Chitosan nanoparticles release nimodipine in response to tissue acidosis to attenuate spreading depolarization evoked during forebrain ischemia

Abstract

Stroke is an important cause of mortality and disability. Treatment options are limited, therefore the progress in this regard is urgently needed. Nimodipine, an L-type voltage-gated calcium channel antagonist dilates cerebral arterioles, but its systemic administration may cause potential side effects. We have previously constructed chitosan nanoparticles as drug carriers, which release nimodipine in response to decreasing pH typical of cerebral ischemia. Here we have set out to evaluate this nanomedical approach to deliver nimodipine selectively to acidic ischemic brain tissue.After washing a nanoparticle suspension with or without nimodipine (100 μM) on the exposed brain surface of anesthetized rats (n = 18), both common carotid arteries were occluded to create forebrain ischemia. Spreading depolarizations (SDs) were elicited by 1M KCl to deepen the ischemic insult. Local field potential, cerebral blood flow (CBF) and tissue pH were recorded from the cerebral cortex. Microglia activation and neuronal survival were evaluated in brain sections by immunocytochemistry.Ischemia-induced tissue acidosis initiated nimodipine release from nanoparticles, confirmed by the significant elevation of baseline CBF (47.8 ± 23.7 vs. 29.3 ± 6.96%). Nimodipine shortened the duration of both SD itself (48.07 ± 23.29 vs. 76.25 ± 17.2 s), and the associated tissue acidosis (65.46 ± 20.2 vs. 138.3 ± 66.07 s), moreover it enhanced the SD-related hyperemia (48.15 ± 42.04 vs. 17.29 ± 11.03%). Chitosan nanoparticles did not activate microglia.The data support the concept that tissue acidosis linked to cerebral ischemia can be employed as a trigger for targeted drug delivery. Nimodipine-mediated vasodilation and SD inhibition can be achieved by pH-responsive chitosan nanoparticles applied directly to the brain surface.