Tissue acidosis associated with ischemic stroke to guide nimodipine
delivery
Authors: M Tóth Orsolya 
Published: May 2022

Background: Ischemic stroke is a leading cause of death and
disability worldwide. Yet, the effective therapy of focal cerebral ischemia
has been an unresolved challenge. We propose here that ischemic tissue
acidosis, a sensitive metabolic indicator of injury progression in cerebral
ischemia, can be harnessed for the targeted delivery of neuroprotective
agents. Ischemic tissue acidosis, which represents the accumulation of
lactic acid in malperfused brain tissue is significantly exacerbated by the
recurrence of SD events. Deepening acidosis itself activates specific ion
channels to cause neurotoxic cellular Ca2+ accumulation and cytotoxic edema.
These processes are thought to contribute to the loss of the ischemic
penumbra. Importantly, acidosis in the ischemic penumbra may also be used to
guide therapeutic intervention. Nimodipine, an L-type VGCC antagonist
dilates cerebral arterioles, but its systemic administration may cause
potential side effects (mainly hypotension). We have 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. Methods: Two sets of experiments are presented in
this thesis. In Experimental Project I, nimodipine was applied in solution
(100 μM), then global forebrain ischemia was induced in half of the animals
by bilateral common carotid artery occlusion under isoflurane anesthesia.
Functional hyperemia in the somatosensory cortex was created by mechanical
stimulation of the contralateral whisker pad under α‐chloralose anesthesia.
SD events were elicited subsequently by 1 M KCl. LFP and CBF in the parietal
somatosensory cortex were monitored by electrophysiology and LDF. In
Experimental Project II, nimodipine was associated with pH-sensitive
nanoparticles in suspension. After washing the nanoparticle suspension with
or without nimodipine (100 μM) on the exposed brain surface of anesthetized
rats, both common carotid arteries were occluded to create forebrain
ischemia. SDs were elicited by 1 M KCl to deepen the ischemic insult. LFP,
CBF and tissue pH were recorded from the cerebral cortex. Microglia
activation and neuronal survival were evaluated in brain sections by
immunocytochemistry. Results: Nimodipine in solution attenuated evoked
potentials and SD. In addition to the elevation of baseline CBF, nimodipine
augmented hyperemia in response to both somatosensory stimulation and SD,
the drug effect was particularly discernable under ischemia.
Ischemia-induced tissue acidosis initiated nimodipine release from
nanoparticles, confirmed by the significant elevation of baseline CBF.
Nimodipine shortened the duration of both SD itself, and the associated
tissue acidosis, moreover it enhanced the SD-related hyperemia. Chitosan
nanoparticles did not activate microglia. Conclusions: The administered
nanoparticles release nimodipine in acidic tissue environment, which
reliably delineates sites at risk of injury. 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. Ultimately, this approach may offer a new way
to treat stroke patients with the hope of more effective therapy, and better
stroke outcome.