Sleep deprivation attenuates acute ischemic stroke-induced hippocampal neuronal injury via the IL-38/NF-κB axis.

BACKGROUND

Although epidemiological studies have identified sleep disorders as a risk factor for stroke, animal studies have yielded conflicting results regarding the impact of sleep deprivation (SD). This study aimed to investigate whether SD preconditioning can alleviate early neurological impairment following acute ischemic stroke and to explore the potential role of the anti-inflammatory cytokine interleukin-38 (IL-38) in this process.

METHODS

Male Sprague-Dawley rats underwent 10-day SD preconditioning using a modified multi-platform method before being subjected to transient middle cerebral artery occlusion (tMCAO). Neurological function was evaluated using the Longa scoring system, while cerebral infarct volume was quantified via 2,3,5-triphenyltetrazolium chloride (TTC) staining. Histopathological changes in brain tissues were assessed through hematoxylin-eosin (H&E) staining, Nissl staining, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining. The expression level of IL-38 and the status of inflammatory responses were analyzed using Western blotting, immunohistochemistry, and immunofluorescence. IL-38 knockout (IL-38 KO) rats were employed to verify the essential role of IL-38 in SD-induced neuroprotection.

RESULTS

SD preconditioning significantly improved neurological function, reduced cerebral infarct volume, and decreased neuronal apoptosis in the CA1 region of the hippocampus. Notably, SD preconditioning markedly upregulated IL-38 expression, which was predominantly localized in neurons and exhibited a time-dependent increase pattern. In IL-38 KO rats, the neuroprotective effects of SD preconditioning were completely abolished, with no improvements observed in neurological scores, infarct size, or neuronal survival. Mechanistically, SD preconditioning reduced the levels of pro-inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-1β [IL-1β]) and inhibited the phosphorylation of p65 in the nuclear factor-κB (NF-κB) signaling pathway, and these regulatory effects were largely dependent on IL-38.

CONCLUSIONS

SD preconditioning confers neuroprotection against acute ischemic stroke by upregulating IL-38 expression. IL-38 mediates this protection, at least in part, by attenuating neuroinflammation through suppression of the NF-κB signaling pathway. These findings identify IL-38 as a critical mediator of SD-induced ischemic tolerance, warranting further clinical investigation.