Evaluation of GABAergic Transmission Modulation as a Novel Functional Target for Management of Multiple Sclerosis: Exploring Inhibitory Effect of GABA on Glutamate-Mediated Excitotoxicity

Gilani, Ankit; Dash, Ranjeet Prasad; Jivrajani, Mehul; Thakur, Sandeep Kumar; Nivsarkar, Manish

doi:10.1155/2014/632376

Cited by 14 publications

(17 citation statements)

References 22 publications

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“…Furthermore, the fact that cognitive impairments are related to the levels of excitatory and inhibitory neurotransmitters in the hippocampus of patients in the remitting stage rather than in the progressive stage (Cawley et al, 2015) helps to address a problem regarding the window of opportunity for clinical intervention. A previous animal study also supports the potential of using positive GABA receptor modulators to manage MS (Gilani, Dash, Jivrajani, Thakur, & Nivsarkar, 2014). Therefore, pharmacological therapies targeting these neurotransmitter systems might be valuable in the future.…”

Section: Discussionmentioning

confidence: 60%

Altered hippocampal GABA and glutamate levels and uncoupling from functional connectivity in multiple sclerosis

et al. 2018

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There is growing evidence for dysfunctional glutamatergic excitation and/or gamma-aminobutyric acid (GABA)ergic inhibition in patients with multiple sclerosis (MS). Cognitive impairment may occur during the early stages of MS and hippocampal abnormalities have been suggested as biomarkers. However, researchers have not clearly determined whether changes in hippocampal GABA and glutamate (Glu) levels are associated with cognitive impairment and aberrant neural activity in patients with MS. We used magnetic resonance spectroscopy to measure GABA+ and Glu levels in the left hippocampal region of 29 patients with relapsing-remitting MS and 29 healthy controls (HCs). Resting-state functional connectivity (FC) with the hippocampus was also examined. Compared to HCs, patients exhibited significantly lower GABA+ and Glu levels, which were associated with verbal and visuospatial memory deficits, respectively. Patients also showed decreased FC strengths between the hippocampus and several cortical regions, which are located within the default mode network. Moreover, hippocampal GABA+ levels and Glu/GABA+ ratios correlated with the FC strengths in HCs but not in patients with MS. This study describes a novel method for investigating the complex relationships among excitatory/inhibitory neurotransmitters, brain connectivity and cognition in health and disease. Strategies that modulate Glu and GABA neurotransmission may represent new therapeutic treatments for patients with MS.

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Section: Discussionmentioning

confidence: 60%

Altered hippocampal GABA and glutamate levels and uncoupling from functional connectivity in multiple sclerosis

et al. 2018

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“…Inflammation in EAE is related with calcium overload of neurons and manifested process of excitotoxicity in which the release of glutamate is a crucial manifestation. Such changes are the main events during the relapse phase of EAE, accordingly, increased GABA expression could indicate suppressed excitotoxicity and promoted inhibitory neuronal pathways [12]. Therapeutic procedures of both TBS induced important changes in investigated molecules expressions, such as BDNF elevation.…”

Section: Discussionmentioning

confidence: 98%

Theta burst stimulation influence the expression of BDNF in the spinal cord on the experimental autoimmune encephalomyelitis

Stevanović¹,

Mancic²,

Ilić³

et al. 2019

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Repetitive transcranial magnetic stimulation (rTMS) induces changes in expression of proteins engaged in the activity of excitatory and inhibitory systems, restores these functions and suppresses the progression of disability in experimental autoimmune encephalitis (EAE). The structural type of TMS, the arrangement as theta burst stimulation (TBS) has been applied as intermittent TBS (iTBS) and continuous TBS (cTBS) protocols to female adult DA rats. The animals were randomly divided into experimental groups: control group (C), group treated with complete Freund's adjuvant (CFA), experimental autoimmune encephalomyelitis (EAE) group, group treated with iTBS post EAE immunization (EAE + iTBS), group treated with cTBS post EAE immunization (EAE + cTBS), group of healthy animals treated with iTBS or cTBS. Therapeutic protocols of iTBS or cTBS in all EAE groups of animals were performed starting from 14 days post immunization (dpi), for 10 days with time point decapitation at 24 dpi. After decapitation, spinal cords were analysed for BDNF and Ki67 expression. The results revealed reduced BDNF expression in the rat's spinal cord of EAE animals in the stage of remission, which was associated with increased Ki67 and GFAP expressions. Decreased Iba 1 and BDNF expression, contrary to increased Iba 1 and Ki67 expression, suggests clustered microglia in the resolution phase of EAE. Enhanced GABA expression in spinal cord sections indicates higher GABA metabolic turnover, and also GAD activity in astrocytes, or prominent activity of GABAergic neurons. Both TBS protocols induced advance BDNF expression; amongst iTBS application provoked elevating of BDNF and stabilizing of GFAP and Ki67 expressions.

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“…Interestingly, alprazolam, another benzodiazepine derivative, also decreased the severity of clinical, histological and neuroendocrine manifestations of EAE in Lewis rats but only when the animals were exposed to stressful conditions [14]. In the context of EAE, it was also observed that phenobarbitone sodium and sodium valproate inhibited the clinical signs of EAE; however, high doses of diazepam failed to control EAE signs in this experiment [15]. …”

Section: Introductionmentioning

confidence: 93%

Diazepam Inhibits Proliferation of Lymph Node Cells Isolated from Rats with Experimental Autoimmune Encephalomyelitis

Hurst

Bibolini²,

Roth³

2015

Neuroimmunomodulation

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Objective: Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease with similarities to human multiple sclerosis involving peripheral activation of autoreactive T cells which infiltrate the central nervous system and react to self antigens leading to damage. In previous studies, we have demonstrated that treatment with diazepam decreases the incidence and histological signs associated with the disease and diminishes immunological responses. The aim of the present work was to evaluate direct effects of diazepam on isolated T cells involved in immune responses during the development of EAE. Methods: Animals were sensitized with whole myelin to induce EAE and sacrificed during the acute phase of the disease. In mononuclear cells isolated from popliteal lymph nodes, cell viability, apoptosis induction, proliferation and cytokine production were evaluated. Results: Diazepam did not have a toxic or proapoptotic effect on the cells, at least up to the concentration of 25 μM, but proliferation, CD8+ T-cell activation and proinflammatory cytokine production were dose-dependently decreased. Conclusions: Diazepam has a direct inhibitory effect on the proliferation and activation of T lymphocytes isolated from the main lymphoid organ involved in disease onset and this could be one of the mechanisms that contribute to the beneficial effect previously observed with diazepam in vivo during EAE development.

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Evaluation of GABAergic Transmission Modulation as a Novel Functional Target for Management of Multiple Sclerosis: Exploring Inhibitory Effect of GABA on Glutamate-Mediated Excitotoxicity

Cited by 14 publications

References 22 publications

Altered hippocampal GABA and glutamate levels and uncoupling from functional connectivity in multiple sclerosis

Altered hippocampal GABA and glutamate levels and uncoupling from functional connectivity in multiple sclerosis

Theta burst stimulation influence the expression of BDNF in the spinal cord on the experimental autoimmune encephalomyelitis

Diazepam Inhibits Proliferation of Lymph Node Cells Isolated from Rats with Experimental Autoimmune Encephalomyelitis

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