Background: Autophagy and phosphatidylinositol 3-kinase (PI3K)/Akt kinase pathways are implicated in cognitive decline associated with cerebrovascular lesions. This decline is reflected in the concept of vascular cognitive impairment and dementia (VCID). However, the underlying molecular mechanism and specific details regarding these types of cognitive deficits induced by chronic brain hypoperfusion have not been elucidated.
Methods: We designed a method to evaluate these mechanisms. Adult male Sprague-Dawley rats were subjected to permanent bilateral occlusion of the common carotid artery (2VO) and randomly divided into three groups: Sham, Vehicle (2VO), and Nimodipine10 (2VO + nimodipine 10 mg/kg). Each group was studied for 4 weeks postoperatively and assessed by the Morris water maze.
Results: The results of this study show that chronic brain hypoperfusion significantly increased the number of autophagic vacuoles with high LC3 II levels, but it decreased p-Akt and p-CREB levels, which were involved in the PI3K/Akt kinase pathway in the hippocampi of rats. Additionally, significant cognitive losses were observed following 2VO. Further analysis showed that, in VCID rats subjected to 2VO, nimodipine administration decreased autophagy, increased the Akt/CREB signaling pathway and significantly reduced brain damage.
Conclusions: We concluded that neuronal pathology and activation of the autophagic and Akt/CREB signaling pathway caused by chronic brain hypoperfusion could suppress cognitive behavior, which may provide a novel way for the prevention of VCID. The results of this study indicate that nimodipine protected the brain from chronic brain hypoperfusion damage by suppressing autophagy and activating the Akt/CREB signaling pathway.
Keywords: 2VO; PI3K/Akt signaling pathway; Vascular cognitive impairment and dementia; autophagy; nimodipine.