title: Sesamin suppresses activation of microglia and p44/42 MAPK pathway, which confers neuroprotection in rat intracerebral hemorrhage.
abstract: Thrombin plays important roles in the pathology of intracerebral hemorrhage (ICH). The recruitment of activated microglia, accompanied by thrombin-induced phosphorylation of the mitogen-activated protein kinase (MAPK) family, contributes to ICH-associated neuron loss. Here we investigated the possibility that sesamin, a lignan of sesame seed oil, is a natural candidate as an inhibitor of microglial activation and MAPK pathways under ICH insults. Sesamin (30-100 μM) suppressed thrombin-induced nitric oxide (NO) production by primary-cultured rat microglia via inhibition of inducible NO synthase (iNOS) protein expression, independently of the antioxidative effect. Sesamin selectively inhibited p44/42 MAPK phosphorylation in the MAPK family (p38 and p44/42) involved in iNOS protein expression in primary-cultured rat microglia. An in vivo rat ICH model was prepared by intrastriatal injection of 0.20U collagenase type IV unilaterally. ICH evoked the phosphorylation of p44/42 MAPK, microglial proliferation with morphological change into the activated ameboid form, and neuron loss. The phosphorylation of p44/42 MAPK was inhibited by intracerebroventricular administration of 30-nmol sesamin. Sesamin prevented ICH-induced increase of microglial cells in the perihematomal area. Notably, ramified microglia, the resting morphology, were observed in brain sections of the animals administrated sesamin. Sesamin furthermore achieved neuroprotection in the perihematomal area but not in the hematomal center. These results suggest that sesamin is a promising natural product as a novel therapeutic strategy based on the regulation of microglial activities accompanied by the activated p44/42 MAPK pathway in ICH.
authors.affiliation: Department of Pharmacotherapeutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Sanzo, 1 Gakuen-cho, Fukuyama, Hiroshima 729-0292, Japan. Electronic address: ohnishi@fupharm.fukuyama-u.ac.jp.
authors.forename: M
authors.initials: M
authors.lastname: Ohnishi
authors.affiliation: Department of Pharmacotherapeutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Sanzo, 1 Gakuen-cho, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Monda
authors.affiliation: Department of Pharmacotherapeutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Sanzo, 1 Gakuen-cho, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Takemoto
authors.affiliation: Department of Pharmacotherapeutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Sanzo, 1 Gakuen-cho, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Matsuoka
authors.affiliation: Department of Natural Product Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Sanzo, 1 Gakuen-cho, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: C
authors.initials: C
authors.lastname: Kitamura
authors.affiliation: Department of Natural Product Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Sanzo, 1 Gakuen-cho, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ohashi
authors.affiliation: Department of Natural Product Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Sanzo, 1 Gakuen-cho, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Shibuya
authors.affiliation: Department of Pharmacotherapeutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Sanzo, 1 Gakuen-cho, Fukuyama, Hiroshima 729-0292, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Inoue
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004149:Dioxoles / Q000494:pharmacology*; D004195:Disease Models, Animal; D017705:Lignans / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D017628:Microglia / Q000187:drug effects* / Q000201:enzymology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004149:Dioxoles; D017705:Lignans; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C054125:sesamin