Abstract
Oxiracetam (ORC) is a commonly used nootropic drug for improving cognition and memory impairments. The therapeutic effect and underlying mechanism of ORC in vascular dementia (VaD) treatment remain unknown. In this study, 3-month-old male Sprague-Dawley rats with permanent bilateral common carotid artery occlusion-induced VaD were treated orally with low (100 mg/kg) or high (200 mg/kg) dose ORC once a day for 4 weeks. The results of the Morris water maze test and Nissl staining showed that ORC treatment significantly alleviated learning and memory deficits and neuronal damage in rats with VaD. Mechanistically, the protein levels of a panel of genes associated with neuronal apoptosis (Bcl-2, Bax) and autophagy (microtubule-associated protein 1 chain 3, Beclin1, p62) were significantly altered by ORC treatment compared with VaD, suggesting a protective role of ORC against VaD-induced neuronal apoptosis and autophagy. Moreover, the Akt/mTOR pathway, which is known to be the upstream signaling governing apoptosis and autophagy, was found to be activated in ORC-treated rats, suggesting an involvement of Akt/mTOR activation in ORC-rendered protection in VaD rats. Taken together, this study demonstrated that ORC may alleviate learning and memory impairments and neuronal damage in VaD rats by altering the expression of apoptosis/autophagy-related genes and activation of the Akt/mTOR signaling pathway in neurons.
Highlights
Vascular dementia (VaD) is the most common cause of dementia in the elderly, second to Alzheimer’s disease (AD), and is characterized by progressive cognitive and behavioral deterioration resulting from vascular events that damage blood vessels and impair blood flow in the brain [1,2]
VaD is characterized by progressive cognitive impairment and extensive neuropathological lesions in brain tissues due to chronic cerebral hypoperfusion [1,2,3,37]
Similar trends were observed in Nissl staining for neurons. These results are consistent with previous research [38,39,40], suggesting that the rat model of VaD used in the present study is reliable
Summary
Vascular dementia (VaD) is the most common cause of dementia in the elderly, second to Alzheimer’s disease (AD), and is characterized by progressive cognitive and behavioral deterioration resulting from vascular events that damage blood vessels and impair blood flow in the brain [1,2]. It is urgently required to find an effective pharmacological compound against VaD due to its high prevalence and morbidity, and lack of effective treatment options It is well-established that the balance of protein expression between antiapoptotic Bcl-2 and proapoptotic Bax plays an important role in cell apoptosis [4]. Activation of the PI3K/Akt pathway can protect neurons from apoptosis in cerebral ischemia-reperfusion (IR) injury via the regulation of Bax and Bcl-2 expression [7,8]. These data suggest Bcl-2/Bax-modulated apoptosis as a potential therapeutic target for prevention and intervention of BCCAO-induced VaD. The interplay between apoptosis and autophagy may cause coexistence of both
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