Abstract
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.
Highlights
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 [1]
No significant inhibition of EAE symptoms was found in the diazepam treated animals as compared to the disease control group, indicating that it may not be effective in preventing the disease progression
The results showed an excessive release of glutamate from the synaptosomes of the diseased control group whereas the levels of glutamate released from the synaptosomes of the animals of normal control and positive control groups were significantly low (P ≤ 0.05)
Summary
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 [1]. Some current findings suggest the role of glutamate excitotoxicity in the development and progression of MS. Glutamate is the major excitatory neurotransmitter of the central nervous system, which has been proven to have a central role in a complex communication network established between all residential brain cells [3]. This has been proved from the magnetic resonance spectroscopy studies of MS brains that showed elevated glutamate levels in acute MS lesions [4]. An excess release of glutamate leads to the activation of ionotropic and metabotropic receptors, resulting in accumulation of toxic cytoplasmic Ca2+ and cell death. One interesting finding in this context is that activate
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
