IL-17A monoclonal antibody as a translational therapy for post-cardiac arrest brain injury: clinical and preclinical evidence.

Abstract

BACKGROUND: Post-cardiac arrest brain injury (PCABI) is a major cause of mortality and disability among cardiac arrest (CA) survivors. The role of interleukin-17A (IL-17A) as a prognostic biomarker and therapeutic target in PCABI remains unvalidated. METHODS: Eighty adult CA patients with return of spontaneous circulation (ROSC) and 10 controls were enrolled. Serum IL-17A was measured at 24&#xa0;h post-ROSC. Thirty-day neurological outcomes were classified by the Cerebral Performance Category (CPC) scale. The prognostic value of IL-17A was evaluated using multivariable logistic regression and ROC curves. In rats asphyxial CA model, animals received vehicle or anti-IL-17A monoclonal antibody (secukinumab). Neurological function, survival, and biomarkers were assessed. RESULTS: Serum IL-17A levels were significantly higher in CA patients than in controls (2.42&#xa0;&#xb1;&#xa0;1.25 vs. 0.63&#xa0;&#xb1;&#xa0;0.34&#xa0;pg/mL, p&#xa0;<&#xa0;0.001). Patients with poor neurological outcomes (CPC 3-5) had higher IL-17A levels (2.72&#xa0;&#xb1;&#xa0;1.25 vs. 1.91&#xa0;&#xb1;&#xa0;1.10&#xa0;pg/mL, p&#xa0;=&#xa0;0.023). IL-17A independently predicted poor neurological outcomes (adjusted OR&#xa0;=&#xa0;3.56, 95&#xa0;% CI&#xa0;=&#xa0;1.31-9.63). ROC analysis showed an AUC of 0.702 for predicting neurological dysfunction. In the rat model, anti-IL-17A mAb treatment significantly increased 11-day survival (62.5&#xa0;% vs. 30.3&#xa0;%), improved neurological scores, and enhanced performance in the Morris water maze test. Mechanistically, anti-IL-17A mAb treatment reduced the levels of TNF-&#x3b1;, NSE, and NfL in serum and brain tissues. CONCLUSIONS: Elevated serum IL-17A is a potential early predictor of poor outcomes in PCABI. Early administration of anti-IL-17A mAb improved neurological recovery and survival in the experimental CA model by attenuating neuroinflammation.