Treatment with fluoxetine and sertraline shifted the lower limit of the mean arterial blood pressure for cerebral blood flow autoregulation toward normal, and significantly increased the expression of heme oxygenase-1 (HO-1) and hypoxia-inducible factor-1 (HIF-1) proteins in the ischemic region. such as (E)-Ferulic acid fluoxetine and sertraline, facilitate recovery following photothrombotic cortical ischemia via enhancement of HO-1 and HIF-1 proteins expression, thereby providing a benefit in therapy of cerebral ischemia. study. Serotonin has been reported to progressively decrease only in the occluded hemisphere of ischemic animals, and preischemic depletion of brain serotonin with p-chlorophenylalanine has been reported to decrease the incidence of ischemia (Welch et al., 1977). The improvement of photothrombotic cortical ischemia with fluoxetine and sertraline is also in accordance with the results of previous studies that have emphasized on serotonergic dysfunction as an etiology of aggression in patients with depressive disorder (Van Praag, 1998) or stroke (Kim et al., 2002). It has been shown that chronic antidepressant treatment (e.g., with fluoxetine) has been shown to up-regulate neurogenesis (Malberg, 2004). Fluoxetine has previously been reported to prevent MDMA (“ecstasy”)-induced degeneration of serotonergic nerve endings (Sanchez et al., 2001) and to increase the proliferation of neuronal stem cells derived from the hippocampus (Chiou et al., 2006). It is generally accepted that HIF-1 exerts beneficial effects that favor neuronal survival after ischemia (Semenza, 2000; Acker and Acker, 2004), and the induction of HO-1 protein may protect cerebral tissues from ischemic damage (Fu et al., 2006). HO-1, the inducible isoform of HO, catalyzes the rate-limiting step of heme oxidation to biliverdin, carbon monoxide, and the free ferrous iron (Otterbein and Choi, 2000; Ryter et al., 2002). Biliverdin is usually then rapidly converted by biliverdin reductase to bilirubin, a molecule with antioxidant properties, and free iron is usually sequestered by ferritin (Otterbein and Choi, 2000; Ryter et al., 2002). HO-1 is usually a heat-shock protein (HSP-32) that is induced in the brain in (E)-Ferulic acid response to permanent focal ischemia (Geddes et al., 1996; Panahian et al., 1999; Bidmon et al., 2001) and has been demonstrated to be an HIF-1 regulated gene (Lee et al., 1997; Dawn and Bolli, 2005). The increase in HO-1 expression in ischemic brain tissue is probably a physiological consequence in the recovery of neuronal tissue following focal cerebral infarction. In the present study, both fluoxetine and sertraline brought about a greater Rabbit Polyclonal to CD70 (E)-Ferulic acid enhancement in the expression of HO-1 protein as compared to the vehicle group along with HIF-1 protein expression in the photothrombotic ischemic cortex, indicative of a neuroprotective action of these drugs. Our findings also suggest that SSRIs protect against ischemic brain damage and facilitate recovery following photothrombotic cortical ischemia. Taken together, it is suggested that SSRIs, such as fluoxetine and sertraline, facilitate recovery following photothrombotic cortical ischemia through the enhancement of HO-1 and HIF-1 protein expression, thereby providing a benefit in the therapy of postischemic brain injury. ACKNOWLEDGEMENTS This work was supported for two years by Pusan National University Research Grant. ABBREVIATIONS SSRIsserotonin reuptake inhibitorsHO-1heme oxygenase-1HIF-1hypoxia-inducible factor-1BBBblood-brain barrierrCBFregional cerebral blood flowMABPmean arterial blood pressureLLlower limitHSP-32heat-shock protein.