Abstract WP449: Short Term (1 month) Daily Remote Ischemic Conditioning (RIC) Induces Vascular Remodeling and Improves Long Term Outcomes (6 month) in a Mouse Model of Vascular Cognitive Impairment (VCI)

Abstract

Background and Purpose: There is presently no specific therapy for the treatment of VCI. The bilateral carotid artery stenosis (BCAS) model is regarded as a valid model for VCI and vascular dementia. We reported that daily RIC is effective by improving cerebral blood flow (CBF), reducing white matter (WM) damage and improving cognition. The purpose of this study was to determine if 1MO RIC is as effective as 4MO RIC and if the treatment effects are durable out to 6MO. Methods: Microcoil induced BCAS model was used to induce chronic hypoperfusion. Adult C57BL/6J male mice (10-weeks) were randomly assigned to 4-different groups (N=10), and subjected to Sham-BCAS, BCAS-(+sham RIC), BCAS+RIC-1MO and BCAS+RIC-4MO. RIC was started 7d post-surgery daily for 1MO or 4MOs. Behavioral test and CBF was performed at 1, 4 and 6MO after BCAS surgery. Functional outcomes were assessed using novel object recognition (NOR) test for non-spatial working memory, and hanging wire test for motor impairment. Histopathology as well as immunohistochemistry for CD31 and myelin basic protein (MBP) were also performed on the of the brain tissue collected after the neurobehavioral tests. Statistical significance was determined at p <0.05. Results: RIC-therapy for 1MO or 4MO significantly improved CBF in the BCAS+RIC groups. The RIC-1MO treatment was effective as the RIC-4MO treatment at improving CBF at 6MO. Mice from the BCAS group showed significant loss in the discrimination index as determined by the NOR test, and poor motor function in hanging wire test. RIC-therapy in BCAS+RIC (1MO & 4MO) groups significantly improved functional outcomes as compared to the BCAS group whereas there was no difference between the RIC groups. Histopathological studies showed prevention of WM degeneration by RIC. Immunohistochemical analysis at 6 MOs showed increased CD31 staining (angiogenesis) and increased MBP staining (myelination) in the RIC groups compared to sham RIC. Conclusions: Both 1MO and 4MO RIC-therapy improve long term CBF and angiogenesis at 6 MO and reduce WM damage and improve functional outcomes. One month of daily RIC is as effective as 4MO of daily RIC at improving CBF and long term functional outcomes (6MO) in the BCAS model. This suggests that 1MO of RIC induces durable vascular remodeling.