Multiple Sclerosis and Glutamate

Abstract

Experimental autoimmune encephalomyelitis reproduces in rodents the features of multiple sclerosis, an immune-mediated, disabling disorder of the human nervous system. No adequate therapy is available for multiple sclerosis, despite anti-inflammatory, immunosuppressive, and immunomodulatory measures. Increasingly glutamate is implicated in the pathogenesis of neurodegenerative diseases. Here we (1) review changes in the glutamatergic system in multiple sclerosis and (2) reveal the effects of glutamate AMPA antagonists in acute and chronic rodent models of multiple sclerosis. Administration of structurally diverse competitive and non-competitive AMPA antagonists reduces neurologic disability in rodents subjected to acute experimental autoimmune encephalomyelitis. In addition, AMPA antagonists are active in both the adoptive transfer and in chronic models of experimental autoimmune encephalomyelitis in rats and mice and affect both the acute and chronic relapsing phases. Moreover, short-term therapy with AMPA antagonists leads to sustained benefit well into the progressive phases. These results imply that therapeutic strategies for multiple sclerosis should be complemented by glutamate AMPA antagonists to reduce neurologic disability.

Preferred Stereoselective Transport of the D-isomer of cis-4-[18F]fluoro-proline at the Blood–Brain Barrier

“…This discovery opens new aspects concerning the physiological role of D-amino acids in the central nervous system. Disturbances of glutamatergic excitatory neurotransmission are involved in many brain diseases such as ischemia and trauma (Arundine and Tymianski, 2004), multiple sclerosis (Groom et al, 2003), schizophrenia (Harrison et al, 2003), Alzheimer's disease (Doraiswamy, 2003;Hynd et al, 2004) and cerebral gliomas (Takano et al, 2001).…”

Differential oxidative stress in oligodendrocytes and neurons after excitotoxic insults and protection by natural polyphenols

“…Interestingly, oxidative stress and in vivo oxidation markers have been identified in white matter tissue of patients affected by this disease (Smith et al, 1999), along with disturbances in glutamate homeostasis, which correlate with the severity of relapses (Matute et al, 2001;Groom et al, 2003;Sarchielli et al, 2003). In MS, this oxidative stress is associated with inflammatory incidents, such as the release of free radicals from activated immune cells (GilgunSherki et al, 2004).…”

P2X7Receptor Blockade Prevents ATP Excitotoxicity in Oligodendrocytes and Ameliorates Experimental Autoimmune Encephalomyelitis

“…Both genetic and environmental factors contribute to MS susceptibility (Zamvil and Steinman, 2003). Among them, primary and/or secondary alterations in glutamate signaling cause excitotoxicity that contributes to MS pathology (Matute et al, 2001;Groom et al, 2003).…”