Drug Delivery to the Ischemic Brain

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 inneurons 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 re-established. 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 (OATPs/Oatps) 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.

Sulfated Polysaccharide Isolated from the Sea Cucumber Stichopus japonicus Against PC12 Hypoxia/Reoxygenation Injury by Inhibition of the MAPK Signaling Pathway

“…Hypoxic injury has been implicated in the central nervous system (CNS) pathology of numerous disorders, including stroke, head trauma, neoplasia, vascular malformations, and neurodegenerative diseases (Thompson and Ronaldson 2014). Cerebral ischemia-reperfusion injury results from the permanent reduction in cerebral blood flow that causes nerve cell function disorder, irreversible necrosis, and even death.…”

Gyógyszertranszporterek szerepe a központi idegrendszerben

“…Újabb kutatások az efflux transzporterek gátlása helyett az uptake transzporterek (OATP) aktiválására helyezik a hangsúlyt a gyógyszerek agyba jutásának elősegí-tésére, ezáltal elkerülve a nemkívánatos mellékhatásokat [51] (például statinok esetében). A statinok HMG-CoA reduktázgátló antioxidáns neuroprotektív hatású anyagok, amelyek szerepet játszanak az agyi ischaemiás/ hypoxiás károsodások terápiájában.…”

Targeting transporters: Promoting blood–brain barrier repair in response to oxidative stress injury

“…It has proposed that Oatp1a4, a rodent homologue of OATP1A2, is the primary drug transporting Oatp isoform expressed at the rat BBB (Hagenbuch and Meier, 2004). Recently, our laboratory demonstrated that Oatp1a4 is a BBB transporter that can be effectively targeted for facilitation of effective CNS drug delivery (Ronaldson et al 2011; Ronaldson and Davis, 2013; Thompson et al 2014; Thompson and Ronaldson, 2014). …”