Mechanisms of ischemic neuroprotection by acetyl-L-carnitine.
Acetyl-L-carnitine is a naturally occurring substance that, when administered at supraphysiologic concentrations, is neuroprotective in several animal models of global and focal cerebral ischemia. Three primary mechanisms of action are supported by neurochemical outcome measures performed with these models and with in vitro models of acute neuronal cell death. The metabolic hypothesis is based on the oxidative metabolism of the acetyl component of acetyl-L-carnitine and is a simple explanation for the reduction in postischemic brain lactate levels and elevation of ATP seen with drug administration. The antioxidant mechanism is supported by reduction of oxidative stress markers, for example, protein oxidation, in both brain tissue and cerebrospinal fluid. The relatively uncharacterized mechanism of inhibiting excitotoxicity could be extremely important in both acute brain injury and chronic neurodegenerative disorders. New experiments performed with primary cultures of rat cortical neurons indicate that the presence of acetyl-L-carnitine significantly inhibits both acute and delayed cell death following exposure to NMDA, an excitotoxic glutamate antagonist. Finally, several other mechanisms of action are possible, including a neurotrophic effect of acetyl-L-carnitine and inhibition of mitochondrial permeability transition. While the multiple potential mechanisms of neuroprotection by acetyl-L-carnitine limit an accurate designation of the most important mode of action, they are compatible with the concept that several brain injury pathways must be inhibited to optimize therapeutic efficacy.
Zanelli
Santina A
SA
Department of Pediatrics, University of Virginia School of Medicine, Charlottesville 22908, USA.
Solenski
Nina J
NJ
Rosenthal
Robert E
RE
Fiskum
Gary
G
D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology*; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D018697:Nootropic Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects
D018696:Neuroprotective Agents; D009498:Neurotoxins; D018697:Nootropic Agents; D000108:Acetylcarnitine