Anti-brain Aging Effects of Small Molecule Inhibitor DDQ.

Abstract

The purpose of our study is to determine the protective effects of the newly discovered molecule DDQ (diethyl (3,4-dihydroxyphenethylamino)(quinolin-4-yl) methylphosphonate) against aging in an in vitro, mouse primary hippocampal neurons, HT22 cells, and in vivo, 24-month-old C57BL6/J mice. Using biochemical and molecular methods, we studied the half-life period in the blood and brain, optimized the dose, determined dose-response (using 1, 5, 10, 20, and 50 mg/kg body weight), and measured the levels of blood, skeletal muscle, and brain. Using Morris water maze (cognitive behavior), q-RT-PCR (mRNA and protein levels of longevity genes SIRTUINS), transmission electron microscopy (mitochondrial number and length), and Golgi-Cox staining (dendritic spine number and length) were assessed in 24-month-old C57BL6/J mice. Out of 5 different doses of DDQ, the 20 mg/kg body weight dose showed the strongest protective effects against aging in C57BL6/J mice. The half-life time of DDQ is 20 h in the serum and 12 h in the brain. Our extensive pharmacodynamics analysis revealed high peak levels of DDQ in the skeletal muscle, followed by serum and brain. Using mouse primary hippocampal (HT22) neurons and 24-month-old C57BL6/J mice, we tested the protective effects of DDQ. Interestingly, longevity genes SIRTUINS were upregulated in DDQ-treated HT22 cells, and DDQ-treated aged wild-type mice relative to DDQ-untreated cells and untreated aged control mice. Dendritic spines and the quality of mitochondria were significantly increased in DDQ-treated aged mice. Current study findings, together with our previous study observations, strongly suggest that DDQ has anti-aging effects and warrants further investigations of anti-inflammatory, anti-DNA damage, and telomerase activity studies.