Neprilysin Inhibitor and Angiotensin Receptor Blocker Attenuate Ischemic Brain Injury: Unveiling the Kinin-Mediated Pathway

Abstract

Kinin peptides play a key role in regulating blood vessel tone, renal function, and protection against ischemia-reperfusion injury. Neprilysin is one of the primary enzymes responsible for degrading several vasoactive peptides including bradykinin. Concurrent inhibition of neprilysin and angiotensin II receptors leads to elevated bradykinin levels by reducing its breakdown, potentially enhancing its interaction with bradykinin receptor complexes. It has therefore been hypothesized that increased bradykinin generation may contribute to the neuroprotective effect of neprilysin inhibitors and angiotensin receptor blockers against global cerebral ischemia-reperfusion injury (GCI/R). GCI/R was induced in mice by transient occlusion of bilateral common carotid arteries. A combination of Sacubitril/Valsartan (30/50 mg/kg and 60/100 mg/kg, PO) was administered for 7 days before subjecting to ischemia. Behavioral changes were assessed using the beam walk test for motor coordination and passive avoidance and Y-maze tests for spatial memory, which were further supported by biochemical and histopathological assessment. Our results demonstrated that prophylactic treatment with Sacubitril/Valsartan led to a dose-dependent improvement in neurological deficits, a reduction in oxidative stress and inflammation, and an increased number of intact neurons in the hippocampus and cortex of GCI/R mice. Interestingly, immunohistochemical analysis revealed upregulation of bradykinin B2 receptors accompanied by changes in eNOS and NFκB expression. However, coadministration of the bradykinin B2 receptor antagonist, Icatibant, attenuated the neuroprotective effects of Sacubitril/Valsartan. Our findings suggest that the neuroprotective effects of Sacubitril/Valsartan may be mediated by the endogenous accumulation of vasodilatory bradykinin. Thus, concurrent inhibition of neprilysin and angiotensin II receptors represents a promising therapeutic target for stroke management.