Fasudil alleviates brain damage in rats after carbon monoxide poisoning through regulating neurite outgrowth inhibitor/oligodendrocytemyelin glycoprotein signalling pathway.

Publisher: Blackwell Country of Publication: England NLM ID: 101208422 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1742-7843 (Electronic) Linking ISSN: 17427835 NLM ISO Abbreviation: Basic Clin Pharmacol Toxicol Subsets: MEDLINE

Publication: <2005-> : Oxford : Blackwell
Original Publication: Copenhagen, Denmark : Oxford, UK : Nordic Pharmacological Society Distributed by Blackwell Munksgaard, 2004-

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/*analogs & derivatives ; Brain/*drug effects ; Carbon Monoxide Poisoning/*drug therapy ; Protein Kinase Inhibitors/*pharmacology ; Signal Transduction/*drug effects; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/therapeutic use ; Animals ; Brain/pathology ; Carbon Monoxide/toxicity ; Carbon Monoxide Poisoning/etiology ; Carbon Monoxide Poisoning/pathology ; Disease Models, Animal ; Drug Evaluation, Preclinical ; GPI-Linked Proteins/metabolism ; Humans ; Male ; Myelin Proteins/metabolism ; Nogo Proteins/metabolism ; Protein Kinase Inhibitors/therapeutic use ; Rats ; rho-Associated Kinases/antagonists & inhibitors ; rho-Associated Kinases/metabolism

Carbon monoxide (CO) poisoning can lead to many serious neurological symptoms. Currently, there are no effective therapies for CO poisoning. In this study, rats exposed to CO received hyperbaric oxygen therapy, and those in the Fasudil group were given additional Fasudil injection once daily. We found that the escape latency in CO poisoning group (CO group) was significantly prolonged, the T 1 /T total was obviously decreased, and the mean escape time and the active escape latency were notably extended compared with those in normal control group (NC group, P < 0.05). After administration of Fasudil, the escape latency was significantly shortened, T 1 /T total was gradually increased as compared with CO group (>1 week, P < 0.05). Ultrastructural damage of neurons and blood-brain barrier of rats was serious in CO group, while the structural and functional integrity of neuron and mitochondria maintained relatively well in Fasudil group. Moreover, we also noted that the expressions of neurite outgrowth inhibitor (Nogo), oligodendrocyte-myelin glycoprotein (OMgp) and Rock in brain tissue were significantly increased in CO group, and the elevated levels of the three proteins were still observed at 2 months after CO poisoning. Fasudil markedly reduced their expressions compared with those of CO group (P < 0.05). In summary, the activation of Nogo-OMgp/Rho signalling pathway is associated with brain injury in rats with CO poisoning. Fasudil can efficiently down-regulate the expressions of Nogo, OMgp and Rock proteins, paving a way for the treatment of acute brain damage after CO poisoning.
(© 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

81571283 National Natural Science Foundation of China; 2018GSF118215 key project of research and development of Shandong province; ZR2016HL21 Natural Science Foundation of Shandong; ZR2017LH068 Natural Science Foundation of Shandong; 2015-420 Traditional Chinese Medicine Science and Technology Development Project in Shandong; 2017-388 Traditional Chinese Medicine Science and Technology Development Project in Shandong

Keywords: CO poisoning; Fasudil; Nogo; OMgp; Rock; cognitive function

0 (GPI-Linked Proteins)
0 (Myelin Proteins)
0 (Nogo Proteins)
0 (Omg protein, rat)
0 (Protein Kinase Inhibitors)
0 (Rtn4 protein, rat)
7U1EE4V452 (Carbon Monoxide)
84477-87-2 (1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine)
EC 2.7.11.1 (rho-Associated Kinases)
Q0CH43PGXS (fasudil)

Date Created: 20190328 Date Completed: 20191223 Latest Revision: 20191223

20240829

10.1111/bcpt.13233

30916885