clozapine and Reperfusion-Injury

Ischemic stroke significantly perturbs neuronal homeostasis leading to a cascade of pathologic events causing brain damage. In this study, we assessed acute stroke outcome after chemogenetic inhibition of forebrain excitatory neuronal activity.. We generated hM4Di-TG transgenic mice expressing the inhibitory hM4Di, a Designer Receptors Exclusively Activated by Designer Drugs (DREADD)-based chemogenetic receptor, in forebrain excitatory neurons. Clozapine-N-oxide (CNO) was used to activate hM4Di DREADD. Ischemic stroke was induced by transient occlusion of the middle cerebral artery. Neurologic function and infarct volumes were evaluated. Excitatory neuronal suppression in the hM4Di-TG mouse forebrain was assessed electrophysiologically in vitro and in vivo, based on evoked synaptic responses, and in vivo based on occurrence of potassium-induced cortical spreading depolarizations.. Detailed characterization of hM4Di-TG mice confirmed that evoked synaptic responses in both in vitro hippocampal slices and in vivo motor cortex were significantly reduced after CNO-mediated activation of the inhibitory hM4Di DREADD. Further, CNO treatment had no obvious effects on physiology and motor function in either control or hM4Di-TG mice. Importantly, hM4Di-TG mice treated with CNO at either 10 min before ischemia or 30 min after reperfusion exhibited significantly improved neurologic function and smaller infarct volumes compared to CNO-treated control mice. Mechanistically, we showed that potassium-induced cortical spreading depression episodes were inhibited, including frequency and duration of DC shift, in CNO-treated hM4Di-TG mice.. Our data demonstrate that acute inhibition of a subset of excitatory neurons after ischemic stroke can prevent brain injury and improve functional outcome. This study, together with the previous work in optogenetic neuronal modulation during the chronic phase of stroke, supports the notion that targeting neuronal activity is a promising strategy in stroke therapy.

Topics: Animals; Cells, Cultured; Clozapine; Cortical Spreading Depression; Electrophysiological Phenomena; Evoked Potentials; Male; Mice; Mice, Transgenic; Motor Cortex; Neuroprotection; Prosencephalon; Psychomotor Performance; Reperfusion Injury; Stroke; Synapses; Treatment Outcome

Inflammatory reactions play an important role in ischemia/reperfusion injury in various organs. Since histamine is closely related to inflammatory reactions and immune responses, effects of postischemic administration of histaminergic ligands on ischemia-induced liver injury were examined in rats. Animals were subjected to warm ischemia for 30 min by occlusion of the left portal vein and hepatic artery under halothane anesthesia, and liver damage was evaluated by assessing plasma concentrations of transaminases after 24 h. Warm ischemia for 30 min provoked severe liver damage after 24 h, and the plasma concentrations of alanine transaminase (ALT) and aspartate transaminase (AST) were 8600 I.U./l and 13100 I.U./l, respectively. Subcutaneous injections of histamine twice, immediately and 6 h after reperfusion (20 mg/kg, each), alleviated liver damage. The plasma concentrations of ALT and AST in the histamine group were 35% and 24% of those in the control group, respectively. Neither mepyramine (3 mg/kg x 2), an H1 antagonist, nor cimetidine (15 mg/kg x 2), an H2 antagonist, affected the outcome in histamine-treated rats. However, thioperamide (5 mg/kg x 2), an H3/H4 antagonist, completely abolished the alleviation caused by histamine. Administration of dimaprit (1-10 mg/kg x 2), an H2/H4 agonist, mimicked the protective effect of histamine, and the effect of dimaprit is reversed by thioperamide, whereas neither H1 nor H2 antagonists altered the outcome caused by dimaprit. Clozapine (15 mg/kg x 2), an H4 agonist, also mimicked the protective effect of histamine. These findings indicate that stimulation of histamine H4 receptors after ischemic events prevents development of reperfusion injury in the liver.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Clozapine; Dimaprit; Dose-Response Relationship, Drug; Histamine; Ischemia; Liver; Male; Rats; Rats, Wistar; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Reperfusion Injury; Time Factors