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      Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis.

      1 ,
      The Lancet. Neurology
      Elsevier BV

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          Abstract

          Multiple sclerosis (MS), an inflammatory demyelinating disease, is a major cause of neurological disability in young adults in the developed world. Although the progressive neurological disability that most patients with MS eventually experience results from axonal degeneration, little is known about the mechanisms of axonal injury in MS. Accumulating evidence suggests that the increased energy demand of impulse conduction along excitable demyelinated axons and reduced axonal ATP production induce a chronic state of virtual hypoxia in chronically demyelinated axons. In response to such a state, key alterations that contribute to chronic necrosis of axons might include mitochondrial dysfunction (due to defective oxidative phosphorylation or nitric oxide production), Na+ influx through voltage-gated Na+ channels and axonal AMPA receptors, release of toxic Ca2+ from the axoplasmic reticulum, overactivation of ionotropic and metabotropic axonal glutamate receptors, and activation of voltage-gated Ca2+ channels, ultimately leading to excessive stimulation of Ca2+-dependent degradative pathways. The development of neuroprotective therapies that target these mechanisms might constitute effective adjuncts to currently used immune-modifying agents.

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          Author and article information

          Journal
          Lancet Neurol
          The Lancet. Neurology
          Elsevier BV
          1474-4422
          1474-4422
          Mar 2009
          : 8
          : 3
          Affiliations
          [1 ] Department of Neurosciences, Cleveland Clinic, Cleveland, OH 44195, USA. trappb@ccf.org
          Article
          S1474-4422(09)70043-2
          10.1016/S1474-4422(09)70043-2
          19233038
          906facef-8c6b-4e1f-86fa-8cf78f717dfa
          History

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