Calcitriol,alleviates global cerebral ischemia-induced cognitive impairment by reducing apoptosis regulated by VDR/ERK signaling pathway in rat hippocampus

Background: Vitamin D (VD) has important neuroprotective functions in the central nervous system. However, further exploration is still needed in the neuroprotective effects of VD monomer therapy on global cerebral ischemia (GCI) and its potential molecular mechanism. Objective: To investigate whether calcitriol, a biologically active metabolite of VD, could alleviate cognitive impairment induced by GCI via reducing cell apoptosis and activating the extracellular signal-regulated kinase (ERK) signaling pathway. Methods: A total of 145 adult male Sprague Dawley rats were randomly divided into five groups: Sham group (n = 45), GCI group (n = 45), calcitriol treatment group (GCI + calcitriol, n = 45), PD98059 treatment group (n = 5) and vehicle group (n = 5). Morris water maze test was used for evaluating spatial learning and memory functions. Neurological Severity Score and wet-dry weight method were applied to detect neurological deficits and brain water content, respectively. Hematoxylin and eosin staining, transmission electron microscopy, and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end-labeling staining were performed for evaluating the changes of hippocampal CA1 neurons. Immunocytochemistry, immunofluorescence chemistry, and western blot analysis were performed for evaluating the changes of related proteins. Results: Calcitriol significantly ameliorated the spatial learning and memory impairments, improved neurological function, attenuated brain edema, and improved the morphological defects in the CA1 area of the hippocampus. Besides, calcitriol reduced GCI-induced cell apoptosis and reversed the up-regulation of pro-apoptotic proteins (Caspase-3 and Bax) and the down-regulation of anti-apoptotic protein (Bch-2). Furthermore, calcitriol also increased the expression of VD receptors (VDR) and activated the ERK signaling pathway. Moreover, the p-ERK1/2 inhibitor PD98059 reversed the effect of calcitriol on the expression of apoptosis-related proteins. Conclusions: Calcitriol may have a protective effect against GCI-induced cognitive impairments via inhibition of apoptotic cascade by activating the VDR/ERK signaling pathway.