Tissue Acidosis Associated with Ischemic Stroke to Guide Neuroprotective Drug Delivery

Abstract

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 spreading depolarizations. 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. The unique metabolic status of the ischemic penumbra has been exploited to identify the penumbra zone with imaging tools. Importantly, acidosis in the ischemic penumbra may also be used to guide therapeutic intervention. Agents with neuroprotective promise are suggested here to be delivered selectively to the ischemic penumbra with pH-responsive smart nanosystems. The administered nanoparticels release their cargo in acidic tissue environment, which reliably delineates sites at risk of injury. Therefore, tissue pH-targeted drug delivery is expected to enrich sites of ongoing injury with the therapeutical agent, without the risk of unfavorable off-target effects.

Dysregulation of Astrocyte Ion Homeostasis and Its Relevance for Stroke-Induced Brain Damage

“…Waves of spreading depolarization result in transient, but long-lasting acidification of the ischemic cortex of rats [ 165 ]. Acidosis accompanying ischemia is a harmful event, reducing astrocyte glutamate uptake [ 166 ] and exacerbating cytotoxic edema and cellular damage [ 167 ]. When exposed to a low extracellular pH, astrocytes are unable to maintain their pH above 7, but acidify and may even undergo cell death [ 159 , 162 , 168 ].…”

DAMPs and RAGE Pathophysiology at the Acute Phase of Brain Injury: An Overview

“…The intranasal administration of nanoparticles can accumulate their cargo in the brain unlike systemic free administration [124]. Moreover, some nanoparticles release their cargo only in an acidic environment, which is a characteristic of ischemic tissue at risk of irreversible damage; this molecular design allows the enriching of acutely injured tissue without the risk of unfavorable off-target effects [125]. These new technological breakthroughs are a major step forward in specifically targeting injured cerebral tissue with drugs that interfere with DAMPs and PPRs.…”

Role of Carbonic Anhydrase in Cerebral Ischemia and Carbonic Anhydrase Inhibitors as Putative Protective Agents

“…In hypoxic/anoxic conditions, in vitro studies have shown a decrease in pH in neurons and glial cells [ 11 ]. Brain acidosis itself causes neuronal injury by generating free radicals, affecting glutamate reuptake, glial cell activation and neuronal apoptosis [ 12 , 13 ] and exacerbates ischemic brain injury [ 14 , 15 ] leading to cerebral infarction such as edema and blood-brain barrier (BBB) dysfunction [ 16 , 17 ].…”