Arizona Health Sciences

Drug delivery to the ischemic brain.

TitleDrug delivery to the ischemic brain.
Publication TypeJournal Article
Year of Publication2014
AuthorsThompson BJ, Ronaldson PT
JournalAdv Pharmacol
Volume71
Pagination165-202
Date Published2014
ISSN1557-8925
KeywordsAnimals, Brain Ischemia, Drug Delivery Systems, Humans, Hypoxia, Pharmaceutical Preparations
Abstract

Cerebral ischemia occurs when blood flow to the brain is insufficient to meet metabolic demand. This can result from cerebral artery occlusion that interrupts blood flow, limits CNS supply of oxygen and glucose, and causes an infarction/ischemic stroke. Ischemia initiates a cascade of molecular events in neurons and cerebrovascular endothelial cells including energy depletion, dissipation of ion gradients, calcium overload, excitotoxicity, oxidative stress, and accumulation of ions and fluid. Blood-brain barrier (BBB) disruption is associated with cerebral ischemia and leads to vasogenic edema, a primary cause of stroke-associated mortality. To date, only a single drug has received US Food and Drug Administration (FDA) approval for acute ischemic stroke treatment, recombinant tissue plasminogen activator (rt-PA). While rt-PA therapy restores perfusion to ischemic brain, considerable tissue damage occurs when cerebral blood flow is reestablished. Therefore, there is a critical need for novel therapeutic approaches that can "rescue" salvageable brain tissue and/or protect BBB integrity during ischemic stroke. One class of drugs that may enable neural cell rescue following cerebral ischemia/reperfusion injury is the HMG-CoA reductase inhibitors (i.e., statins). Understanding potential CNS drug delivery pathways for statins is critical to their utility in ischemic stroke. Here, we review molecular pathways associated with cerebral ischemia and novel approaches for delivering drugs to treat ischemic disease. Specifically, we discuss utility of endogenous BBB drug uptake transporters such as organic anion transporting polypeptides and nanotechnology-based carriers for optimization of CNS drug delivery. Overall, this chapter highlights state-of-the-art technologies that may improve pharmacotherapy of cerebral ischemia.

DOI10.1016/bs.apha.2014.06.013
Alternate JournalAdv. Pharmacol.
PubMed ID25307217
PubMed Central IDPMC4281266
Grant ListR01 NS084941 / NS / NINDS NIH HHS / United States
Faculty Member Reference: 
Patrick T Ronaldson, Ph.D.