title: Cholinergic agonist physostigmine suppresses excessive superoxide anion radical generation in blood, oxidative stress, early inflammation, and endothelial injury in rats with forebrain ischemia/reperfusion.
abstract: The cholinergic anti-inflammatory pathway is reportedly important in modulating the inflammatory response in local and systemic diseases, including ischemia/reperfusion pathophysiology. In this study, we investigated the effects of the cholinergic agonist, physostigmine, on jugular venous superoxide radical (O(2)(-)) generation, oxidative stress, early inflammation, and endothelial activation during forebrain ischemia/reperfusion (FBI/R) in rats. Fourteen male Wistar rat were allocated to the control group (n=7) or physostigmine group (n=7). The physostigmine group received 80 ng/g physostigmine intraperitoneally 24 h and 1 h before forebrain ischemia was established. The jugular venous O(2)(-) current was measured for 10 min during forebrain ischemia and for 120 min after reperfusion. The O(2)(-) current increased gradually during forebrain ischemia in both groups. The current increased markedly immediately after reperfusion in the control group but was significantly attenuated in the physostigmine group after reperfusion. Brain and plasma malondialdehyde, high-mobility group box 1 (HMGB1) protein, and intercellular adhesion molecule 1 (ICAM1) were significantly attenuated in the physostigmine group compared with the control group, except for brain HMGB1. The amount of O(2)(-) generated during FBI/R correlated with malondialdehyde, HMGB1, and ICAM1 in both the brain and plasma. In conclusion, the cholinergic agonist physostigmine suppressed jugular venous O(2)(-) generation, oxidative stress, early inflammation, and endothelial activation in the brain and plasma in the acute phase of cerebral ischemia/reperfusion. Therefore, the suppression of O(2)(-) is a key mechanism of the cholinergic anti-inflammatory pathway in the pathophysiology of cerebral ischemia/reperfusion.
authors.affiliation: Advanced Medical Emergency and Critical Care Center, Yamaguchi University Hospital, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kutsuna
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tsuruta
authors.forename: Motoki
authors.initials: M
authors.lastname: Fujita
authors.forename: Masaki
authors.initials: M
authors.lastname: Todani
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yagi
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Ogino
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Igarashi
authors.forename: Koshiro
authors.initials: K
authors.lastname: Takahashi
authors.forename: Tomonori
authors.initials: T
authors.lastname: Izumi
authors.forename: Shunji
authors.initials: S
authors.lastname: Kasaoka
authors.forename: Makoto
authors.initials: M
authors.lastname: Yuasa
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Maekawa
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D018679:Cholinergic Agonists / Q000494:pharmacology; D004560:Electricity; D004660:Encephalitis / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D024243:HMGB1 Protein / Q000097:blood / Q000378:metabolism; D007601:Jugular Veins / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000097:blood / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010830:Physostigmine / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D013481:Superoxides / Q000097:blood / Q000378:metabolism; D013997:Time Factors
chemical_list: D018679:Cholinergic Agonists; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D018696:Neuroprotective Agents; D013481:Superoxides; D008315:Malondialdehyde; D010830:Physostigmine