Systemic administration of urocortin after intracerebral hemorrhage reduces neurological deficits and neuroinflammation
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JOURNAL OF NEUROINFLAMMATION
RESEARCH
Open Access
Systemic administration of urocortin after intracerebral hemorrhage reduces neurological deficits and neuroinflammation in rats Hock-Kean Liew1,2, Cheng-Yoong Pang2,3, Chih-Wei Hsu4,5, Mei-Jen Wang2,3, Ting-Yi Li2, Hsiao-Fen Peng2, Jon-Son Kuo3 and Jia-Yi Wang1,6*
Abstract Background: Intracerebral hemorrhage (ICH) remains a serious clinical problem lacking effective treatment. Urocortin (UCN), a novel anti-inflammatory neuropeptide, protects injured cardiomyocytes and dopaminergic neurons. Our preliminary studies indicate UCN alleviates ICH-induced brain injury when administered intracerebroventricularly (ICV). The present study examines the therapeutic effect of UCN on ICH-induced neurological deficits and neuroinflammation when administered by the more convenient intraperitoneal (i.p.) route. Methods: ICH was induced in male Sprague-Dawley rats by intrastriatal infusion of bacterial collagenase VII-S or autologous blood. UCN (2.5 or 25 μg/kg) was administered i.p. at 60 minutes post-ICH. Penetration of i.p. administered fluorescently labeled UCN into the striatum was examined by fluorescence microscopy. Neurological deficits were evaluated by modified neurological severity score (mNSS). Brain edema was assessed using the dry/ wet method. Blood-brain barrier (BBB) disruption was assessed using the Evans blue assay. Hemorrhagic volume and lesion volume were assessed by Drabkin’s method and morphometric assay, respectively. Pro-inflammatory cytokine (TNF-a, IL-1b, and IL-6) expression was evaluated by enzyme-linked immunosorbent assay (ELISA). Microglial activation and neuronal loss were evaluated by immunohistochemistry. Results: Administration of UCN reduced neurological deficits from 1 to 7 days post-ICH. Surprisingly, although a higher dose (25 μg/kg, i.p.) also reduced the functional deficits associated with ICH, it is significantly less effective than the lower dose (2.5 μg/kg, i.p.). Beneficial results with the low dose of UCN included a reduction in neurological deficits from 1 to 7 days post-ICH, as well as a reduction in brain edema, BBB disruption, lesion volume, microglial activation and neuronal loss 3 days post-ICH, and suppression of TNF-a, IL-1b, and IL-6 production 1, 3 and 7 days post-ICH. Conclusion: Systemic post-ICH treatment with UCN reduces striatal injury and neurological deficits, likely via suppression of microglial activation and inflammatory cytokine production. The low dose of UCN necessary and the clinically amenable peripheral route make UCN a potential candidate for development into a clinical treatment regimen. Keywords: anti-neuroinflammation, brain edema, intracerebral hemorrhage, urocortin
Background Spontaneous intracerebral hemorrhage (ICH) accounts for approximately 15% of stroke incidents in Western populations and an even higher proportion, up to 2030%, in Asian populations [1]. ICH is one of the most * Correspondence: [email protected] 1 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, T
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