Neuroprotective signal transduction: relevance to stroke.
Studies of ischemic brain injury in cell culture, animal models, and humans have revealed inter- and intra-cellular signaling pathways that increase resistance to cell degeneration and death. Brain injury induces expression of many different growth factors and cytokines which can protect neurons against insults relevant to the pathogenesis of ischemic brain injury including excitotoxicity, hypoxia, hypoglycemia, acidosis, and pro-oxidants. Neuroprotective signal transduction pathways elicit changes that promote the maintenance of cellular ion homeostasis and/or suppress the accumulation of free radicals. For example: basic fibroblast growth factor suppresses expression of a glutamate receptor protein and induces antioxidant enzymes; tumor necrosis factor induces expression of a Ca(2+)-binding protein and Mn-superoxide dismutase; and secreted forms of beta-amyloid precursor protein hyperpolarize neurons by activating K+ channels. Transcriptional regulation involves activation of tyrosine phosphorylation cascades and NFkB. Interestingly, similar neuroprotective pathways can be activated by moderate levels of cell "stress" such as that induced by glutamate in cell culture or a brief period of cerebral ischemia in vivo. Novel rapid and delayed intracellular neuroprotective signaling mechanisms are being revealed, such as the regulation of Ca2+ influx by actin filaments and the induction of genes by Ca2+ and radicals. New therapeutic approaches arising from this research include low molecular weight lipophilic compounds that activate neurotrophic factor signaling pathways and agents that selectively depolymerize actin.
Mattson
M P
MP
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536, USA.
D000818:Animals; D002561:Cerebrovascular Disorders / Q000188:drug therapy*; D006133:Growth Substances / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D006133:Growth Substances; D018696:Neuroprotective Agents