Abstract
Shikonin (SK) exerts neuroprotective effects; however, to date, its protective effect against chronic cerebral hypoperfusion- (CCH-) induced vascular dementia (VaD) has not been investigated. Therefore, the current study investigated whether SK could mitigate the cognitive deficits caused by CCH. The effects of SK treatment on the PTEN/Akt/CREB/BDNF signaling pathway and apoptosis in hippocampal neurons were examined in a rat model of VaD established via bilateral common carotid artery occlusion (BCCAO). Fifty-two rats were randomly divided into 4 groups: sham, vehicle, SK-L (10 mg/kg SK per day), and SK-H (25 mg/kg SK per day). SK was regularly administered by gavage for 2 weeks. The results of the water maze test revealed that the escape latency in the vehicle group was significantly longer than that in the sham group, and rats in the vehicle group spent a smaller proportion of time in the target quadrant than those in the sham group. SK treatment reduced the escape latencies and increased the proportion of time spent in the target quadrant. Nissl staining showed morphological damage in the CA1 areas of the hippocampus in the vehicle group. SK treatment alleviated the injuries to hippocampal neurons. Western blot analysis showed higher p-PTEN and lower p-Akt, p-CREB, and BDNF expression in the vehicle group than in the sham group. SK administration reversed the upregulation of p-PTEN and the downregulation of p-Akt, p-CREB, and BDNF. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling- (TUNEL-) positive cells in the hippocampal CA1 region of the vehicle group was significantly increased. Treatment with SK decreased the number of positive cells. Furthermore, as marker proteins of apoptosis, bcl-2 expression was decreased and bax expression was increased; thus, the ratio of bcl-2/bax was decreased in the vehicle group. SK treatment upregulated the expression of bcl-2 and downregulated the expression of bax, thereby elevating the bcl-2/bax ratio. Moreover, the aforementioned effects of SK were dose-dependent. The effect of 25 mg/kg per day was more obvious than that of 10 mg/kg per day. In conclusion, SK inhibited hippocampal neuronal apoptosis to protect against CCH-induced injury by regulating the PTEN/Akt/CREB/BDNF signaling pathway, consequently improving cognitive impairment.
Highlights
With the increasing incidence rate of cerebrovascular disease, vascular dementia (VaD) has become one of the common dementia types in elderly individuals [1]
We investigated whether the neuroprotective effects were achieved via the PTEN/Akt/ cAMP-response element binding protein (CREB)/brainderived neurotrophic factor (BDNF) pathway
Compared with the vehicle group, both the SK-L and SK-H groups had shorter escape latencies during the five days (p < 0.01 for both groups; Figure 1(a)). e ratio of the time spent in the target quadrant in the absence of a submerged platform was significantly different between the groups
Summary
With the increasing incidence rate of cerebrovascular disease, vascular dementia (VaD) has become one of the common dementia types in elderly individuals [1]. Diseases that lead to VaD include hemorrhagic cerebrovascular disease, ischemic cerebrovascular disease, and acute and chronic hypoxic cerebrovascular disease [2]. Chronic cerebral hypoperfusion (CCH) has an especially close relationship with the pathogenesis of VaD [1]. The mechanism of CCH-induced VaD is still unclear. Studies have shown that CCH causes ischemia and hypoxia, which activate a series of pathological reactions, including neuroinflammation, oxidative stress, glutamate excitotoxicity, and calcium overload [3,4,5]. Ese events interact with each other and activate downstream signaling pathways, leading to neuronal damage through Studies have shown that CCH causes ischemia and hypoxia, which activate a series of pathological reactions, including neuroinflammation, oxidative stress, glutamate excitotoxicity, and calcium overload [3,4,5]. ese events interact with each other and activate downstream signaling pathways, leading to neuronal damage through
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