Dimemorfan protects rats against ischemic stroke through activation of sigma‐1 receptor‐mediated mechanisms by decreasing glutamate accumulation

Abstract

phosphate buffer; RMCA, right middle cerebral artery; RNS, reactive nitrogen species; ROS, reactive oxygen species; STAT-1, signal transducer and activator of transcription-1; TNF, tumor necrosis factor. AbstractDimemorfan, an antitussive and a sigma-1 (r 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 lg/kg and 10 lg/ kg, i.v.) either 15 min before ischemia or at the time of reperfusion, like the putative r 1 receptor agonist, PRE084 (10 lg/kg, i.v.), ameliorated the size of the infarct zone by 67-72% or 51-52%, respectively, which was reversed by pretreatment with the selective r 1 receptor antagonist, BD1047 (20 lg/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 lg/kg, i.v., at the time of reperfusion) inhibited the expressions of monocyte chemoattractant protein-1 and interleukin-1b, which occurred in parallel with decreases in neutrophil infiltration, activation of inflammationrelated signals (p38 mitogen-activated protein kinase, nuclear factor-jB, 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 r 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 r 1 receptor-dependent signals to prevent subsequent glutamate accumulation and its downstream pathologic events.

Ferulic acid inhibits nitric oxide-induced apoptosis by enhancing GABAB1 receptor expression in transient focal cerebral ischemia in rats

“…In addition, colocalization of nitrotyrosine-and cleaved caspase-3-positive cells markedly increased in the ischemic cortex at 24 h of reperfusion; however, it was suppressed by FA treatment in the S-FA and R-FA groups. These results are consistent with previous reports which demonstrated that nNOS and iNOS expression are markedly increased in the ischemic area 24 h after cerebral ischemia, and pharmacologically-selective inhibitors of the glutamate receptor-PSD-95-nNOS complex and iNOS reduce nitrotyrosine formation, attenuate caspase-3 activation, and ameliorate ischemic brain injury [6,[20][21][22] . On the basis of these findings, we posit that FA exerts its protective effect against PSD-95, nNOS, and iNOS-mediated oxidative/ nitrative stress (nitrotyrosine) in the ischemic cortex of the S-FA and R-FA groups at 24 h of reperfusion, and the antioxidative/nitrative effect of FA further contributes to the inhibition of caspase-3-dependent apoptosis.…”

“…Excitotoxicity induced by activation of glutamate receptors is the predominant mechanism underlying neuronal apoptosis in stroke [4] . Cerebral ischemic damage is associated with excessive release of excitatory glutamate, which subsequently upregulates not only the expression of neuronal nitric oxide synthase (nNOS), but also inducible nitric oxide synthase (iNOS) [5,6] . Numerous studies [7][8][9][10] have shown that the glutamate receptor-postsynaptic density-95 (PSD-95)-nNOS complex and iNOS produce an excessive amount of nitric oxide (NO) during cerebral I/R injury; NO immediately reacts with superoxide radicals to form peroxynitrite, which subsequently nitrates protein tyrosine residues, generating nitrotyrosine and leading to oxidative/nitrative stress.…”

Deciphering the neuroprotective mechanisms of Bu-yang Huan-wu decoction by an integrative neurofunctional and genomic approach in ischemic stroke mice

“…It has been well documented that "excitotoxicity" is the major pathophysiological mechanism underlying ischemic stroke-induced brain injury. In such cases, excessive glutamate accumulation in the extracellular space causes an inappropriate activation of ionotropic N-methyl-daspartate (NMDA) receptors in the brain as a result of stroke onset (Lo et al, 2003;Shen et al, 2008). This excessive amount of glutamate stimulates neuron death through oxidative and/or nitrosative stresses that induce overproduction of reactive oxygen species (ROS), such as hydroxyl radicals (OH − ), superoxide anions (O 2 •− ) and hydrogen peroxide (H 2 O 2 ), or reactive nitrogen species (RNS) such as nitric oxide (NO • ) and peroxynitrite (OONO − ) (Shen et al, 2005(Shen et al, , 2008.…”

Implications of Immune System in Stroke for Novel Therapeutic Approaches

“…Rats subjected to transient MCAO had reduced infarct volume when various sigma ligands such as dimemorphan [113], (+)pentazosin [114], and 4-phenyl-1-(4-phenylbutyl) piperidine [115] were administered during reperfusion. Inhibition of various components of the early response to stroke, such as NMDA receptor activation, neuronal nitric oxide synthesis, and inducible nitric oxide synthesis have been postulated to mediate this neuroprotection.…”