Pituitary Adenylate Cyclase-Activating Polypeptide Protects Against Cognitive Impairment Caused by Chronic Cerebral Hypoperfusion

Pituitary adenylate cyclase-activating polypeptide (PACAP) has beneficial effects in learning and memory. However, the mechanism by which PACAP improves cognitive impairment of vascular dementia (VaD) is not clear. We established a VaD model by bilateral common carotid stenosis (BCAS) to investigate the molecular mechanism of cognitive impairment. Protein levels of PACAP, Sirtuin 3 (Sirt3), brain-derived neurotrophic factor (BDNF), and postsynaptic density 95 (PSD-95) were assessed by Western blot. In vitro, oxygen glucose deprivation (OGD) was used to simulate the ischemia/hypoxia state. HT22 cells were transfected with Sirt3 knockdown and overexpression to study the relationship between PACAP, Sirt3, and BDNF. In vivo, PACAP was administered intranasally to assess its protective effects on BCAS. The study showed that the levels of PACAP, Sirt3, BDNF, and PSD-95 were decreased in the BCAS model of VaD. PACAP increased the protein levels of Sirt3, BDNF, PSD-95, Bcl-2, and Bax under OGD condition in vitro. Sirt3 regulated BDNF and synaptic plasticity. Intranasal PACAP increased the protein levels of PAC1, Sirt3, BDNF, and PSD-95 in vivo. This study provides evidence that PACAP regulates synaptic plasticity and plays an antiapoptotic role through Sirt3.