Dimemorfan protects rats against ischemic stroke through activation of sigma-1 receptor-mediated mechanisms by decreasing glutamate accumulation.
Dimemorfan, an antitussive and a sigma-1 (sigma(1)) receptor agonist, has been reported to display neuroprotective properties. We set up an animal model of ischemic stroke injury by inducing cerebral ischemia (for 1 h) followed by reperfusion (for 24 h) (CI/R) in rats to examine the protective effects and action mechanisms of dimemorfan against stroke-induced damage. Treatment with dimemorfan (1.0 microg/kg and 10 microg/kg, i.v.) either 15 min before ischemia or at the time of reperfusion, like the putative sigma(1) receptor agonist, PRE084 (10 microg/kg, i.v.), ameliorated the size of the infarct zone by 67-72% or 51-52%, respectively, which was reversed by pre-treatment with the selective sigma(1) receptor antagonist, BD1047 (20 microg/kg, i.v.). Major pathological mechanisms leading to CI/R injury including excitotoxicity, oxidative/nitrosative stress, inflammation, and apoptosis are all downstream events initiated by excessive accumulation of extracellular glutamate. Dimemorfan treatment (10 microg/kg, i.v., at the time of reperfusion) inhibited the expressions of monocyte chemoattractant protein-1 and interleukin-1beta, which occurred in parallel with decreases in neutrophil infiltration, activation of inflammation-related signals (p38 mitogen-activated protein kinase, nuclear factor-kappaB, and signal transducer and activator of transcription-1), expression of neuronal and inducible nitric oxide synthase, oxidative/nitrosative tissue damage (lipid peroxidation, protein nitrosylation, and 8-hydroxy-guanine formation), and apoptosis in the ipsilateral cortex after CI/R injury. Dimemorfan treatment at the time of reperfusion, although did not prevent an early rise of glutamate level, significantly prevented subsequent glutamate accumulation after reperfusion. This inhibitory effect was lasted for more than 4 h and was reversed by pre-treatment with BD1047. These results suggest that dimemorfan activates the sigma(1) receptor to reduce glutamate accumulation and then suppresses initiation of inflammation-related events and signals as well as induction of oxidative and nitrosative stresses, leading to reductions in tissue damage and cell death. In conclusion, our results demonstrate for the first time that dimemorfan exhibits protective effects against ischemic stroke in CI/R rats probably through modulation of sigma(1) receptor-dependent signals to prevent subsequent glutamate accumulation and its downstream pathologic events.
Shen
Yuh-Chiang
YC
National Research Institute of Chinese Medicine, Taipei, Taiwan.
Wang
Yea-Hwey
YH
Chou
Yueh-Ching
YC
Liou
Kuo-Tong
KT
Yen
Jiin-Cherng
JC
Wang
Wen-Yen
WY
Liao
Jyh-Fei
JF
D000704:Analysis of Variance; D000818:Animals; D020520:Brain Infarction / Q000209:etiology / Q000517:prevention & control; D002545:Brain Ischemia / Q000188:drug therapy*; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009019:Morphinans / Q000627:therapeutic use*; D009025:Morpholines / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D017480:Receptors, sigma / Q000819:agonists / Q000378:metabolism*; D015427:Reperfusion Injury / Q000517:prevention & control*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000097605:Sigma-1 Receptor; D000097782:NF-kappaB-Inducing Kinase
D018932:Chemokine CCL2; D018698:Glutamic Acid; D009019:Morphinans; D009025:Morpholines; D019001:Nitric Oxide Synthase; D009195:Peroxidase; D017346:Protein Serine-Threonine Kinases; D017480:Receptors, sigma; D050794:STAT1 Transcription Factor; D000097605:Sigma-1 Receptor; D000097782:NF-kappaB-Inducing Kinase; C491766:Ccl2 protein, rat; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C012621:dimemorfan