Drug development improving mitochondrial pathology in Amyotrophic lateral sclerosis

2017 Fiscal Year Final Research Report

• Project/Area Number: 16K14574
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tohoku University
• Principal Investigator: Fukunaga Kohji 東北大学, 薬学研究科, 教授 (90136721)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Keywords: 筋萎縮性側索硬化症 / Sigma-1受容体 / ミトコンドリア / SA4503

Outline of Final Research Achievements

We have been demonstrated that sigma-1 receptor (E102Q) mutation in amyotrophic lateral sclerosis (ALS) patients triggers mitochondrial injury in neuro2A cells. Sigma-1R(E102Q) is accumulated in the mitochondria and reduces ATP production. We here investigated downregulation of sigma-1R and effects of SA4503, a sigma-1 R agonist in transverse aortic constriction (TAC) model mice. Those mice exhibited heart failure with reduced sigma-1R levels in heart. The oral administration of SA4503 (0.1-1mg/kg) dose-dependently restored the reduced sigma-1R and ATP production in heart, thereby improving heart functions. Notably, the reduced sigma-1R was also observed in the central nervous system. Then, SA4503 treatments also improved impaired brain functions. We are now preparing sigma-1R(E102Q) mutant mice to investigate effects of mitochondrial function improvers including pyruvate, aminolevulinic acid and SA4503.

Free Research Field

神経薬理学