Targeting organic cation transporters at the blood-brain barrier to treat ischemic stroke in rats.

TitleTargeting organic cation transporters at the blood-brain barrier to treat ischemic stroke in rats.
Publication TypeJournal Article
Year of Publication2022
AuthorsStanton JA, Williams EI, Betterton RD, Davis TP, Ronaldson PT
JournalExp Neurol
Date Published2022 Nov
KeywordsAnimals, Blood-Brain Barrier, Cations, Cimetidine, Infarction, Middle Cerebral Artery, Ischemic Stroke, Male, Memantine, Neuroprotective Agents, Organic Cation Transport Proteins, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate, Stroke

Drug discovery and development for stroke is challenging as evidenced by few drugs that have advanced beyond a Phase III clinical trial. Memantine is a N-methyl-d-aspartate (NMDA) receptor antagonist that has been shown to be neuroprotective in various preclinical studies. We have identified an endogenous BBB uptake transport system for memantine: organic cation transporters 1 and 2 (Oct1/Oct2). Our goal was to evaluate Oct1/Oct2 as a required BBB mechanism for memantine neuroprotective effects. Male Sprague-Dawley rats (200-250 g) were subjected to middle cerebral artery occlusion (MCAO) for 90 min followed by reperfusion. Memantine (5 mg/kg, i.v.) was administered 2 h following intraluminal suture removal. Specificity of Oct-mediated transport was evaluated using cimetidine (15 mg/kg, i.v.), a competitive Oct1/Oct2 inhibitor. At 2 h post-MCAO, [H]memantine uptake was increased in ischemic brain tissue. Cimetidine inhibited blood-to-brain uptake of [H]memantine, which confirmed involvement of an Oct-mediated transport mechanism. Memantine reduced post-MCAO infarction and brain edema progression as well as improved neurological outcomes during post-stroke recovery. All positive effects of memantine were attenuated by co-administration of cimetidine, which demonstrates that Oct1/Oct2 transport is required for memantine to exert neuroprotective effects in ischemic stroke. Furthermore, Oct1/Oct2-mediated transport was shown to be the dominant mechanism for memantine brain uptake in the MCAO model despite a concurrent increase in paracellular "leak." These novel and translational findings provide mechanistic evidence for the critical role of BBB transporters in CNS delivery of stroke therapeutics, information that can help such drugs advance in clinical trials.

Alternate JournalExp Neurol
PubMed ID35905840
PubMed Central IDPMC9620710
Grant ListR01 NS084941 / NS / NINDS NIH HHS / United States
Faculty Member Reference: 
Thomas P Davis, PhD
Patrick T Ronaldson, PhD, FAAPS