Cerebral ischemia is a major cause of death and long-term disability. NOD-like receptor protein 3 (NLRP3) inflammasome plays a central role in post-ischemic inflammation, with reactive oxygen species (ROS)-induced thioredoxin-interacting protein (TXNIP) activation contributing to its assembly. Calcitriol, the active form of vitamin D3, has anti-inflammatory and antioxidant properties. Here, we investigated the neuroprotective effects of calcitriol via modulation of the ROS/TXNIP/NLRP3 pathway in cerebral ischemia. We employed a rat model of transient middle cerebral artery occlusion (tMCAO) to induce ischemia/reperfusion (I/R) injury. Adult male Wistar rats (280–320 g) were randomly assigned to three experimental groups: sham, I/R, and calcitriol-treated. Calcitriol (1 µg/kg) was administered intraperitoneally at 30 minutes, 24 hours, and 48 hours post-surgery. At 72 hours, neurological deficits and infarct volume were assessed. Oxidative stress was evaluated by measuring ROS, malondialdehyde (MDA), nitric oxide (NO), and total antioxidant capacity (TAC). ELISA was utilized to assay the levels of Interleukin-1 beta (IL-1β) and, Interleukin-18 (IL-18). Protein expression of TXNIP, NLRP3, ASC, and Caspase-1 was analyzed via Western blot, and neuronal injury was assessed using Nissl staining. Molecular docking was used to assess the interaction strength between calcitriol and NLRP3. Results showed that calcitriol significantly alleviated neurological impairments, reduced infarct size of stroke, lowered oxidative stress and pro-inflammatory markers, and downregulated NLRP3 inflammasome components and TXNIP. Histological analysis confirmed neuroprotection, and docking analysis revealed favorable binding of calcitriol to NLRP3's NACHT domain. The present study suggests that calcitriol mitigates I/R-induced neuroinflammation by targeting the ROS/TXNIP/NLRP3 signaling pathway. • Calcitriol improves neurological outcomes in a cerebral ischemia/reperfusion injury. • Calcitriol reduces infarct volume and attenuates oxidative stress. • Calcitriol suppresses the inflammation via ROS/TXNIP/NLRP3 pathway. • Molecular docking shows calcitriol binds to the NLRP3 NACHT domain. • Calcitriol acts as a potential neuroprotective agent in ischemic stroke.
Behdarvandy et al. (Wed,) studied this question.