title: Prevention of acute/severe hypoglycemia-induced neuron death by lactate administration.
abstract: Hypoglycemia-induced cerebral neuropathy can occur in patients with diabetes who attempt tight control of blood glucose and may lead to cognitive dysfunction. Accumulating evidence from animal models suggests that hypoglycemia-induced neuronal death is not a simple result of glucose deprivation, but is instead the end result of a multifactorial process. In particular, the excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) consumes cytosolic nicotinamide adenine dinucleotide (NAD(+)), resulting in energy failure. In this study, we investigate whether lactate administration in the absence of cytosolic NAD(+) affords neuroprotection against hypoglycemia-induced neuronal death. Intraperitoneal injection of sodium L-lactate corrected arterial blood pH and blood lactate concentration after hypoglycemia. Lactate administered without glucose was not sufficient to promote electroencephalogram recovery from an isoelectric state during hypoglycemia. However, supplementation of glucose with lactate reduced neuronal death by ∼80% in the hippocampus. Hypoglycemia-induced superoxide production and microglia activation was also substantially reduced by administration of lactate. Taken together, these results suggest an intriguing possibility: that increasing brain lactate following hypoglycemia offsets the decrease in NAD(+) due to overactivation of PARP-1 by acting as an alternative energy substrate that can effectively bypass glycolysis and be fed directly to the citric acid cycle to maintain cellular ATP levels.
authors.affiliation: Department of Neurology, University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, CA, USA.
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Won
authors.forename: Bong Geom
authors.initials: BG
authors.lastname: Jang
authors.forename: Byung Hoon
authors.initials: BH
authors.lastname: Yoo
authors.forename: Min
authors.initials: M
authors.lastname: Sohn
authors.forename: Min Woo
authors.initials: MW
authors.lastname: Lee
authors.forename: Bo Young
authors.initials: BY
authors.lastname: Choi
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Hong Ki
authors.initials: HK
authors.lastname: Song
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Suh
mesh_terms: D000208:Acute Disease; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D003929:Diabetic Neuropathies / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D004562:Electrocardiography / Q000379:methods; D006019:Glycolysis / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006863:Hydrogen-Ion Concentration; D007003:Hypoglycemia / Q000378:metabolism / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D019344:Lactic Acid / Q000494:pharmacology*; D008297:Male; D009243:NAD / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009243:NAD; D019344:Lactic Acid; D000255:Adenosine Triphosphate; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases