Glutamate and Multiple Sclerosis

Abstract

Multiple sclerosis (MS) has been considered for a long time a typical inflammatory demyelinating disease of the central nervous system due to autoimmunity targeting oligodendrocytes with sparing of axons until advanced stages of the disease. For this reason, most of the earliest experimental studies focused on the role of cytokines and chemokines at the site of oligodendrocytes loss and on the importance in MS pathogenesis of classical inflammatory mechanisms. As a result, several attempts to treat MS through reduction of the local inflammatory milieau have been performed, leading to the current "immunomodulatory" treatment of the disease. However, more recently the importance of axonal loss and neurodegeneration even in the earliest stages of MS has been also recognized, and additional or concomitant players have been therefore searched. Evidence is now increasing that excessive glutamate is released at the site of demyelination and axonal degeneration in MS plaques, and the most probable candidates for this cellular release are infiltrating leukocytes and activated microglia. These observations are no longer simply preclinical results obtained in the MS animal model, i.e. experimental allergic encephalomyelitis, but have already been partially confirmed by post-mortem studies and in vivo analysis in MS patients, thus raising the possibility that modulation of glutamate release and transport as well as receptors blockade might be relevant targets for the development of future therapeutic interventions.

Small non-coding RNA signature in multiple sclerosis patients after treatment with interferon-β

“…In our research, mir-26a-5p, showed a significant change in the level of expression, based on the INF-βresponse, at the different stages of treatment in INF-β treated responder RRMS (Figure 2). Studies have demonstrated that glutamatergic regulation can take place in MS symptoms and treatment [27]. Under pathological conditions an excess of glutamate in the synaptic space can trigger a toxic cascade leading to cell death.…”

Glutamate signalling: A multifaceted modulator of oligodendrocyte lineage cells in health and disease

“…Inflammation might be the primary cause of neurodegeneration occurring independent of oligodendrocyte damage, as neuronal loss can be observed in normalappearing white matter in MS patients (Evangelou et al, 2000). This inflammation-induced neurodegeneration might be due to disruptions of glutamate release and clearance that are documented in MS tissue (reviewed by Frigo et al, 2012;Tilleux and Hermans, 2007). Glutamate concentrations are significantly increased in the cerebrospinal fluid, in acute brain lesions and in normal appearing white matter of MS patients (Srinivasan et al, 2005;Stover et al, 1997).…”

The Chemistry of Neurodegeneration: Kinetic Data and Their Implications

“…Additional possible strategies for preventing ROS formation from glutamate sources is the inhibition of the NMDA receptor with a selective antagonist and the chelation of calcium ions [119], as well as inhibition of the enzyme glutamate carboxypeptidase II [120,121]. Moreover, evidence is now increasing that excessive glutamate is released at the site of demyelination and axonal degeneration in multiple sclerosis plaques [122], thus raising the possibility that the modulation of glutamate release and transport, as well as a receptors blockade, might be relevant targets for the development of future neurodegenerative disease therapeutic interventions.…”