The protective effect of betulinic acid on microvascular responsivity and protein expression in alzheimer disease induced by cerebral micro‐injection of beta‐amyloid and streptozotocin

Abstract Objective Alzheimer's disease (AD) is mainly caused by accumulation of β‐amyloid (Aβ) in vessels or parenchyma of the brain. Accordingly, natural compounds such as betulinic acid (BA) might improve the AD signs by increase in blood flow and through reduction in amyloid plaques. Methods Intra‐hippocampal injection of BA (0.2 and 0.4 μmol/L /10 μL DMSO /rat) was done at intervals of 180 and 10 min before co‐microinjection of 0.1 μmol/L Aβ dissolved in PBS (5 μL/rat, hippocampi) and 1.5 mg/kg Streptozotocin dissolved in aCSF (10 μL/rat, lateral ventricles). Cerebro‐vascular responsivity tested by Laser Doppler, BBB leakage, Elisa assays of cytokines (TNF‐α and IL‐10), and Western blot analysis of proteins (BDNF and AchE) in the hippocampus were assessed 1 month after the injections. Results Microvascular reaction and BBB function were significantly impaired in AD rats, which were improved via BA pretreatment. BA could increase BDNF expression and decrease cytokine levels in the hippocampus of AD rats (especially 0.1 μmol/L Aβ: 0.4 μmol/L BA); however, no significant changes were detected in the blotting of AchE among the groups. Conclusions Betulinic acid could have a role in AD through protecting microcirculation, alleviating inflammation, and up‐regulating BDNF expression which is clearer toward 1:4 molar ratios of Aβ to BA.