title: Mitochondrial dysfunction induced by nuclear poly(ADP-ribose) polymerase-1: a treatable cause of cell death in stroke.
abstract: Many drugs targeting excitotoxic cell death have demonstrated robust neuroprotective effects in animal models of cerebral ischemia. However, these neuroprotective effects have almost universally required drug administration at relatively short time intervals after ischemia onset. This finding has translated to clinical trial results; interventions targeting excitotoxicity have had no demonstrable efficacy when initiated hours after ischemia onset, but beneficial effects have been reported with more rapid initiation. Consequently, there continues to be a need for interventions with efficacy at later time points after ischemia. Here, we focus on mitochondrial dysfunction as both a relatively late event in ischemic neuronal death and a recognized cause of delayed neuronal death. Activation of poly(ADP-ribose) polymerase-1 (PARP-1) is a primary cause of mitochondrial depolarization and subsequent mitochondria-triggered cell death in ischemia reperfusion. PARP-1 consumes cytosolic NAD(+), thereby blocking both glycolytic ATP production and delivery of glucose carbon to mitochondria for oxidative metabolism. However, ketone bodies such as pyruvate, beta- and gamma-hydroxybutyrate, and 1,4-butanediol can fuel mitochondrial metabolism in cells with depleted cytosolic NAD(+) as long as the mitochondria remain functional. Ketone bodies have repeatedly been shown to be highly effective in preventing cell death in animal models of ischemia, but a rigorous study of the time window of opportunity for this approach remains to be performed.
authors: Department of Neurology, University of California San Francisco and Neurology Service, San Francisco Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA, 94121, USA.
authors: Paul
authors: P
authors: Baxter
authors: Yanting
authors: Y
authors: Chen
authors: Yun
authors: Y
authors: Xu
authors: Raymond A
authors: RA
authors: Swanson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D018696:Neuroprotective Agents / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D019289:Pyruvic Acid / Q000494:pharmacology; D051381:Rats; D020521:Stroke / Q000201:enzymology*
chemical_list: D018696:Neuroprotective Agents; D019289:Pyruvic Acid; D011065:Poly(ADP-ribose) Polymerases