiol primed female rats. Horm Behav 2019; 112:89-99. [PMID: 30981690 DOI: 10.1016/j.yhbeh.2019.04.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Revised: 03/26/2019] [Accepted: 04/08/2019] [Indexed: 11/29/2022]
Abstract
In estradiol-primed nonreceptive ovariectomized rats, activation of G protein-coupled estrogen receptor 1 (GPER) in the arcuate nucleus of the hypothalamus (ARH) rapidly facilitates sexual receptivity (lordosis). Estradiol priming activates ARH β-endorphin (β-END) neurons that then activate medial preoptic (MPN) μ-opioid receptors (MOP) to inhibit lordosis. ARH infusion of non-esterified 17β-estradiol (E2) 47.5 h after 17β-estradiol benzoate (2 μg EB) priming deactivates MPN MOP and rapidly facilitates lordosis within 30 min via activation of GPER. Since it was unclear where GPERs were located in the neuron, we tested the hypothesis that GPER signaling is initiated at the plasma membrane. Membrane impermeable estradiol (17β-estradiol conjugated to biotin; E-Biotin) infused into the ARH of EB primed rats facilitated lordosis within 30 min, and MPN MOP was deactivated. These actions were blocked by pretreating with GPER antagonist, G-15. Further, we used cell fractionation and western blot techniques to demonstrate that GPER is expressed both in plasma membrane and cytosolic ARH fractions. In previous studies, the orphanin FQ/nociceptin-opioid receptor-like receptor-1 (OFQ/N-ORL-1) system mediated estradiol-only facilitation of lordosis. Therefore, we tested whether the OFQ/N-ORL-1 system mediates E-Biotin-GPER facilitation of lordosis. Pretreatment of UFP-101, an ORL-1 selective antagonist, blocked the facilitation of lordosis and deactivation of MPN MOP by ARH infusion of E-Biotin. Double-label immunohistochemistry revealed that GPER is expressed within approximately 70% of OFQ/N neurons. These data indicate that membrane GPER mediates the E2/E-Biotin facilitation of lordosis by inducing OFQ/N neurotransmission, which inhibits β-END neurotransmission to reduce MPN MOP activation.
Collapse
Affiliation(s)
- Reema Tominna
- Department of Biological Sciences, California State University, Long Beach, Long Beach, CA, United States of America
| | - Sima Chokr
- Department of Biological Sciences, California State University, Long Beach, Long Beach, CA, United States of America
| | - Micah Feri
- Department of Biological Sciences, California State University, Long Beach, Long Beach, CA, United States of America
| | - Timbora Chuon
- Department of Biological Sciences, California State University, Long Beach, Long Beach, CA, United States of America
| | - Kevin Sinchak
- Department of Biological Sciences, California State University, Long Beach, Long Beach, CA, United States of America.
| |
Collapse
|
|
30
|
Olivares-Bañuelos TN, Chí-Castañeda D, Ortega A. Glutamate transporters: Gene expression regulation and signaling properties. Neuropharmacology 2019; 161:107550. [PMID: 30822498 DOI: 10.1016/j.neuropharm.2019.02.032] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 02/22/2019] [Accepted: 02/24/2019] [Indexed: 12/24/2022]
Abstract
Glutamate is the major excitatory neurotransmitter in the vertebrate central nervous system. During synaptic activity, glutamate is released and binds to specific membrane receptors and transporters activating, in the one hand, a wide variety of signal transduction cascades, while in the other hand, its removal from the synaptic cleft. Extracellular glutamate concentrations are maintained within physiological levels mainly by glia glutamate transporters. Inefficient clearance of this amino acid is neurotoxic due to a prolonged hyperactivation of its postsynaptic receptors, exacerbating a wide array of intracellular events linked to an ionic imbalance, that results in neuronal cell death. This process is known as excitotoxicity and is the underlying mechanisms of an important number of neurodegenerative diseases. Therefore, it is important to understand the regulation of glutamate transporters function. The transporter activity can be regulated at different levels: gene expression, transporter protein targeting and trafficking, and post-translational modifications of the transporter protein. The identification of these mechanisms has paved the way to our current understanding the role of glutamate transporters in brain physiology and will certainly provide the needed biochemical information for the development of therapeutic strategies towards the establishment of novel therapeutic approaches for the treatment and/or prevention of pathologies associated with excitotoxicity insults. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.
Collapse
Affiliation(s)
- Tatiana N Olivares-Bañuelos
- Instituto de Investigaciones Oceanológicas, Universidad Autónoma de Baja California, Carretera Tijuana-Ensenada No. 3917, Fraccionamiento Playitas, 22860, Ensenada, Baja California, Mexico
| | - Donají Chí-Castañeda
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, Ciudad de México, 07000, Mexico
| | - Arturo Ortega
- Departamento de Toxicología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, Ciudad de México, 07000, Mexico.
| |
Collapse
|
|
31
|
Mahmoud S, Gharagozloo M, Simard C, Gris D. Astrocytes Maintain Glutamate Homeostasis in the CNS by Controlling the Balance between Glutamate Uptake and Release. Cells 2019; 8:E184. [PMID: 30791579 PMCID: PMC6406900 DOI: 10.3390/cells8020184] [Citation(s) in RCA: 384] [Impact Index Per Article: 64.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 02/15/2019] [Accepted: 02/19/2019] [Indexed: 01/26/2023] Open
Abstract
Glutamate is one of the most prevalent neurotransmitters released by excitatory neurons in the central nervous system (CNS); however, residual glutamate in the extracellular space is, potentially, neurotoxic. It is now well-established that one of the fundamental functions of astrocytes is to uptake most of the synaptically-released glutamate, which optimizes neuronal functions and prevents glutamate excitotoxicity. In the CNS, glutamate clearance is mediated by glutamate uptake transporters expressed, principally, by astrocytes. Interestingly, recent studies demonstrate that extracellular glutamate stimulates Ca2+ release from the astrocytes' intracellular stores, which triggers glutamate release from astrocytes to the adjacent neurons, mostly by an exocytotic mechanism. This released glutamate is believed to coordinate neuronal firing and mediate their excitatory or inhibitory activity. Therefore, astrocytes contribute to glutamate homeostasis in the CNS, by maintaining the balance between their opposing functions of glutamate uptake and release. This dual function of astrocytes represents a potential therapeutic target for CNS diseases associated with glutamate excitotoxicity. In this regard, we summarize the molecular mechanisms of glutamate uptake and release, their regulation, and the significance of both processes in the CNS. Also, we review the main features of glutamate metabolism and glutamate excitotoxicity and its implication in CNS diseases.
Collapse
Affiliation(s)
- Shaimaa Mahmoud
- Program of Immunology, Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
| | - Marjan Gharagozloo
- Program of Immunology, Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
| | - Camille Simard
- Program of Immunology, Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
| | - Denis Gris
- Program of Immunology, Department of Pharmacology-Physiology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.
| |
Collapse
|
|
32
|
Hannou L, Roy P, Ballester Roig MN, Mongrain V. Transcriptional control of synaptic components by the clock machinery. Eur J Neurosci 2019; 51:241-267. [DOI: 10.1111/ejn.14294] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/01/2018] [Accepted: 11/27/2018] [Indexed: 12/21/2022]
Affiliation(s)
- Lydia Hannou
- Center for Advanced Research in Sleep Medicine and Research CenterHôpital du Sacré‐Cœur de Montréal (CIUSSS‐NIM) Montreal Quebec Canada
- Department of PsychiatryUniversité de Montréal Montreal Quebec Canada
| | - Pierre‐Gabriel Roy
- Center for Advanced Research in Sleep Medicine and Research CenterHôpital du Sacré‐Cœur de Montréal (CIUSSS‐NIM) Montreal Quebec Canada
- Department of NeuroscienceUniversité de Montréal Montreal Quebec Canada
| | - Maria Neus Ballester Roig
- Center for Advanced Research in Sleep Medicine and Research CenterHôpital du Sacré‐Cœur de Montréal (CIUSSS‐NIM) Montreal Quebec Canada
- Department of NeuroscienceUniversité de Montréal Montreal Quebec Canada
| | - Valérie Mongrain
- Center for Advanced Research in Sleep Medicine and Research CenterHôpital du Sacré‐Cœur de Montréal (CIUSSS‐NIM) Montreal Quebec Canada
- Department of NeuroscienceUniversité de Montréal Montreal Quebec Canada
| |
Collapse
|
|
33
|
Baez-Jurado E, Rincón-Benavides MA, Hidalgo-Lanussa O, Guio-Vega G, Ashraf GM, Sahebkar A, Echeverria V, Garcia-Segura LM, Barreto GE. Molecular mechanisms involved in the protective actions of Selective Estrogen Receptor Modulators in brain cells. Front Neuroendocrinol 2019; 52:44-64. [PMID: 30223003 DOI: 10.1016/j.yfrne.2018.09.001] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 09/09/2018] [Accepted: 09/12/2018] [Indexed: 02/06/2023]
Abstract
Synthetic selective modulators of the estrogen receptors (SERMs) have shown to protect neurons and glial cells against toxic insults. Among the most relevant beneficial effects attributed to these compounds are the regulation of inflammation, attenuation of astrogliosis and microglial activation, prevention of excitotoxicity and as a consequence the reduction of neuronal cell death. Under pathological conditions, the mechanism of action of the SERMs involves the activation of estrogen receptors (ERs) and G protein-coupled receptor for estrogens (GRP30). These receptors trigger neuroprotective responses such as increasing the expression of antioxidants and the activation of kinase-mediated survival signaling pathways. Despite the advances in the knowledge of the pathways activated by the SERMs, their mechanism of action is still not entirely clear, and there are several controversies. In this review, we focused on the molecular pathways activated by SERMs in brain cells, mainly astrocytes, as a response to treatment with raloxifene and tamoxifen.
Collapse
Affiliation(s)
- E Baez-Jurado
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
| | - M A Rincón-Benavides
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
| | - O Hidalgo-Lanussa
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
| | - G Guio-Vega
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
| | - G M Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - A Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - V Echeverria
- Universidad San Sebastián, Fac. Cs de la Salud, Lientur 1457, Concepción 4080871, Chile; Research & Development Service, Bay Pines VA Healthcare System, Bay Pines, FL 33744, USA
| | - L M Garcia-Segura
- Instituto Cajal, CSIC, Madrid, Spain; Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - G E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia; Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile.
| |
Collapse
|
|
34
|
Xin H, Cui Y, An Z, Yang Q, Zou X, Yu N. Attenuated glutamate induced ROS production by antioxidative compounds in neural cell lines. RSC Adv 2019; 9:34735-34743. [PMID: 35530670 PMCID: PMC9074000 DOI: 10.1039/c9ra03848e] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 10/21/2019] [Indexed: 12/21/2022] Open
Abstract
Glutamate is an excitatory neurotransmitter involved in neural function. Excess accumulation of intercellular glutamate leads to increasing concentration of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in neuronal cells. In this study, we investigated the antioxidant activity of several typical superior compounds among four neuronal cells, and determined the scavenging activity of free radicals. The in vivo assay was also carried out to compare the protective effect of glutamate-induced cell damage. Hierarchical clustering analysis was used to identify the common properties. Glutamate induced neurotoxicity and ROS production, suggesting glutamate cytotoxicity was related to oxidative stress and widely exists in different cell lines. Those screening compounds exhibited strong antioxidant ability, but low cytotoxicity to neuronal cells, acting as agents against neurodegenerative diseases. Finally, a hierarchical clustering analysis assay indicated that hyperoside and rutin hydrate are the most effective compounds for attenuating intercellular ROS levels. The results suggested the activity more or less relies on structure, rather than residues. These data generate new supporting ideas to remove intracellular ROS and the identified compounds serve as potential therapeutic agents in multiple neurological diseases. Glutamate is an excitatory neurotransmitter involved in neural function.![]()
Collapse
Affiliation(s)
- Haolin Xin
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases
- Department of Neurology
- Nankai University
- Huanhu Hospital
- Tianjin
| | - Ying Cui
- Tianjin University of Traditional Chinese Medicine
- Tianjin
- China
| | - Zhongping An
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases
- Department of Neurology
- Nankai University
- Huanhu Hospital
- Tianjin
| | - Qian Yang
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases
- Department of Neurology
- Nankai University
- Huanhu Hospital
- Tianjin
| | - Xuan Zou
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases
- Department of Neurology
- Nankai University
- Huanhu Hospital
- Tianjin
| | - Ning Yu
- Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases
- Department of Neurology
- Nankai University
- Huanhu Hospital
- Tianjin
| |
Collapse
|
|
35
|
Martin-Jiménez C, Gaitán-Vaca DM, Areiza N, Echeverria V, Ashraf GM, González J, Sahebkar A, Garcia-Segura LM, Barreto GE. Astrocytes Mediate Protective Actions of Estrogenic Compounds after Traumatic Brain Injury. Neuroendocrinology 2019; 108:142-160. [PMID: 30391959 DOI: 10.1159/000495078] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 11/02/2018] [Indexed: 11/19/2022]
Abstract
Traumatic brain injury (TBI) is a serious public health problem. It may result in severe neurological disabilities and in a variety of cellular metabolic alterations for which available therapeutic strategies are limited. In the last decade, the use of estrogenic compounds, which activate protective mechanisms in astrocytes, has been explored as a potential experimental therapeutic approach. Previous works have suggested estradiol (E2) as a neuroprotective hormone that acts in the brain by binding to estrogen receptors (ERs). Several steroidal and nonsteroidal estrogenic compounds can imitate the effects of estradiol on ERs. These include hormonal estrogens, phytoestrogens and synthetic estrogens, such as selective ER modulators or tibolone. Current evidence of the role of astrocytes in mediating protective actions of estrogenic compounds after TBI is reviewed in this paper. We conclude that the use of estrogenic compounds to modulate astrocytic properties is a promising therapeutic approach for the treatment of TBI.
Collapse
Affiliation(s)
- Cynthia Martin-Jiménez
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Diana Milena Gaitán-Vaca
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Natalia Areiza
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Valentina Echeverria
- Universidad San Sebastián, Fac. Cs de la Salud, Concepción, Chile
- Research and Development Service, Bay Pines VA Healthcare System, Bay Pines, Florida, USA
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Janneth González
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Luis Miguel Garcia-Segura
- Instituto Cajal, CSIC, Madrid, Spain
- Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias Pontificia Universidad Javeriana, Bogotá, Colombia,
| |
Collapse
|
|
36
|
Toro-Urrego N, Vesga-Jiménez DJ, Herrera MI, Luaces JP, Capani F. Neuroprotective Role of Hypothermia in Hypoxic-ischemic Brain Injury: Combined Therapies using Estrogen. Curr Neuropharmacol 2019; 17:874-890. [PMID: 30520375 PMCID: PMC7052835 DOI: 10.2174/1570159x17666181206101314] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 10/26/2018] [Accepted: 11/28/2018] [Indexed: 12/15/2022] Open
Abstract
Hypoxic-ischemic brain injury is a complex network of factors, which is mainly characterized by a decrease in levels of oxygen concentration and blood flow, which lead to an inefficient supply of nutrients to the brain. Hypoxic-ischemic brain injury can be found in perinatal asphyxia and ischemic-stroke, which represent one of the main causes of mortality and morbidity in children and adults worldwide. Therefore, knowledge of underlying mechanisms triggering these insults may help establish neuroprotective treatments. Selective Estrogen Receptor Modulators and Selective Tissue Estrogenic Activity Regulators exert several neuroprotective effects, including a decrease of reactive oxygen species, maintenance of cell viability, mitochondrial survival, among others. However, these strategies represent a traditional approach of targeting a single factor of pathology without satisfactory results. Hence, combined therapies, such as the administration of therapeutic hypothermia with a complementary neuroprotective agent, constitute a promising alternative. In this sense, the present review summarizes the underlying mechanisms of hypoxic-ischemic brain injury and compiles several neuroprotective strategies, including Selective Estrogen Receptor Modulators and Selective Tissue Estrogenic Activity Regulators, which represent putative agents for combined therapies with therapeutic hypothermia.
Collapse
Affiliation(s)
- Nicolás Toro-Urrego
- Address correspondence to this author at the Laboratorio de Citoarquitectura y Plasticidad Neuronal, Instituto de Investigaciones Cardiológicas, Universidad de Buenos Aires, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina; E-mail:
| | | | | | | | | |
Collapse
|
|
37
|
Vesga‐Jiménez DJ, Hidalgo‐Lanussa O, Baez‐Jurado E, Echeverria V, Ashraf GM, Sahebkar A, Barreto GE. Raloxifene attenuates oxidative stress and preserves mitochondrial function in astrocytic cells upon glucose deprivation. J Cell Physiol 2018; 234:2051-2057. [DOI: 10.1002/jcp.27481] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 09/06/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Diego J. Vesga‐Jiménez
- Departamento de Nutrición y BioquímicaFacultad de Ciencias, Pontificia Universidad JaverianaBogotá Colombia
| | - Oscar Hidalgo‐Lanussa
- Departamento de Nutrición y BioquímicaFacultad de Ciencias, Pontificia Universidad JaverianaBogotá Colombia
| | - Eliana Baez‐Jurado
- Departamento de Nutrición y BioquímicaFacultad de Ciencias, Pontificia Universidad JaverianaBogotá Colombia
| | - Valentina Echeverria
- Facultad de Ciencias de la Salud, Universidad San SebastiánConcepción Chile
- Bay Pines VA Healthcare System, Research and DevelopmentBay Pines Florida
| | - Ghulam Md Ashraf
- King Fahd Medical Research Center, King Abdulaziz University Jeddah Saudi Arabia
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical SciencesMashhad Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical SciencesMashhad Iran
- School of Pharmacy, Mashhad University of Medical SciencesMashhad Iran
| | - George E. Barreto
- Departamento de Nutrición y BioquímicaFacultad de Ciencias, Pontificia Universidad JaverianaBogotá Colombia
- Instituto de Ciencias Biomédicas, Universidad Autónoma de ChileSantiago Chile
| |
Collapse
|
|
38
|
Qi J, Xian XH, Li L, Zhang M, Hu YY, Zhang JG, Li WB. Sulbactam Protects Hippocampal Neurons Against Oxygen-Glucose Deprivation by Up-Regulating Astrocytic GLT-1 via p38 MAPK Signal Pathway. Front Mol Neurosci 2018; 11:281. [PMID: 30158854 PMCID: PMC6104165 DOI: 10.3389/fnmol.2018.00281] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 07/25/2018] [Indexed: 12/20/2022] Open
Abstract
Sulbactam is an atypical β-lactam medication and reported to be neuroprotective by up-regulating glial glutamate transporter-1 (GLT-1) in rats. The present study was undertaken to study the role of p38 MAPK signal pathway in sulbactam induced up-regulation of GLT-1 expression in astrocytes and anti-ischemic effect. Neuron-astrocyte co-cultures and astrocyte cultures from neonatal Wistar rats were used. Cerebral ischemia was mimicked by oxygen-glucose deprivation (OGD). Hoechst (HO)/propidium iodide (PI) double fluorescence staining and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay were used to evaluate neuronal death and cell viability, respectively. Immunocytochemistry and Western blot were used to detect protein expressions. Sulbactam pre-incubation significantly and dose-dependently prevented neuronal death and decline in cell viability induced by OGD in neuron-astrocyte co-cultures, and upregulated GLT-1 expression in astrocyte cultures endured OGD, which suggested that sulbactam might protect neurons against OGD by up-regulating astrocytic GLT-1 expression. It was further shown that the phosphorylated-p38 MAPK expression in astrocytes was up-regulated after the sulbactam pre-incubation and this up-regulation was moderate in amplitude. Especially, the time course of the up-regulation of phosphorylated-p38 MAPK was obviously earlier than that of GLT-1, which suggested possibility that p38 MAPK might be an upstream signal for GLT-1 up-regulation induced by sulbactam. We further found that SB203580, the specific inhibitor of p38 MAPK, dose-dependently inhibited the GLT-1 up-regulation induced by sulbactam either in non- or OGD-treated astrocytes and the protective effect of sulbactam on co-cultured neurons against OGD. Taken together, it might be concluded that sulbactam protects cerebral neurons against OGD by up-regulating astrocytic GLT-1 expression via p38 MAPK signal pathway.
Collapse
Affiliation(s)
- Jie Qi
- Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Xiao-Hui Xian
- Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Li Li
- Department of Science and Technology, Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Min Zhang
- Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China.,Neuroscience Center, Hebei Medical University, Shijiazhuang, China
| | - Yu-Yan Hu
- Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Jing-Ge Zhang
- Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China
| | - Wen-Bin Li
- Department of Pathophysiology, Hebei Medical University, Shijiazhuang, China.,Neuroscience Center, Hebei Medical University, Shijiazhuang, China.,Aging and Cognition Neuroscience Laboratory of Hebei Province, Shijiazhuang, China
| |
Collapse
|
|
39
|
Giatti S, Garcia-Segura LM, Barreto GE, Melcangi RC. Neuroactive steroids, neurosteroidogenesis and sex. Prog Neurobiol 2018; 176:1-17. [PMID: 29981391 DOI: 10.1016/j.pneurobio.2018.06.007] [Citation(s) in RCA: 80] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 05/25/2018] [Accepted: 06/30/2018] [Indexed: 12/12/2022]
Abstract
The nervous system is a target and a source of steroids. Neuroactive steroids are steroids that target neurons and glial cells. They include hormonal steroids originated in the peripheral glands, steroids locally synthesized by the neurons and glial cells (neurosteroids) and synthetic steroids, some of them used in clinical practice. Here we review the mechanisms of synthesis, metabolism and action of neuroactive steroids, including the role of epigenetic modifications and the mitochondria in their sex specific actions. We examine sex differences in neuroactive steroid levels under physiological conditions and their role in the establishment of sex dimorphic structures in the nervous system and sex differences in its function. In addition, particular attention is paid to neuroactive steroids under pathological conditions, analyzing how pathology alters their levels and their role as neuroprotective factors, considering the influence of sex in both cases.
Collapse
Affiliation(s)
- Silvia Giatti
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy
| | - Luis M Garcia-Segura
- Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain; Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain
| | - George E Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá D.C., Colombia
| | - Roberto C Melcangi
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milano, Italy.
| |
Collapse
|
|
40
|
Astrocytic JWA deletion exacerbates dopaminergic neurodegeneration by decreasing glutamate transporters in mice. Cell Death Dis 2018; 9:352. [PMID: 29500411 PMCID: PMC5834463 DOI: 10.1038/s41419-018-0381-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 02/01/2018] [Accepted: 02/05/2018] [Indexed: 12/29/2022]
Abstract
Astrocytic JWA exerts neuroprotective roles by alleviating oxidative stress and inhibiting inflammation. However, the molecular mechanisms of how astrocytic JWA is involved in dopaminergic neurodegeneration in Parkinson's disease (PD) remain largely unknown. In this study, we found that astrocyte-specific JWA knockout mice (JWA CKO) exacerbated dopamine (DA) neuronal loss and motor dysfunction, and reduced the levels of DA and its metabolites in a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced PD model. Astrocytic JWA deficiency repressed expression of excitatory amino-acid transporter 2 (GLT-1) and glutamate uptake both in vivo and in vitro. Further, the regulation of GLT-1 expression was involved in JWA-triggered activation of the MAPK and PI3K signaling pathways. JWA-increased GLT-1 expression was abolished by inhibitors of MEK and PI3K. Silencing CREB also abrogated JWA-increased GLT-1 expression and glutamate uptake. Additionally, JWA deficiency activated glial fibrillary acidic protein (GFAP), and increased the expression of STAT3. Similarly to the MPTP model, paraquat (PQ) exposure produced PD-like phenotypes in JWA CKO mice. Taken together, our findings provide novel insights into astrocytic JWA function in the pathogenesis of neurotoxin mouse models of PD.
Collapse
|
|
41
|
Cicvaric A, Yang J, Bulat T, Zambon A, Dominguez-Rodriguez M, Kühn R, Sadowicz MG, Siwert A, Egea J, Pollak DD, Moeslinger T, Monje FJ. Enhanced synaptic plasticity and spatial memory in female but not male FLRT2-haplodeficient mice. Sci Rep 2018; 8:3703. [PMID: 29487336 PMCID: PMC5829229 DOI: 10.1038/s41598-018-22030-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Accepted: 02/14/2018] [Indexed: 12/30/2022] Open
Abstract
The Fibronectin Leucine-Rich Transmembrane protein 2 (FLRT2) has been implicated in several hormone -and sex-dependent physiological and pathological processes (including chondrogenesis, menarche and breast cancer); is known to regulate developmental synapses formation, and is expressed in the hippocampus, a brain structure central for learning and memory. However, the role of FLRT2 in the adult hippocampus and its relevance in sex-dependent brain functions remains unknown. We here used adult single-allele FLRT2 knockout (FLRT2+/-) mice and behavioral, electrophysiological, and molecular/biological assays to examine the effects of FLRT2 haplodeficiency on synaptic plasticity and hippocampus-dependent learning and memory. Female and male FLRT2+/- mice presented morphological features (including body masses, brain shapes/weights, and brain macroscopic cytoarchitectonic organization), indistinguishable from their wild type counterparts. However, in vivo examinations unveiled enhanced hippocampus-dependent spatial memory recall in female FLRT2+/- animals, concomitant with augmented hippocampal synaptic plasticity and decreased levels of the glutamate transporter EAAT2 and beta estrogen receptors. In contrast, male FLRT2+/- animals exhibited deficient memory recall and decreased alpha estrogen receptor levels. These observations propose that FLRT2 can regulate memory functions in the adulthood in a sex-specific manner and might thus contribute to further research on the mechanisms linking sexual dimorphism and cognition.
Collapse
Affiliation(s)
- Ana Cicvaric
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria
| | - Jiaye Yang
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria
| | - Tanja Bulat
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria
| | - Alice Zambon
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria
| | - Manuel Dominguez-Rodriguez
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria
| | - Rebekka Kühn
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria
| | - Michael G Sadowicz
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria
| | - Anjana Siwert
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria
| | - Joaquim Egea
- Molecular and Developmental Neurobiology Research Group, Universitat de Lleida - IRBLleida, Office 1.13, Lab. 1.06. Avda. Rovira Roure, 80, 25198, Lleida, Spain
| | - Daniela D Pollak
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria
| | - Thomas Moeslinger
- Institute for Physiology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria
| | - Francisco J Monje
- Department of Neurophysiology and Neuropharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090, Vienna, Austria.
| |
Collapse
|
|
42
|
Abstract
Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.
Collapse
Affiliation(s)
- Alexei Verkhratsky
- The University of Manchester , Manchester , United Kingdom ; Achúcarro Basque Center for Neuroscience, IKERBASQUE, Basque Foundation for Science , Bilbao , Spain ; Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain ; Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark ; and Center for Translational Neuromedicine, University of Rochester Medical Center , Rochester, New York
| | - Maiken Nedergaard
- The University of Manchester , Manchester , United Kingdom ; Achúcarro Basque Center for Neuroscience, IKERBASQUE, Basque Foundation for Science , Bilbao , Spain ; Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain ; Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark ; and Center for Translational Neuromedicine, University of Rochester Medical Center , Rochester, New York
| |
Collapse
|
|
43
|
Verkhratsky A, Nedergaard M. Physiology of Astroglia. Physiol Rev 2018; 98:239-389. [PMID: 29351512 PMCID: PMC6050349 DOI: 10.1152/physrev.00042.2016] [Citation(s) in RCA: 1012] [Impact Index Per Article: 144.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 03/22/2017] [Accepted: 04/27/2017] [Indexed: 02/07/2023] Open
Abstract
Astrocytes are neural cells of ectodermal, neuroepithelial origin that provide for homeostasis and defense of the central nervous system (CNS). Astrocytes are highly heterogeneous in morphological appearance; they express a multitude of receptors, channels, and membrane transporters. This complement underlies their remarkable adaptive plasticity that defines the functional maintenance of the CNS in development and aging. Astrocytes are tightly integrated into neural networks and act within the context of neural tissue; astrocytes control homeostasis of the CNS at all levels of organization from molecular to the whole organ.
Collapse
Affiliation(s)
- Alexei Verkhratsky
- The University of Manchester , Manchester , United Kingdom ; Achúcarro Basque Center for Neuroscience, IKERBASQUE, Basque Foundation for Science , Bilbao , Spain ; Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain ; Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark ; and Center for Translational Neuromedicine, University of Rochester Medical Center , Rochester, New York
| | - Maiken Nedergaard
- The University of Manchester , Manchester , United Kingdom ; Achúcarro Basque Center for Neuroscience, IKERBASQUE, Basque Foundation for Science , Bilbao , Spain ; Department of Neuroscience, University of the Basque Country UPV/EHU and CIBERNED, Leioa, Spain ; Center for Basic and Translational Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark ; and Center for Translational Neuromedicine, University of Rochester Medical Center , Rochester, New York
| |
Collapse
|
|
44
|
Pajarillo E, Johnson J, Kim J, Karki P, Son DS, Aschner M, Lee E. 17β-estradiol and tamoxifen protect mice from manganese-induced dopaminergic neurotoxicity. Neurotoxicology 2017; 65:280-288. [PMID: 29183790 DOI: 10.1016/j.neuro.2017.11.008] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 11/20/2017] [Accepted: 11/22/2017] [Indexed: 01/14/2023]
Abstract
Chronic exposure to manganese (Mn) causes neurotoxicity, referred to as manganism, with common clinical features of parkinsonism. 17β-estradiol (E2) and tamoxifen (TX), a selective estrogen receptor modulator (SERM), afford neuroprotection in several neurological disorders, including Parkinson's disease (PD). In the present study, we tested if E2 and TX attenuate Mn-induced neurotoxicity in mice, assessing motor deficit and dopaminergic neurodegeneration. We implanted E2 and TX pellets in the back of the neck of ovariectomized C57BL/6 mice two weeks prior to a single injection of Mn into the striatum. One week later, we assessed locomotor activity and molecular mechanisms by immunohistochemistry, real-time quantitative PCR, western blot and enzymatic biochemical analyses. The results showed that both E2 and TX attenuated Mn-induced motor deficits and reversed the Mn-induced loss of dopaminergic neurons in the substantia nigra. At the molecular level, E2 and TX reversed the Mn-induced decrease of (1) glutamate aspartate transporter (GLAST) and glutamate transporter 1 (GLT-1) mRNA and protein levels; (2) transforming growth factor-α (TGF-α) and estrogen receptor-α (ER-α) protein levels; and (3) catalase (CAT) activity and glutathione (GSH) levels, and Mn-increased (1) malondialdehyde (MDA) levels and (2) the Bax/Bcl-2 ratio. These results indicate that E2 and TX afford protection against Mn-induced neurotoxicity by reversing Mn-reduced GLT1/GLAST as well as Mn-induced oxidative stress. Our findings may offer estrogenic agents as potential candidates for the development of therapeutics to treat Mn-induced neurotoxicity.
Collapse
Affiliation(s)
- Edward Pajarillo
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL 32301, United States
| | - James Johnson
- Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, United States
| | - Judong Kim
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL 32301, United States
| | - Pratap Karki
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL 32301, United States
| | - Deok-Soo Son
- Department of Biochemistry and Cancer Biology, Meharry Medical College Nashville, TN 37208, United States
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine Bronx, NY 10461, United States
| | - Eunsook Lee
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL 32301, United States.
| |
Collapse
|
|
45
|
Karki P, Hong P, Johnson J, Pajarillo E, Son DS, Aschner M, Lee EY. Arundic Acid Increases Expression and Function of Astrocytic Glutamate Transporter EAAT1 Via the ERK, Akt, and NF-κB Pathways. Mol Neurobiol 2017; 55:5031-5046. [PMID: 28812276 PMCID: PMC5964991 DOI: 10.1007/s12035-017-0709-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Accepted: 08/02/2017] [Indexed: 12/22/2022]
Abstract
Glutamate is the major excitatory neurotransmitter in the brain, but excessive synaptic glutamate must be removed to prevent excitotoxic injury and death. Two astrocytic glutamate transporters, excitatory amino acid transporter (EAAT) 1 and 2, play a major role in eliminating excess glutamate from the synapse. Dysregulation of EAAT1 contributes to the pathogenesis of multiple neurological disorders, such as Alzheimer's disease (AD), ataxia, traumatic brain injuries, and glaucoma. In the present study, we investigated the effect of arundic acid on EAAT1 to determine its efficacy in enhancing the expression and function of EAAT1, and its possible mechanisms of action. The studies were carried out in human astrocyte H4 cells as well as in human primary astrocytes. Our findings show that arundic acid upregulated EAAT1 expression at the transcriptional level by activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Arundic acid increased astrocytic EAAT1 promoter activity, messenger RNA (mRNA)/protein levels, and glutamate uptake, while pharmacological inhibition of NF-κB or mutation on NF-κB binding sites in the EAAT1 promoter region abrogated these effects. Arundic acid increased NF-κB reporter activity and induced NF-κB nuclear translocation as well as its bindings to the EAAT1 promoter. Furthermore, arundic acid activated the Akt and ERK signaling pathways to enhance EAAT1 mRNA/protein levels. Finally, arundic acid attenuated manganese-induced decrease in EAAT1 expression by inhibiting expression of the transcription factor Ying Yang 1 (YY1). These results demonstrate that arundic acid increases the expression and function of EAAT1 via the Akt, ERK, and NF-κB signaling pathways, and reverses Mn-induced EAAT1 repression by inhibiting the Mn-induced YY1 activation.
Collapse
Affiliation(s)
- Pratap Karki
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Peter Hong
- Department of Physiology, Meharry Medical College, Nashville, TN, 37208, USA
| | - James Johnson
- Department of Physiology, Meharry Medical College, Nashville, TN, 37208, USA
| | - Edward Pajarillo
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL, 32307, USA
| | - Deok-Soo Son
- Department of Physiology, Meharry Medical College, Nashville, TN, 37208, USA
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Eunsook Y Lee
- Department of Pharmaceutical Sciences, College of Pharmacy, Florida A&M University, Tallahassee, FL, 32307, USA.
| |
Collapse
|
|
46
|
Jover-Mengual T, Castelló-Ruiz M, Burguete MC, Jorques M, López-Morales MA, Aliena-Valero A, Jurado-Rodríguez A, Pérez S, Centeno JM, Miranda FJ, Alborch E, Torregrosa G, Salom JB. Molecular mechanisms mediating the neuroprotective role of the selective estrogen receptor modulator, bazedoxifene, in acute ischemic stroke: A comparative study with 17β-estradiol. J Steroid Biochem Mol Biol 2017; 171:296-304. [PMID: 28479229 DOI: 10.1016/j.jsbmb.2017.05.001] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Revised: 04/26/2017] [Accepted: 05/03/2017] [Indexed: 12/11/2022]
Abstract
As the knowledge on the estrogenic system in the brain grows, the possibilities to modulate it in order to afford further neuroprotection in brain damaging disorders so do it. We have previously demonstrated the ability of the selective estrogen receptor modulator, bazedoxifene (BZA), to reduce experimental ischemic brain damage. The present study has been designed to gain insight into the molecular mechanisms involved in such a neuroprotective action by investigating: 1) stroke-induced apoptotic cell death; 2) expression of estrogen receptors (ER) ERα, ERβ and the G-protein coupled estrogen receptor (GPER); and 3) modulation of MAPK/ERK1/2 and PI3K/Akt signaling pathways. For comparison, a parallel study was done with 17β-estradiol (E2)-treated animals. Male Wistar rats subject to transient right middle cerebral artery occlusion (tMCAO, intraluminal thread technique, 60min), were distributed in vehicle-, BZA- (20.7±2.1ng/mL in plasma) and E2- (45.6±7.8pg/mL in plasma) treated groups. At 24h from the onset of tMCAO, RT-PCR, Western blot and histochemical analysis were performed on brain tissue samples. Ischemia-reperfusion per se increased apoptosis as assessed by both caspase-3 activity and TUNEL-positive cell counts, which were reversed by both BZA and E2. ERα and ERβ expression, but not that of GPER, was reduced by the ischemic insult. BZA and E2 had different effects: while BZA increased both ERα and ERβ expression, E2 increased ERα expression but did not change that of ERβ. Both MAPK/ERK1/2 and PI3K/Akt pathways were stimulated under ischemic conditions. While BZA strongly reduced the increased p-ERK1/2 levels, E2 did not. Neither BZA nor E2 modified ischemia-induced increase in p-Akt levels. These results show that modulation of ERα and ERβ expression, as well as of the ERK1/2 signaling pathway accounts, at least in part, for the inhibitory effect of BZA on the stroke-induced apoptotic cell death. This lends mechanistic support to the consideration of BZA as a potential neuroprotective drug in acute ischemic stroke treatment.
Collapse
Affiliation(s)
- Teresa Jover-Mengual
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - María Castelló-Ruiz
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain; Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia Spain
| | - María C Burguete
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - María Jorques
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Mikahela A López-Morales
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Alicia Aliena-Valero
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Andrés Jurado-Rodríguez
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Salvador Pérez
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - José M Centeno
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Francisco J Miranda
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Enrique Alborch
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Germán Torregrosa
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain; Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia Spain.
| | - Juan B Salom
- Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Departamento de Fisiología, Universidad de Valencia, Hospital Universitario y Politécnico La Fe, Valencia, Spain; Unidad Mixta de Investigación Cerebrovascular, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia Spain
| |
Collapse
|
|
47
|
Differential expression of glutamate transporters in cerebral cortex of paraoxon-treated rats. Neurotoxicol Teratol 2017; 62:20-26. [PMID: 28603072 DOI: 10.1016/j.ntt.2017.06.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 05/12/2017] [Accepted: 06/07/2017] [Indexed: 01/05/2023]
Abstract
Glutamatergic system is involved in pathological effects of organophosphorus (OP) compounds. We aimed to determine in vivo effects of paraoxon, the bioactive metabolite of parathion, on the expression of glutamate transporters as well as Bax and Bcl2 in rat cerebral cortex. Male Wistar rats received an intraperitoneal (i.p.) injection of one of three doses of paraoxon (0.3, 0.7, or 1mg/kg) or corn oil as vehicle (1ml/kg). After 4 or 18h, cerebral cortices were dissected out and used for quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot assays to measure mRNA and protein levels, respectively. The cortical glial glutamate transporters (GLAST and GLT-1) were up-regulated in animals treated with 0.7mg/kg of paraoxon, but down-regulated in 1mg/kg group. Neuronal glutamate transporter (EAAC1) was unchanged in 0.7mg/kg treated rats, while reduced in 1mg/kg group. No significant difference was found in the mRNA and protein expression of EAAC1 in animals intoxicated with 0.3mg/kg of paraoxon. Paraoxon (1mg/kg) resulted in an up-regulation of Bax and down-regulation of Bcl2 mRNA levels in the rat cerebral cortex. These results indicate that paraoxon can differentially regulate expression of glutamate transporters at mRNA and protein levels in the cerebral cortex. Changes in the expression of glutamate transporters are closely related to paraoxon-induced seizure activity.
Collapse
|
|
48
|
Deng LJ, Cheng C, Wu J, Wang CH, Zhou HB, Huang J. Oxabicycloheptene Sulfonate Protects Against β-Amyloid-induced Toxicity by Activation of PI3K/Akt and ERK Signaling Pathways Via GPER1 in C6 Cells. Neurochem Res 2017; 42:2246-2256. [DOI: 10.1007/s11064-017-2237-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2016] [Revised: 02/20/2017] [Accepted: 03/14/2017] [Indexed: 10/19/2022]
|
|
49
|
Amyloid-beta peptide decreases expression and function of glutamate transporters in nervous system cells. Int J Biochem Cell Biol 2017; 85:75-84. [DOI: 10.1016/j.biocel.2017.01.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 12/26/2016] [Accepted: 01/29/2017] [Indexed: 12/26/2022]
|
|
50
|
Kardos J, Héja L, Jemnitz K, Kovács R, Palkovits M. The nature of early astroglial protection-Fast activation and signaling. Prog Neurobiol 2017; 153:86-99. [PMID: 28342942 DOI: 10.1016/j.pneurobio.2017.03.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 09/22/2016] [Accepted: 03/05/2017] [Indexed: 12/14/2022]
Abstract
Our present review is focusing on the uniqueness of balanced astroglial signaling. The balance of excitatory and inhibitory signaling within the CNS is mainly determined by sharp synaptic transients of excitatory glutamate (Glu) and inhibitory γ-aminobutyrate (GABA) acting on the sub-second timescale. Astroglia is involved in excitatory chemical transmission by taking up i) Glu through neurotransmitter-sodium transporters, ii) K+ released due to presynaptic action potential generation, and iii) water keeping osmotic pressure. Glu uptake-coupled Na+ influx may either ignite long-range astroglial Ca2+ transients or locally counteract over-excitation via astroglial GABA release and increased tonic inhibition. Imbalance of excitatory and inhibitory drives is associated with a number of disease conditions, including prevalent traumatic and ischaemic injuries or the emergence of epilepsy. Therefore, when addressing the potential of early therapeutic intervention, astroglial signaling functions combating progress of Glu excitotoxicity is of critical importance. We suggest, that excitotoxicity is linked primarily to over-excitation induced by the impairment of astroglial Glu uptake and/or GABA release. Within this framework, we discuss the acute alterations of Glu-cycling and metabolism and conjecture the therapeutic promise of regulation. We also confer the role played by key carrier proteins and enzymes as well as their interplay at the molecular, cellular, and organ levels. Moreover, based on our former studies, we offer potential prospect on the emerging theme of astroglial succinate sensing in course of Glu excitotoxicity.
Collapse
Affiliation(s)
- Julianna Kardos
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Hungary.
| | - László Héja
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Hungary
| | - Katalin Jemnitz
- Functional Pharmacology Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Hungary
| | - Richárd Kovács
- Institute of Neurophysiology, Charité - Universitätsmedizin, Berlin, Germany
| | - Miklós Palkovits
- Human Brain Tissue Bank and Laboratory, Semmelweis University, Budapest, Hungary
| |
Collapse
|