期刊
EXPERIMENTAL NEUROLOGY
卷 357, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2022.114181
关键词
Blood-brain barrier; Drug delivery; Endothelial cell; Ischemic stroke; Memantine; Organic cation transporters
资金
- National Institute of Neurological Diseases and Stroke (National Institute of Neurological Diseases and Stroke) [R01 NS084941]
- American Heart Association [19TPA34910113]
The neuroprotective effects of memantine in stroke rely on the involvement of organic cation transporters 1 and 2 (Oct1/Oct2), as shown in a middle cerebral artery occlusion (MCAO) model. Additionally, this study provides evidence for the critical role of blood-brain barrier transporters in the delivery of stroke therapeutics.
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, [3H]memantine uptake was increased in ischemic brain tissue. Cimetidine inhibited blood-to-brain uptake of [3H]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.
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