Effects of Alda-1, an Aldehyde Dehydrogenase-2 Agonist, on Hypoglycemic Neuronal Death

Abstract

Hypoglycemic encephalopathy (HE) is caused by a lack of glucose availability to neuronal cells, and no neuroprotective drugs have been developed as yet. Studies on the pathogenesis of HE and the development of new neuroprotective drugs have been conducted using animal models such as the hypoglycemic coma model and non-coma hypoglycemia model. However, both models have inherent problems, and establishment of animal models that mimic clinical situations is desirable. In this study, we first developed a short-term hypoglycemic coma model in which rats could be maintained in an isoelectric electroencephalogram (EEG) state for 2 min and subsequent hyperglycemia without requiring anti-seizure drugs and an artificial ventilation. This condition caused the production of 4-hydroxy-2-nonenal (4-HNE), a cytotoxic aldehyde, in neurons of the hippocampus and cerebral cortex, and a marked increase in neuronal death as evaluated by Fluoro-Jade B (FJB) staining. We also investigated whether N-(1,3-benzodioxole-5-ylmethyl)-2,6-dichlorobenzamide (Alda-1), a small-molecule agonist of aldehyde dehydrogenase-2, could attenuate 4-HNE levels and reduce hypoglycemic neuronal death. After confirming that EEG recordings remained isoelectric for 2 min, Alda-1 (8.5 mg/kg) or vehicle (dimethyl sulfoxide; DMSO) was administered intravenously with glucose to maintain a blood glucose level of 250 to 270 mg/dL. Fewer 4-HNE and FJB-positive cells were observed in the cerebral cortex of Alda-1-treated rats than in DMSO-treated rats 24 h after glucose administration (P = 0.002 and P = 0.020). Thus, activation of the ALDH2 pathway could be a molecular target for HE treatment, and Alda-1 is a potentially neuroprotective agent that exerts a beneficial effect on neurons when intravenously administered simultaneously with glucose.

Left Hemiplegia Possibly Due to Glucose Reperfusion Injury after Recovery of Severe Hypoglycemia in a Woman with Type 2 Diabetes Mellitus

“…Several mechanisms are thought to be involved in hypo-glycemia (12)(13)(14)(15). During hypoglycemia, reduced glycolysis can lead to an increase in excitatory amino acids, such as glutamate and aspartate, in the extracellular space, and these amino acids further damage postsynaptic cells (12,13).…”

“…Furthermore, recent studies have demonstrated that hypoglycemic superoxide production and neuronal death are increased during glucose reperfusion rather than by the hypoglycemia itself (12)(13)(14). Glucose reperfusion leads to activation of NADPH oxidase and superoxide production and a subsequent increase in several factors, such as 4-hydroxy-2nonenal (4-HNE), a cytotoxic aldehyde that causes neuronal death (14,15). It has also been reported that administration of Alda-1 : N-( 1,3-benzodioxole-5-ylmethyl ) -2,6dichbrobenzamide inhibits both the production of 4-HNE and neuronal death associated with glucose reperfusion injury (15).…”