Additional increased effects of mannitol-temozolomide combined treatment on blood-brain barrier permeability

• Published in: Biochemical and biophysical research communications 2018-03, Vol.497 (2), p.769-775
• Main Authors: Choi, Chunggab, Kim, Hye Min, Shon, Jeeheun, Park, Jiae, Kim, Hyeong-Taek, Oh, Seung-Hun, Kim, Nam Keun, Kim, Ok Joon
• Format: Article
• Language: English
• Subjects: Animals; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blood−brain barrier; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Capillary Permeability - drug effects; Cell Line; Dacarbazine - analogs & derivatives; Dacarbazine - pharmacology; Dacarbazine - therapeutic use; Drug Synergism; Humans; Ischemia; Male; Mannitol; Mannitol - pharmacology; Mannitol - therapeutic use; Permeability; Rats; Rats, Sprague-Dawley; Stroke; Temozolomide; Tight Junction Proteins - analysis; Tight Junction Proteins - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2018.02.149

The blood−brain barrier (BBB) is major obstacle in drug or stem cell treatment in chronic stroke. We hypothesized that adding mannitol to temozolomide (TMZ) is a practically applicable method for resolving the low efficacy of intravenous mannitol therapy. In this study, we investigated whether BBB permeability could be increased by this combined treatment. First, we established a chronic ischemic stroke rat model and examined changes in leakage of Evans blue dye within a lesion site, and in expression of tight junction proteins (TJPs), by this combined treatment. Additionally, in an in vitro BBB model using trans-wells, we analyzed changes in diffusion of a fluorescent tracer and in expression of TJPs. Mannitol-TMZ combined treatment not only increased the amount of Evans blue dye within the stroke lesion site, but also reduced occludin expression in rat brain microvessels. The in vitro study also showed that combined treatment increased the permeability for two different-sized fluorescent tracers, especially large size, and decreased expression of TJPs, such as occludin and ZO-1. Increased BBB permeability effects were more prominent with combined than with single treatments. Mannitol-TMZ combined treatment induced a decrease of TJPs with a consequent increase in BBB permeability. This combined treatment is clinically useful and might provide new therapeutic options by enabling efficient intracerebral delivery of various drugs that could not otherwise be used to treat many CNS diseases due to their inability to penetrate the BBB. •The blood−brain barrier (BBB) poses a major obstacle to therapeutic drug delivery.•Mannitol-temozolomide (TMZ) combined treatment induced decreased tight junction protein expression.•Mannitol-TMZ combined treatment increased BBB permeability.•This combined treatment may improve intracerebral delivery of various drugs.