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 hypoglycemiainduced 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 B80% 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.

Protection of Hypoglycemia-Induced Neuronal Death by β-Hydroxybutyrate Involves the Preservation of Energy Levels and Decreased Production of Reactive Oxygen Species

“…11,16,17,33 We also tested the protective effect of pyruvate and lactate, which can also be used by brain as alternative substrates to glucose through its metabolism by the tricarboxylic acid cycle. In agreement with previous studies, [37][38][39] we observed a reduction of neuronal death in the in vitro model by both substrates, while the effect of pyruvate was similar to that of D-BHB, lactate was less effective.…”

The urinary 1H‐NMR metabolomics profile of an italian autistic children population and their unaffected siblings

“…Experimental evidence indicates that changes in the concentration of three of the discriminant metabolites we identified—namely lactate, creatine, and taurine—can be associated with an increased oxidative stress [Jang & Kim, ; Lobysheva et al, ; Ribeiro, Silva, Rodrigues, Naia, & Rego, ; Won et al, ]. By being described that these molecules can have a protective effect by decreasing the formation of reactive oxygen species or the production of superoxide anion, their decrease in our patients can support the presence of an oxidative stress condition in autistic individuals.…”

Neuroprotective, neurotherapeutic, and neurometabolic effects of carbon monoxide

“…The authors concluded that neuronal tissue appears to be able to handle excess lactic acid [48]. Several studies show that lactate may be the preferred energy substrate of activated neurons and is neuroprotective [49-54] and lactate may be a major substrate for the mitochondrial tricarboxylic acid cycle. Lactate preserves neuronal function in experimental models of excitotoxicity, posthypoxic recovery, cerebral ischemia, and energy deprivation and can sustain neuronal integrity as an alternative energy substrate.…”

“…The authors concluded that increased brain lactate during hypoxia may be neuroprotective in IUGR piglets [55]. In a rat model of acute/severe hypoglycemia, Won and colleagues concluded that supplementation of glucose with lactate reduced neuronal death in the hippocampus and hypothesized that increasing brain lactate in this model 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 [56]. Our results in newborn piglets preconditioned with inhaled CO before CPB/DHCA are also consistent with a change to lactate as the metabolic substrate and resulting neuroprotection [45].…”