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.