Resveratrol Mitigates Cognitive Impairments and Cholinergic Cell Loss in the Medial Septum in a Mouse Model of Gradual Cerebral Hypoperfusion.

Vascular cognitive impairment and dementia (VCID) is the second leading cause of dementia. There is currently no effective treatment for VCID. Resveratrol (RSV) is considered an antioxidant; however, our group has observed pleiotropic effects in stroke paradigms, suggesting more effects may contribute to mechanistic changes beyond antioxidative properties. The main goal of this study was to investigate if administering RSV twice a week could alleviate cognitive declines following the induction of a VCID model. Additionally, our aim was to further describe whether this treatment regimen could decrease cell death in brain areas vulnerable to changes in cerebral blood flow, such as the hippocampus and medial septum. We hypothesized RSV treatments in a mouse model of gradual cerebral hypoperfusion protect against cognitive impairment. We utilized gradual bilateral common carotid artery stenosis (GBCCAS) via the surgical implantation of ameroid constrictor devices. RSV treatment was administered on the day of implantation and twice a week thereafter. Cerebral perfusion was measured by laser speckle contrast imaging, and cognitive functions, including the recognition memory, the spatial working memory, and associative learning, were assessed by novel object recognition (NOR), Y-maze testing, and contextual fear conditioning (CFC), respectively. RSV treatment did not alleviate cerebral perfusion deficits but mitigated cognitive deficits in CFC and NOR after GBCCAS. Despite these deficits, no hippocampal pathology was observed; however, cholinergic cell loss in the medial septum was significantly increased after GBCCAS. This cholinergic cell loss was mitigated by RSV. This study describes a novel mechanism by which chronic RSV treatments protect against a VCID-induced cognitive decline through the preservation of cholinergic cell viability to improve memory performance.

Sirtuins and cognition: implications for learning and memory in neurological disorders.

Sirtuins are an evolutionarily conserved family of regulatory proteins that function in an NAD+ -dependent manner. The mammalian family of sirtuins is composed of seven histone deacetylase and ADP-ribosyltransferase proteins (SIRT1-SIRT7) that are found throughout the different cellular compartments of the cell. Sirtuins in the brain have received considerable attention in cognition due to their role in a plethora of metabolic and age-related diseases and their ability to induce neuroprotection. More recently, sirtuins have been shown to play a role in normal physiological cognitive function, and aberrant sirtuin function is seen in pathological cellular states. Sirtuins are believed to play a role in cognition through enhancing synaptic plasticity, influencing epigenetic regulation, and playing key roles in molecular pathways involved with oxidative stress affecting mitochondrial function. This review aims to discuss recent advances in the understanding of the role of mammalian sirtuins in cognitive function and the therapeutic potential of targeting sirtuins to ameliorate cognitive deficits in neurological disorders.