The role of SIRT2 inhibition on the aging process of brain in male rats.

Background: Though the exact mechanisms regarding brain aging and its relation to neurodegenerative disorders are not precise, oxidative stress, the key regulators of apoptosis and autophagy, such as bcl-2 and beclin 1, seem to be the potential players in the aging of the cerebral cortex and hippocampus. As a type of nicotinamide adenine dinucleotide (NAD)-dependent deacetylases, sirtuin 2 (SIRT2) has been associated to age-related diseases. However, the exact role of SIRT2 in brain aging is not well studied. The objective of the current study was to study the role of SIRT2 inhibition on brain aging through the neuroprotective mechanisms.

Methods: We tested the effects of AGK-2, a SIRT2 inhibitor, on oxidative stress parameters, apoptosis and autophagy regulators including bcl-2, bax, beclin1 in young and old rats. 24 Wistar albino rats (3 months-old and 22 months-old) were divided into four groups; Young-Control (4% DMSO+PBS), Young-AGK-2 (10 µM/bw, ip), Aged-Control, and Aged-AGK-2. Following the 30 days of drug administration period the rats were sacrificed and the cerebral cortex, hippocampus, and cerebellum were isolated. Total antioxidant status (TAS) and total oxidant status (TOS) were measured as oxidative stress parameters in all three brain regions. SIRT2, bcl-2, and bax protein expression levels were measured by western blot and gene expression level of beclin 1, Atg5, and SIRT2 by real-time PCR.

Results: The bcl-2, bcl-2/bax ratio, beclin 1, and TAS in the cerebral cortex of the aged group were significantly decreased; however, the TOS, oxidative stress index (OSI), and SIRT2 expression in the cerebral cortex and hippocampus increased. SIRT2 inhibition by AGK-2 reduced TOS and OSI levels in all brain regions and increased bcl-2, bcl-2/bax ratio. In aged animals, AGK-2 also increased the beclin 1 levels in the cortex and hippocampus.

Conclusion: Our results indicate that SIRT2 has an essential role in brain aging. The inhibition of SIRT2 by AGK-2 may increase cell survival and decrease aging related processes in the cerebral cortex and hippocampus via decreasing oxidative stress, and increasing bcl-2 and beclin 1 expression.