AbstractThis study aimed to investigate the role of interleukin‐6 (IL‐6) in the pathogenesis of neonatal hypoxic‐ischemic encephalopathy (NHIE). Sprague‐Dawley (SD) rats were used for the establishment of hypoxic‐ischemic (HI) model. The Zea‐Longa scoring was used to evaluate the extent of the neurological deficits. Triphenyl tetrazolium chloride (TTC) staining was used to measure the volume of infarction in the brain following HI protocol. The expression of IL‐6 in the cortex and/or hippocampus at multiple time points after HI was examined by immunohistochemistry, western blotting and immunofluorescence. Moreover, small interfering RNAs (siRNA) were used to inhibit the expression of IL‐6 in‐vitro and in‐vivo, and the concomitant expression of the Bcl‐2 associated X protein (BAX) and caspase 3 was also measured. HI induced a significant brain damage, and these pathological changes were accompanied by IL‐6 upregulation which was found localized in cortical neurons. The inhibition of IL‐6 expression fostered neuronal and axonal growth, and a reduction in cellular apoptosis in cortical neuronal cultures, and cortex and hippocampus of neonatal rats. The expression of apoptotic markers such as BAX and caspase 3 was closely associated with IL‐6. Downregulation of IL‐6 could ameliorate HI‐induced deficiencies by mediating the expression of caspase 3 and BAX.