Abstract Details

Title Effects of ALDH2 Agonist, Alda-1, on Hypoglycemic Neuronal Death Associated with Glucose Reperfusion Injury

Topic Neurotoxicology

Presentation(s) P01 - (-)

Poster/Presentation
Number 054

Objective

Background Hypoglycemic encephalopathy (HE) is a common complication of insulin and/or oral hypoglycemia therapy. The only treatment for HE is blood glucose (BG) correction. Animal studies demonstrated that neuronal degeneration is aggravated when glucose concentrations rise rapidly and hyperglycemia occurs after hypoglycemia ("glucose reperfusion injury"). Herein, we established a new rat hypoglycemic short time coma model that is a simple and useful model for drug screening, and investigated whether Alda-1, a small-molecule agonist for the ALDH2, could ameliorate 4HNE (4-hydroxy-2-nonenal) production, a product and mediator of oxidative stress, as well as hypoglycemic neuronal degeneration.

Design/Methods Male Sprague-Dawley rats were subjected to hypoglycemia by intraperitoneal injection of insulin (15 IU/kg). After confirming that electroencephalogram (EEG) recordings were maintained isoelectric for 2 min or 10 min, Alda-1 (8.5 mg/kg) or DMSO was administered intravenously in addition to 50% glucose to maintain BG level 200-250 mg/dL. Brains were harvested at 24h after glucose administration. 4HNE production and neuronal degeneration were evaluated by using immunofluorescence using an antibody against 4HNE and Fluoro-Jade B (FJB) staining of the brain sections, respectively.

Results 4HNE- and FJB-positive cells were not observed in sham-treated rats. 4HNE-positive cells in isoelectric-EEG 10 min group were more frequent than those in isoelectric-EEG 2 min group (P = 0.001). FJB-positive cells in isoelectric-EEG 10 min group were more frequent than those in isoelectric-EEG 2 min group (P = 0.018). Alda-1 suppressed 4HNE- and FJB- positive cells in the brain sections from isoelectric-EEG 2 min group than DMSO, respectively (P = 0.042 and P = 0.007).

Conclusions We have established the simple and physiological new rat HE model for drug screening and we found that Alda-1 was promising drug for HE.

Authors/Disclosures
Tetsuhiko Ikeda, MD PRESENTER	No disclosure on file
Tetsuya Takahashi, PhD (Dept. of Neurology, Niigata University BRI)	No disclosure on file
Mark S. Freedman, MD, FAAN (University of Ottawa)	Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Actelion(Janssen/J&J). Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alexion. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BiogenIdec. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS/Celgene. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for EMD Inc. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi-Genzyme. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Actelion (Janssen/J&J). Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Atara Biotherapeutics. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Bayer Healthcare. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for BiogenIdec. Dr. Freedman has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Clene Nanomedicine. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GRI Bio. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Magenta Therapeutics. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck Serono. Dr. Freedman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Freedman has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi Genzyme. Dr. Freedman has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Sanofi Genzyme. Dr. Freedman has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for EMD Serono. The institution of Dr. Freedman has received research support from Sanofi Genzyme.
	No disclosure on file
Masato Kanazawa, MD, FAAN (Niigata University of Health and Welfare)	Dr. Kanazawa has nothing to disclose.
Kosuke Itoh	No disclosure on file
Tsutomu Nakada, MD, PhD	No disclosure on file
Masatoyo Nishizawa, MD (Niigata University of Health and Welfare)	No disclosure on file
Takayoshi Shimohata, MD, FAAN (Department of Neurology, Gifu University)	Dr. Shimohata has nothing to disclose.

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