Mitochondrial permeability transition in acute neurodegeneration.
Acute neurodegeneration in man is encountered during and following stroke, transient cardiac arrest, brain trauma, insulin-induced hypoglycemia and status epilepticus. All these severe clinical conditions are characterized by neuronal calcium overload, aberrant cell signaling, generation of free radicals and elevation of cellular free fatty acids, conditions that favor activation of the mitochondrial permeability transition pore (mtPTP). Cyclosporin A (CsA) and its analog N-methyl-valine-4-cyclosporin A (MeValCsA) are potent blockers of the mtPTP and protect against neuronal death following excitotoxicity and oxygen glucose deprivation. Also, CsA and MeValCsA diminish cell death following cerebral ischemia, trauma, and hypoglycemia. Here we present data that strongly imply the mtPT in acute neurodegeneration in vivo. Compounds that readily pass the blood-brain-barrier (BBB) and block the mtPT may be neuroprotective in stroke.
Friberg
Hans
H
Laboratory for Experimental Brain Research, Wallenberg Neuroscience Center, BMC A13, 221 84 Lund, Sweden.
Wieloch
Tadeusz
T
D000208:Acute Disease; D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology; D002463:Cell Membrane Permeability / Q000187:drug effects; D003524:Cyclosporins / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007473:Ion Channels / Q000378:metabolism*; D008928:Mitochondria / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D019636:Neurodegenerative Diseases / Q000473:pathology*; D009474:Neurons / Q000502:physiology*; D051381:Rats
D003524:Cyclosporins; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore