Pyruvate administered after severe hypoglycemia reduces neuronal death and cognitive impairment.
Hypoglycemia-induced brain injury is a significant obstacle to optimal blood glucose control in diabetic patients. Severe hypoglycemia triggers a cascade of events in vulnerable neurons that may culminate in cell death even after glucose normalization. A key event in this cascade is the activation of poly(ADP-ribose) polymerase-1 (PARP-1). Activated PARP-1 consumes cytosolic NAD, and because NAD is required for glycolysis, hypoglycemia-induced PARP-1 activation may render cells unable to use glucose even when glucose availability is restored. Pyruvate, however, can be metabolized in the absence of cytosolic NAD. Here we tested whether pyruvate could improve the outcome in rats subjected to insulin-induced hypoglycemia by terminating hypoglycemia with either glucose alone or glucose plus pyruvate. In the four brain regions studied--CA1, subiculum, dentate gyrus of the hippocampus, and piriform cortex--the addition of pyruvate reduced neuron death by 70-90%. Improved neuron survival was also observed when pyruvate delivery was delayed for up to 3 h. The improved neuron survival was accompanied by a sustained improvement in cognitive function as assessed by the Morris water maze. These results suggest that pyruvate may significantly improve the outcome after severe hypoglycemia by circumventing a sustained impairment in neuronal glucose utilization resulting from PARP-1 activation.
Suh
Sang Won
SW
Department of Neurology, University of California, San Francisco, USA.
Aoyama
Koji
K
Matsumori
Yasuhiko
Y
Liu
Jialing
J
Swanson
Raymond A
RA
D000818:Animals; D016923:Cell Death / Q000187:drug effects*; D003072:Cognition Disorders / Q000503:physiopathology* / Q000517:prevention & control; D004195:Disease Models, Animal; D007003:Hypoglycemia / Q000139:chemically induced / Q000503:physiopathology* / Q000523:psychology; D007328:Insulin / Q000494:pharmacology; D007656:Ketoglutaric Acids / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000473:pathology*; D019289:Pyruvic Acid / Q000494:pharmacology*; D051381:Rats
D007328:Insulin; D007656:Ketoglutaric Acids; D019289:Pyruvic Acid