**Background:** Cardiac arrest (CA) followed by return of spontaneous circulation (ROSC) causes multi-organ dysfunction, with renal ischemia-reperfusion injury (IRI) occurring in approximately 50% of cases. Renal inflammation is a key pathogenic component, involving pro-inflammatory cytokines (TNF-α, IL-6) that amplify injury and anti-inflammatory cytokines (IL-4, IL-13) that promote repair. Risperidone, a second-generation antipsychotic, has been shown to induce hypothermia and protect neurons from IRI in animal models, but its effects on renal IRI following CA/ROSC had not been studied.
**Methods:** Male Sprague-Dawley rats (n=7 per group for biochemical/histological analyses; n=21 per group for CA groups for survival) were divided into four groups: Sham-vehicle, Sham-Risp, CA-vehicle, and CA-Risp. CA was induced by asphyxia for 5 minutes followed by CPR. Risperidone (10 mg/kg) or vehicle (saline) was administered intravenously after CA/CPR. Body temperature was monitored, and survival was assessed over 2 days using Kaplan-Meier analysis. Serum BUN, creatinine, and LDH were measured at 12 h, 1 day, and 2 days post-ROSC. Kidney histopathology was evaluated using H&E staining with a 0-5 injury scale. Immunohistochemistry quantified IL-6, TNF-α, IL-4, and IL-13 expression as relative optical density (ROD).
**Key Results:** Risperidone induced significant hypothermia (33 ± 0.5°C) from 1-2 hours after CA, with spontaneous return to normothermia. The survival rate at 2 days was 100% in sham groups, 6.25% in the CA-vehicle group, and 63.64% in the CA-Risp group. Serum BUN, creatinine, and LDH were significantly elevated in the CA-vehicle group versus Sham-vehicle (p < 0.05), and were significantly reduced in the CA-Risp group from 12 h to 2 days post-ROSC (p < 0.05 vs. CA-vehicle). Histopathological injury (tubular necrosis, brush border loss, vacuolization, glomerular capillary dilatation, inflammatory infiltration) was severe in the CA-vehicle group and markedly attenuated in the CA-Risp group. IL-6 immunoreactivity in the CA-vehicle group increased progressively to 207.9% of Sham-vehicle at 2 days; in the CA-Risp group, it was significantly lower (69.7% of CA-vehicle at 2 days). TNF-α immunoreactivity in the CA-vehicle group reached 248.8% of Sham-vehicle at 2 days; in the CA-Risp group, it was 73.1% of CA-vehicle at 2 days. Conversely, IL-4 immunoreactivity in the CA-vehicle group fell to 42.6% of Sham-vehicle at 2 days, while in the CA-Risp group it remained at 90.0% of Sham-vehicle. IL-13 immunoreactivity in the CA-vehicle group dropped to 21.8% of Sham-vehicle at 2 days, but was not significantly altered in the CA-Risp group.
**Clinical Implications:** This study provides preclinical evidence that risperidone, administered after CA/ROSC, can protect the kidneys from IRI through anti-inflammatory effects—suppressing pro-inflammatory cytokines (TNF-α, IL-6) while preserving anti-inflammatory cytokines (IL-4, IL-13). The improved survival rate (63.64% vs. 6.25%) is striking, though the study is limited by its animal model and small sample sizes. The hypothermic effect of risperidone may contribute to renal protection, consistent with known benefits of therapeutic hypothermia. If confirmed in further studies, risperidone could represent a readily available, inexpensive adjunct to post-cardiac arrest care, potentially reducing the high incidence of acute kidney injury (30-50% of CA survivors) and improving outcomes. However, the exact protective mechanisms remain unclear, and human studies are needed to assess efficacy and safety in patients with CA/ROSC.