Multiple sclerosis (MS) is a suspected autoimmune disease of the central nervous system characterized by infiltration of immune cells, loss of myelin, oligodendrocyte death and axonal damage. Among the mechanisms suspected in oligodendrocyte death and axonal damage are cell-cell contact and soluble factors such as TNF-alpha, reactive oxygen species, metalloproteinases and autoantibodies. Current therapeutic approaches attempt to modulate or suppress the aberrant immune reaction characteristic for MS and EAE. However, overlooked in most concepts is the fact that activated leukocytes and microglia also release glutamate in large quantities during inflammation. In an animal model of MS, experimental autoimmune encephalomyelitis (EAE), the investigators found that glutamate excitotoxicity plays a significant role in clinical impairment, axonal damage and demise of oligodendrocytes, work which introduced this novel mechanism to the MS problem. The hypothesis to be tested is that glutamate excitotoxicity is a major mechanism of damage in MS. Relevance to MS will be assured by studying MS material alongside EAE throughout. Using pharmacological agents which prevent excitotoxcity, they will test the hypothesis with the following experiments: 1. Dose-response studies with NBQX in EAE. This is to define the optimally protective dose of NBQX and lay the groundwork for 2., Treatment of relapsing-remitting EAE to investigate the long-term benefit of NBQX in EAE. 3. The role of glutamate excitotoxicity in axonal damage, assessed by immunohistochemistry and Western blotting will be addressed by treating EAE with NBQX and by co-localization of glutamate-producing immune cells and axonal damage in MS and EAE. 4. Determination of the developmental stage of oligodendrocytes protected by NBQX in EAE, and effect on remyelination using MBP-isoform-specific antibodies as well as MBP exon-2 RNAse protection assays. Developing oligodendrocytes are more vulnerable to glutamate excitotoxicity than mature cells and this may be important to the repair process following demyelination. 5. Charac-terization of the altered glutamate detoxification in both MS and EAE, assessed by immunohistochemistry, Western blotting and enzyme assays. A suspected role of TNF-alpha in these changes will also be determined in vitro (primary oligodendrocyte cultures) via glutamate uptake studies. 6. EAE experiments using Ca++-antagonists to reduce clinical impairment as well as pathological outcome will address the apparent role of voltage-gated Ca++ channels in excitotoxic damage in autoimmune demyelination. Their proposed work focuses on a new mechanism of CNS damage in MS. By studying the apparent benefit of glutamate antagonist And CA++-antagonists, they hope to take advantage of ongoing research in diseases such as stroke to find new avenues of intervention in the MS patient.
| Brand-Schieber, Elimor; Werner, Peter; Iacobas, Dumitru A et al. (2005) Connexin43, the major gap junction protein of astrocytes, is down-regulated in inflamed white matter in an animal model of multiple sclerosis. J Neurosci Res 80:798-808 |
| Brand-Schieber, Elimor; Werner, Peter (2003) (+/-)-Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid and kainate receptor subunit expression in mouse versus rat spinal cord white matter: similarities in astrocytes but differences in oligodendrocytes. Neurosci Lett 345:126-30 |
| Brand-Schieber, Elimor; Werner, Peter (2003) AMPA/kainate receptors in mouse spinal cord cell-specific display of receptor subunits by oligodendrocytes and astrocytes and at the nodes of Ranvier. Glia 42:12-24 |
| Werner, P; Pitt, D; Raine, C S (2001) Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann Neurol 50:169-80 |
