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

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 ±â€¯23.7 vs. 29.3 ±â€¯6.96%). Nimodipine shortened the duration of both SD itself (48.07 ±â€¯23.29 vs. 76.25 ±â€¯17.2 s), and the associated tissue acidosis (65.46 ±â€¯20.2 vs. 138.3 ±â€¯66.07 s), moreover it enhanced the SD-related hyperemia (48.15 ±â€¯42.04 vs. 17.29 ±â€¯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.

High incidence of adverse cerebral blood flow responses to spreading depolarization in the aged ischemic rat brain.

Spreading depolarizations (SDs) occur spontaneously in the brain after stroke, exacerbate ischemic injury, and thus emerge as a potential target of intervention. Aging predicts worse outcome from stroke; yet, the impact of age on SD evolution is not clear. Cerebral ischemia was induced by bilateral common carotid artery occlusion in young (8-9 weeks old, n = 8) and old (2 year olds, n = 6) anesthetized rats. Sham-operated animals of both age groups served as control (n = 12). Electrocorticogram, direct current potential, and cerebral blood flow (CBF) variations were acquired via a small craniotomy above the parietal cortex. SDs were elicited by KCl through a second craniotomy distal to the recording site. Ischemia and age delayed the recovery from SD. CBF decreased progressively during ischemia in the old animals selectively, and inverse neurovascular coupling with SD evolved in the old but not in the young ischemic group. We propose that (mal)adaptation of cerebrovascular function with aging impairs the SD-related CBF response, which is implicated in the intensified expansion of ischemic damage in the old brain.