Glutamate excitotoxicity in a model of multiple sclerosis

Abstract

Glutamate excitotoxicity mediated by the AMPA/kainate type of glutamate receptors damages not only neurons but also the myelin-producing cell of the central nervous system, the oligodendrocyte. In multiple sclerosis, myelin, oligodendrocytes and some axons are lost as a result of an inflammatory attack on the central nervous system. Because glutamate is released in large quantities by activated immune cells, we expected that during inflammation in MS, glutamate excitotoxicity might contribute to the lesion. We addressed this by using the AMPA/kainate antagonist NBQX to treat mice sensitized for experimental autoimmune encephalomyelitis, a demyelinating model that mimics many of the clinical and pathologic features of multiple sclerosis. Treatment resulted in substantial amelioration of disease, increased oligodendrocyte survival and reduced dephosphorylation of neurofilament H, an indicator of axonal damage. Despite the clinical differences, treatment with NBQX had no effect on lesion size and did not reduce the degree of central nervous system inflammation. In addition, NBQX did not alter the proliferative activity of antigen-primed T cells in vitro, further indicating a lack of effect on the immune system. Thus, glutamate excitotoxicity seems to be an important mechanism in autoimmune demyelination, and its prevention with AMPA/kainate antagonists may prove to be an effective therapy for multiple sclerosis.

Antioxidants and polyunsaturated fatty acids in multiple sclerosis

“…Demyelinated lesions caused by excitotoxins can be similar to those observed in MS, and glutamate-induced excitotoxicity may cause axonal loss. Together with the beneficial effects of glutamate receptor antagonists in EAE, these findings indicate that oligodendrocyte excitotoxicity plays a role in the pathogenesis of MS (Pitt et al, 2000).…”

In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica‐related pathology

“…Although we cannot exclude a possible direct “by‐stander” attack of activated complement factors or an indirect effect by another cell type,39 the timing, lack of associated pathology, and localization of the axonal changes make these unlikely, and suggest that axonal swelling is the consequence of astrocyte loss. Indeed, this is not entirely surprising,40, 41, 42 given that numerous vital interactions between astrocytes and axons have been documented43, 44, 45, 46: For example, astrocytes are known to scavenge glutamate,47 and excitotoxicity has been implicated in axonal pathology during neuroinflammation 48, 49, 50. This, together with the well‐established role of excitotoxicity after hypoxia,43, 51 warrants future investigation in our NMO‐related model using in vivo real‐time optical techniques,52 calcium sensors,22, 53 and selective pharmacological inhibitors.…”

Functions of optic nerve glia: axoglial signalling in physiology and pathology

“…[35][36][37] In an experimental model, sustained activation of oligodendrocyte iGluR by injection of kainate in the optic nerve induces lesions and compromises axon conduction, which has the major features of MS and ischaemic damage. [36][37][38] It is significant, therefore, that antagonists of iGluR ameliorate the symptoms of EAE and attenuate excitotoxic injury. 39,40 The loss of oligodendrocytes and myelin results in secondary axonal damage, 10 although axons may also express iGluR, indicating that glutamate may directly compromise axons.…”