Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy.

Autor: Nissinen J; Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland., Andrade P; Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland., Natunen T; Institute of Biomedicine, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, PO Box 1627, FI-70211 Kuopio, Finland., Hiltunen M; Institute of Biomedicine, University of Eastern Finland and Department of Neurology, Kuopio University Hospital, PO Box 1627, FI-70211 Kuopio, Finland., Malm T; Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland., Kanninen K; Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland., Soares JI; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal; Instituto de Biologia Molecular e Celular da, Universidade do Porto, Porto, Portugal; Programa Doutoral em Neurociências, Universidade do Porto, Porto, Portugal., Shatillo O; Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland., Sallinen J; Orion Corporation ORION PHARMA, PO Box 425, Tengströminkatu 8, 20101 Turku, Finland., Ndode-Ekane XE; Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland., Pitkänen A; Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, PO Box 1627, FI-70211 Kuopio, Finland. Electronic address: asla.pitkanen@uef.fi.
Jazyk: angličtina
Zdroj: Epilepsy research [Epilepsy Res] 2017 Oct; Vol. 136, pp. 18-34. Date of Electronic Publication: 2017 Jul 12.
DOI: 10.1016/j.eplepsyres.2017.07.005
Abstrakt: Treatment of TBI remains a major unmet medical need, with 2.5 million new cases of traumatic brain injury (TBI) each year in Europe and 1.5 million in the USA. This single-center proof-of-concept preclinical study tested the hypothesis that pharmacologic neurostimulation with proconvulsants, either atipamezole, a selective α 2 -adrenoceptor antagonist, or the cannabinoid receptor 1 antagonist SR141716A, as monotherapy would improve functional recovery after TBI. A total of 404 adult Sprague-Dawley male rats were randomized into two groups: sham-injured or lateral fluid-percussion-induced TBI. The rats were treated with atipamezole (started at 30min or 7 d after TBI) or SR141716A (2min or 30min post-TBI) for up to 9 wk. Total follow-up time was 14 wk after treatment initiation. Outcome measures included motor (composite neuroscore, beam-walking) and cognitive performance (Morris water-maze), seizure susceptibility, spontaneous seizures, and cortical and hippocampal pathology. All injured rats exhibited similar impairment in the neuroscore and beam-walking tests at 2 d post-TBI. Atipamezole treatment initiated at either 30min or 7 d post-TBI and continued for 9 wk via subcutaneous osmotic minipumps improved performance in both the neuroscore and beam-walking tests, but not in the Morris water-maze spatial learning and memory test. Atipamezole treatment initiated at 7 d post-TBI also reduced seizure susceptibility in the pentylenetetrazol test 14 wk after treatment initiation, although it did not prevent the development of epilepsy. SR141716A administered as a single dose at 2min post-TBI or initiated at 30min post-TBI and continued for 9 wk had no recovery-enhancing or antiepileptogenic effects. Mechanistic studies to assess the α 2 -adrenoceptor subtype specificity of the disease-modifying effects of atipametzole revealed that genetic ablation of α 2A -noradrenergic receptor function in Adra2A mice carrying an N79P point mutation had antiepileptogenic effects after TBI. On the other hand, blockade of α 2C -adrenoceptors using the receptor subtype-specific antagonist ORM-12741 had no favorable effects on the post-TBI outcome. Finally, to assess whether regulation of the post-injury inflammatory response by atipametzole in glial cells contributed to a favorable outcome, we investigated the effect of atipamezole on spontaneous and/or lipopolysaccharide-stimulated astroglial or microglial cytokine release in vitro. We observed no effect. Our data demonstrate that a 9-wk administration of α2A-noradrenergic antagonist, atipamezole, is recovery-enhancing after TBI.
(Copyright © 2017 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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