Multiple sclerosis and glutamate excitotoxicity

Abstract

The previous understanding of multiple sclerosis was solely related to neuroinflammation and its harmful effects; however, countless data indicate the importance of some inflammation-independent, neurodegenerative mechanisms associated with mitochondria malfunction, iron deposition and oxidative stress. Recently, it has been postulated that glutamate excitotoxicity, a phenomenon that takes place when an excessive amount of glutamate overactivates its cellular receptors and induces cell death, could be a missing link between inflammatory and neurodegenerative processes evident in multiple sclerosis. 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, including neurons, astrocytes, oligodendrocytes and microglia. Thus, the disturbance of glutamate homeostasis could affect practically all physiological functions and interactions of brain cells, leading to heterogeneity of pathological events. The understanding of glutamate excitotoxicity as a valid mechanism of central nervous system damage in multiple sclerosis, requires the revision of the current knowledge about a source of elevated extracellular glutamate, glutamate receptor alterations, alterations of glutamate transporters and metabolizing enzymes, as well as molecular mechanism of excitotoxic damage.

Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis

“…Glutamate excitotoxicity, a phenomenon due to an excessive amount of glutamate resulting in cell death, could be a link between inflammatory and neurodegenerative processes evident in MS [9]. Inhibition of voltage-gated calcium channels (VGCCs) is a potential neuroprotective mechanism against excitotoxicity [10][11][12], and pregabalin (Lyrica®) could be the key to overcome autoimmune neurodegeneration in diseases like MS.…”

Leber hereditary optic neuropathy and multiple sclerosis: the mitochondrial connection

“…7 Tissue injury caused by mitochondrial dysfunction has been shown to be caused by at least 3 different mechanisms 8 : reactive oxygen species production, energy failure, and apoptosis induction. In the acute MS lesion, axonal degeneration is believed to result from glutamate excitotoxicity 9 and increased nitric oxide levels released by macrophages, leading to loss of mitochondrial function, inhibition of aerobic respiration, and production of toxic free radical in demyelinated axons. 10 In the chronic MS plaque, studies have shown that loss of myelin and the resultant negative effects on "salutatory conduction" leads to increased energy demand from mitochondria.…”

Glufosinate binds N-methyl-d-aspartate receptors and increases neuronal network activity in vitro

“…Disruption of this receptor has been associated with neurological disease including Alzheimer's disease (Hynd et al, 2004;Ong et al, 2013), multiple sclerosis (Kostic et al, 2013), autism (Essa et al, 2013), amyotrophic lateral sclerosis (Guo et al, 2003), and stroke (Hansen, 1995;Choi, 1998;Wang et al, 2010). Although human GLF poisoning cases are primarily from acute exposure, evidence suggests that GLF can produce chronic neurotoxic effects (Calas et al, 2008;Meme et al, 2009) or detrimentally impact the developing brain (Fujii et al, 1996;Watanabe, 1997).…”