title: 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.
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Tetsuhiko
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Tsujita
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kanazawa
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Toriyabe
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Misaki
authors.initials: M
authors.lastname: Koyama
authors.affiliation: Department of Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Department of Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakada
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Masatoyo
authors.initials: M
authors.lastname: Nishizawa
authors.affiliation: Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Shimohata
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D016923:Cell Death; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003128:Coma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005947:Glucose / Q000008:administration & dosage / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007003:Hypoglycemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007275:Injections, Intravenous; D008297:Male; D024101:Mitochondrial Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000447:Aldehydes; D001549:Benzamides; D052117:Benzodioxoles; D024101:Mitochondrial Proteins; C531525:N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; D018696:Neuroprotective Agents; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; C505112:Aldh2 protein, rat; D005947:Glucose; C027576:4-hydroxy-2-nonenal