The Multiple Sclerosis Society of Canada and the Multiple Sclerosis Scientific Research Foundation announced a $3.8 million grant to investigate the complex interplay between degeneration and inflammation in multiple sclerosis (MS).
The grant will fund a study led by Dr. Peter Stys from the University of Calgary's Hotchkiss Brain Institute, which would investigate damage that occurs in MS prior to inflammation. This research may have special relevance for those with progressive forms of MS.
From the Peter K. Stys paper: General mechanisms of axonal damage and its prevention.
Together, these data present evidence that mechanisms of injury to white matter in anoxia/ischemia and neuro-inflammatory diseases may be surprisingly similar, and neuro-protectants designed for ischemia may be effective adjuncts in neuro-inflammatory disorders such as MS.
Barnett and Prineas reported that in the post mortem examination of the brains of people who had died shortly after a relapse they discovered that the newly formed lesions showed signs of oligodendrocite apoptosis but no sign of immune activity. The changes showing in the oligodendrocite indicated damage by hypoxia, ischemia and excitotoxins. (Cregan et al. 2002)
Dr. Stys is a neurologist/neuroscientist and a world leader in the detailed study of pathophysiological mechanisms of white matter injury in stroke and trauma. He has extensive expertise in electrophysiological recording methods in myelinated axons and his team has recently developed confocal, multiphoton and coherent anti-Stokes Raman scattering (CARS) imaging techniques for both fixed immunostained and live myelinated axons and glial cells.
Dr. Stys’ team discovered several novel injury mechanisms responsible for axo-glial damage in ischemia/trauma: Ca overload secondary to reverse Na-Ca exchange (Stys et al., J Neurosci, 1992) and glutamate excitotoxicty due to reversal of Na-dependent glutamate transport in damaged spinal axons (Li and Stys, J Neurosci, 1999). This endogenously released glutamate then activates newly discovered AMPA/kainate receptors on axons (Ouardouz et al., J Physiol, 2006), and surprisingly, NMDA receptors on oligodendrocytes and the myelin sheath itself (Micu et al., Nature, 2006). In addition, depolarization of damaged fibers leads to release of toxic amounts of Ca from intra-axonal Ca stores, dependent on L-type Ca channels and ryanodine receptors (Ouardouz et al., Neuron, 2003), via a mechanism very similar to excitation-contraction coupling in muscle cells. The various signaling molecules (glutamate receptors, Ca channels, nNOS, RyRs, and likely many others) are organized along the internodal axolemma under the myelin sheath in discrete “axonal nanocomplexes”, very reminiscent of arrangements at the post-synaptic membrane of conventional interneuronal synapses.
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