Evaluation of GABAergic Transmission Modulation as a Novel Functional Target for Management of Multiple Sclerosis: Exploring Inhibitory Effect of GABA on Glutamate-Mediated Excitotoxicity
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) where the communication ability of nerve cells in the brain and spinal cord with each other gets impaired. Some current findings suggest the role of glutamate excitotoxicity in the development and progr...
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| Format: | Article |
| Language: | English |
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Wiley
2014-01-01
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| Series: | Advances in Pharmacological Sciences |
| Online Access: | http://dx.doi.org/10.1155/2014/632376 |
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| author | Ankit A. Gilani Ranjeet Prasad Dash Mehul N. Jivrajani Sandeep Kumar Thakur Manish Nivsarkar |
| author_facet | Ankit A. Gilani Ranjeet Prasad Dash Mehul N. Jivrajani Sandeep Kumar Thakur Manish Nivsarkar |
| author_sort | Ankit A. Gilani |
| collection | DOAJ |
| description | Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) where the communication ability of nerve cells in the brain and spinal cord with each other gets impaired. Some current findings suggest the role of glutamate excitotoxicity in the development and progression of MS. An excess release of glutamate leads to the activation of ionotropic and metabotropic receptors, thus resulting in accumulation of toxic cytoplasmic Ca2+ and cell death. However, it has been observed that gamma-aminobutyric acid-A (GABAA) receptors located in the nerve terminals activate presynaptic Ca2+/calmodulin-dependent signaling to inhibit depolarization-evoked Ca2+ influx and glutamate release from isolated nerve terminals, which suggest a potential implication of GABAA receptor in management of MS. With this proof of concept, we tried to explore the potential of selective GABAA receptor agonists or positive allosteric modulators (diazepam and phenobarbitone sodium) and GABAA level enhancer (sodium valproate) for management of MS by screening them for their activity in experimental autoimmune encephalomyelitis (EAE) model in rats and cuprizone-induced demyelination model in mice. In this study, sodium valproate was found to show the best activity in the animal models whereas phenobarbitone sodium showed moderate activity. However, diazepam was found to be ineffective. |
| format | Article |
| id | doaj-art-cfe7564ab1a04955a4bfaa9256f19e29 |
| institution | Kabale University |
| issn | 1687-6334 1687-6342 |
| language | English |
| publishDate | 2014-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advances in Pharmacological Sciences |
| spelling | doaj-art-cfe7564ab1a04955a4bfaa9256f19e292025-02-03T05:51:51ZengWileyAdvances in Pharmacological Sciences1687-63341687-63422014-01-01201410.1155/2014/632376632376Evaluation of GABAergic Transmission Modulation as a Novel Functional Target for Management of Multiple Sclerosis: Exploring Inhibitory Effect of GABA on Glutamate-Mediated ExcitotoxicityAnkit A. Gilani0Ranjeet Prasad Dash1Mehul N. Jivrajani2Sandeep Kumar Thakur3Manish Nivsarkar4Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, C/O-B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad, Gujarat 380054, IndiaDepartment of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad, Gujarat 380054, IndiaDepartment of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad, Gujarat 380054, IndiaDepartment of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad, Gujarat 380054, IndiaDepartment of Pharmacology and Toxicology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, S. G. Highway, Thaltej, Ahmedabad, Gujarat 380054, IndiaMultiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) where the communication ability of nerve cells in the brain and spinal cord with each other gets impaired. Some current findings suggest the role of glutamate excitotoxicity in the development and progression of MS. An excess release of glutamate leads to the activation of ionotropic and metabotropic receptors, thus resulting in accumulation of toxic cytoplasmic Ca2+ and cell death. However, it has been observed that gamma-aminobutyric acid-A (GABAA) receptors located in the nerve terminals activate presynaptic Ca2+/calmodulin-dependent signaling to inhibit depolarization-evoked Ca2+ influx and glutamate release from isolated nerve terminals, which suggest a potential implication of GABAA receptor in management of MS. With this proof of concept, we tried to explore the potential of selective GABAA receptor agonists or positive allosteric modulators (diazepam and phenobarbitone sodium) and GABAA level enhancer (sodium valproate) for management of MS by screening them for their activity in experimental autoimmune encephalomyelitis (EAE) model in rats and cuprizone-induced demyelination model in mice. In this study, sodium valproate was found to show the best activity in the animal models whereas phenobarbitone sodium showed moderate activity. However, diazepam was found to be ineffective.http://dx.doi.org/10.1155/2014/632376 |
| spellingShingle | Ankit A. Gilani Ranjeet Prasad Dash Mehul N. Jivrajani Sandeep Kumar Thakur Manish Nivsarkar Evaluation of GABAergic Transmission Modulation as a Novel Functional Target for Management of Multiple Sclerosis: Exploring Inhibitory Effect of GABA on Glutamate-Mediated Excitotoxicity Advances in Pharmacological Sciences |
| title | Evaluation of GABAergic Transmission Modulation as a Novel Functional Target for Management of Multiple Sclerosis: Exploring Inhibitory Effect of GABA on Glutamate-Mediated Excitotoxicity |
| title_full | Evaluation of GABAergic Transmission Modulation as a Novel Functional Target for Management of Multiple Sclerosis: Exploring Inhibitory Effect of GABA on Glutamate-Mediated Excitotoxicity |
| title_fullStr | Evaluation of GABAergic Transmission Modulation as a Novel Functional Target for Management of Multiple Sclerosis: Exploring Inhibitory Effect of GABA on Glutamate-Mediated Excitotoxicity |
| title_full_unstemmed | Evaluation of GABAergic Transmission Modulation as a Novel Functional Target for Management of Multiple Sclerosis: Exploring Inhibitory Effect of GABA on Glutamate-Mediated Excitotoxicity |
| title_short | Evaluation of GABAergic Transmission Modulation as a Novel Functional Target for Management of Multiple Sclerosis: Exploring Inhibitory Effect of GABA on Glutamate-Mediated Excitotoxicity |
| title_sort | evaluation of gabaergic transmission modulation as a novel functional target for management of multiple sclerosis exploring inhibitory effect of gaba on glutamate mediated excitotoxicity |
| url | http://dx.doi.org/10.1155/2014/632376 |
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