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The Journal of Neuroscience, November 19, 2003, 23(33):10681-10690

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Cellular/Molecular
Hypoglycemic Neuronal Death and Cognitive Impairment Are Prevented by Poly(ADP-Ribose) Polymerase Inhibitors Administered after Hypoglycemia

Sang Won Suh,^1,3 Koji Aoyama,^1,3 Yongmei Chen,^1,3 Philippe Garnier,^1,3 Yasuhiko Matsumori,^2,3 Elizabeth Gum,^1,3 Jialing Liu,^2,3 and Raymond A. Swanson^1,3

Departments of ¹Neurology and ²Neurosurgery, University of California, San Francisco, California 94143, and ³Veterans Affairs Medical Center, San Francisco, California 94121

Severe hypoglycemia causes neuronal death and cognitive impairment. Evidence suggests that hypoglycemic neuronal death involves excitotoxicity and DNA damage. Poly(ADP-ribose) polymerase-1 (PARP-1) normally functions in DNA repair, but promotes cell death when extensively activated by DNA damage. Cortical neuron cultures were subjected to glucose deprivation to assess the role of PARP-1 in hypoglycemic neuronal death. PARP-1^-/- neurons and wild-type, PARP-1^+/+ neurons treated with the PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone both showed increased resistance to glucose deprivation. A rat model of insulin-induced hypoglycemia was used to assess the therapeutic potential of PARP inhibitors after hypoglycemia. Rats subjected to severe hypoglycemia (30 min EEG isoelectricity) accumulated both nitrotyrosine and the PARP-1 product, poly(ADP-ribose), in vulnerable neurons. Treatment with PARP inhibitors immediately after hypoglycemia blocked production of poly(ADP-ribose) and reduced neuronal death by >80% in most brain regions examined. Increased neuronal survival was also achieved when PARP inhibitors were administered up to 2 hr after blood glucose correction. Behavioral and histological assessments performed 6 weeks after hypoglycemia confirmed a sustained salutary effect of PARP inhibition. These results suggest that PARP-1 activation is a major factor mediating hypoglycemic neuronal death and that PARP-1 inhibitors can rescue neurons that would otherwise die after severe hypoglycemia.

Key words: diabetes; glucose; glutamate; neuron; nitrotyrosine; water maze; 7-nitroindazole; 3-aminobenzamide

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Received April 29, 2001; revised September 10, 2003; accepted September 26, 2003.

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