In the present study, we investigated whether SSRIs such as fluoxetine and sertraline reduce brain injury and facilitate recovery following photothrombotic cortical ischemia in mice. Thus, it was speculated that postischemic treatment with SSRIs would exert a favorable influence on progressive ischemic brain damage and alterations in cerebral hemodynamics through the induction of HIF-1α and HO-1. A growing body of evidence suggests that HO may play an important role in protection against cerebral ischemia, confirming that induction of the HO-1 protein following cerebral ischemia can lead to a beneficial outcome ( Geddes et al., 1996 Nimura et al., 1996 Panahian et al., 1999 Bidmon et al., 2001 Fu et al., 2006). Heme oxygenase (HO)-1 (HO-1) is an inducible form of HO, which is the rate-limiting enzyme in the degradation of heme to yield equimolar quantities of biliverdin, carbon monoxide and iron ( Marks et al., 1991 Verma et al., 1993 Maines, 1997), and has been demonstrated to be an HIF-1α-regulated gene ( Lee et al., 1997 Dawn and Bolli, 2005). Emerging evidence suggests that after ischemia, HIF-1α exerts beneficial effects that favor neuronal survival ( Semenza, 2000 Acker and Acker, 2004). HIF-1 has been suggested to represent a novel therapeutic target in cerebrovascular disease, and HIF-1α gene therapy or treatment with HIF-1 activity inducers could provide protection against ischemia-induced cell death ( Semenza, 2001). The expression of hypoxia-inducible factor (HIF)-1α (HIF-1α), a specific oxygen-regulated subunit of HIF-1, is tightly regulated by the cellular O 2 concentration ( Semenza, 2001). This possibility is based on the evidence that depression may increase the risk of ischemic stroke ( Ramasubbu and Patten, 2003) and on the assumption that depression is a common indication for treatment with SSRIs. SSRI use may have a protective effect against the depression-related increase in the risk of ischemic stroke ( Jakovljevic and Tuomilehto, 2002). SSRIs induce vasoconstriction of large cerebral arteries and vasodilatation of small cerebral vessels ( Bonvento et al., 1991 Muhonen et al., 1997). However, it is essential to understand the cerebrovascular effects of SSRIs, since serotonin is a potent vasoactive amine with complex actions on the cerebral arteries. Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants, and may prove to be effective in the treatment of post-stroke depression because previous studies have reported that the symptoms of post-stroke depression are related to serotonergic dysfunction in the brain ( Kim et al., 2002). Although antidepressants have been effectively used to treat post-stroke depression ( Primeau, 1988 Gainotti et al., 2001 Paolucci et al., 2001), their prescription is critically influenced by their safety, tolerability, and their impact on co-morbid conditions ( Rampello et al., 2005). Post-stroke depression has negative effects on functional recovery ( Parikh et al., 1990 Kotila et al., 1999), and these effects can be overcome by pharmacological treatment of depression ( Gainotti et al., 2001).
These results suggest that SSRIs, such as fluoxetine and sertraline, facilitate recovery following photothrombotic cortical ischemia via enhancement of HO-1 and HIF-1α proteins expression, thereby providing a benefit in therapy of cerebral ischemia.ĭepression is a frequent and important problem among patients with stroke and presents as post-stroke depression in 20~50% of stroke survivors ( Starkstein and Robinson, 1989 Andersen et al., 1994b Bhogal et al., 2005).
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-1α (HIF-1α) proteins in the ischemic region.
The Evans blue extravasation indices of the fluoxetine- and sertraline-treated groups were significantly lower than that of the vehicle group. Treatment with fluoxetine and sertraline significantly reduced the infarct size. The animals were treated with fluoxetine or sertraline once a day for 14 d starting 1 h after ischemic insult. Permanent focal ischemia was induced in the medial frontal and somatosensory cortices by irradiating the skull with cold light laser.
Male ICR mice were anesthetized and systemically administered Rose Bengal. This study aimed to investigate whether selective serotonin reuptake inhibitors (SSRIs) attenuate brain injury and facilitate recovery following photothrombotic cortical ischemia in mice.
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