Melatonin attenuates the postischemic increase in blood–brain barrier permeability and decreases hemorrhagic transformation of tissue‐plasminogen activator therapy following ischemic stroke in mice

Abstract

Melatonin protects against transient middle cerebral artery (MCA) occlusion and may be suited as an add-on therapy of tissue plasminogen activator (t-PA) thrombolysis. Herein, we examined whether melatonin would reduce postischemic increase in the blood-brain barrier (BBB) permeability and, therefore, attenuate the risk of hemorrhagic transformation after t-PA therapy in experimental stroke. Twelve mice were subjected to transient occlusion of the MCA for 1 hr, followed by 24 hr of reperfusion. Melatonin (5 mg/kg, i.p.) or vehicle was given at the beginning of reperfusion. BBB permeability was evaluated by quantitation of Evans Blue leakage. An additional 32 mice underwent photothrombotic occlusion of the distal MCA, and were administered vehicle or t-PA (10 mg/kg, i.v.), alone or in combination with melatonin (5 mg/kg, i.p.), at 6 hr postinsult. The animals were then killed after 24 hr for the determination of infarct and hemorrhage volumes. Relative to controls, melatonin-treated animals had significantly reduced BBB permeability (by 52%; P < 0.001). Additionally, we found that at 6 hr after photo-irradiation, either t-PA or melatonin, or a combined administration of t-PA plus melatonin, did not significantly affect brain infarction (P > 0.05), compared with controls. Mice treated with t-PA alone, however, had significantly increased hemorrhagic formation (P < 0.05), and the event was effectively reversed by co-treatment with melatonin (P < 0.05). Thus, melatonin improved postischemic preservation of the BBB permeability and a decreased risk of adverse hemorrhagic transformation after t-PA therapy for ischemic stroke. The findings further highlight melatonin's potential role in the field of thrombolytic treatment for ischemic stroke patients.

Protective Effect of Melatonin upon Neuropathology, Striatal Function, and Memory Ability after Intracerebral Hemorrhage in Rats

“…Melatonin (5 mg=kg) has been shown to reduce blood-brain barrier permeability and the hemorrhagic transformation into ICH after ischemic stroke in mice (Chen et al, 2006b), and this reduction in bleeding is likely to be mediated by attenuation of matrix metalloproteinase (MMP)-9 activation (Hung et al, 2008). Similar findings relating to MMP-9 and hemorrhagic transformation have been reported after edaravone treatment in rats (Yagi et al, 2009).…”

“…ICH shares several pathophysiological mechanisms with ischemic stroke , and the treatment of cerebral ischemia with melatonin has repeatedly been shown to exert cytoprotective effects (Chen et al, 2006a(Chen et al, , 2006bKilic et al, 2005;Kondoh et al, 2002;Lee et al, 2007;Pei et al, 2003Pei et al, , 2002Torii et al, 2004). In light of the available evidence, we hypothesized that melatonin treatment would ameliorate free-radical generation, decrease brain edema, reduce brain injury, and improve functional outcomes after intracerebral hemorrhage in rats.…”

Delayed Treatment with Carboxy-PTIO Permits a 4-h Therapeutic Window of Opportunity and Prevents Against Ischemia-Induced Energy Depletion Following Permanent Focal Cerebral Ischemia in Mice

“…Laser-Doppler flowmetry was used for LCBF measurements [7,[18][19][20][21]. The scalp was incised along the midline, and two 1-mm areas in bilateral parietal bones were thinned 1.5 mm posterior and 5 mm lateral to the bregma for placement of the LDF probe (model P436).…”

“…Focal cerebral ischemia was employed by intra-arterial suture occlusion of the proximal right middle cerebral artery (MCA) [7,[16][17][18][19][20][21]. Briefly, the bifurcation of the right common carotid artery was exposed under an operative microscope.…”

Imaging in Acute Stroke – a Personal View*

“…Permeability imaging [145,146] should be applied additionally immediately before and a short time after recanalizing therapy to identify an additional risk for later symptomatic hemorrhage. Closure of early BBB leakage could represent a target for possible adjunctive therapy [147,148]. If the existence of a toxic effect of thrombolytics could be verified in man, it should be time to consider a more widespread use of mechanical alternatives for recanalization [149,150].…”