• KSBNS 2024


Original Article

Exp Neurobiol 2018; 27(1): 45-56

Published online February 28, 2018

© The Korean Society for Brain and Neural Sciences

The Improving Effect of HL271, a Chemical Derivative of Metformin, a Popular Drug for Type II Diabetes Mellitus, on Aging-induced Cognitive Decline

Eunyoung Bang1,2†, Boyoung Lee1†, Joon-Oh Park3,4†, Yooncheol Jang1,3, Aekyong Kim5, Sungwuk Kim5,6 and Hee-Sup Shin1,2*

1Center for Cognition and Sociality, Institute for Basic Science, Daejeon 34141, 2Basic Science, IBS School, University of Science and Technology, Daejeon 34113, 3Center for Neuroscience, Korea Institute of Science and Technology, Seoul 02792, 4Division of Insect Pests, National Institute of Forest Science, Seoul 02455, Korea, 5ImmunoMet, Texas Medical Center,Houston, TX 77021, USA, 6Hanall Biopharma Inc., Seoul 06170, Korea

Correspondence to: *To whom correspondence should be addressed.
TEL: 82-42-861-7016, FAX: 82-42-861-7060
These authors contributed equally

Received: November 7, 2017; Revised: December 11, 2017; Accepted: January 2, 2018

In recent years, as the aging population grows, aging-induced cognitive impairments including dementia and Alzheimer's disease (AD) have become the biggest challenges for global public health and social care. Therefore, the development of potential therapeutic drugs for aging-associated cognitive impairment is essential. Metabolic dysregulation has been considered to be a key factor that affects aging and dementia. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a primary sensor of cellular energy states and regulates cellular energy metabolism. Metformin (1,1-dimethylbiguanide hydrochloride) is a well-known AMPK activator and has been widely prescribed for type 2 diabetes mellitus (T2DM). Since the incidence of T2DM and dementia increases with aging, metformin has been considered to be one of the most promising drugs to target dementia and its related disorders. To that end, here, we tested the efficacy of metformin and HL271, a novel metformin derivative, in aging-induced cognitive decline. Water (control), metformin (100 mg/kg) or HL271 (50 mg/kg) were orally administered to aged mice for two months; then, the mice were subjected to behavioral tests to measure their cognitive function, particularly their contextual, spatial and working memory. AMPK phosphorylation was also measured in the drug-treated mouse brains. Our results show that oral treatment with HL271 (50 mg/kg) but not metformin (100 mg/kg) improved cognitive decline in aged mice. AMPK activation was correlated with behavior recovery after aging-induced cognitive decline. Taken together, these results suggest that the newly synthesized AMPK activator, HL271, could be a potential therapeutic agent to treat age-related cognitive decline.

Graphical Abstract

Keywords: Aging, Cognitive decline, AMPK, Metformin, HL271