Korean J Physiol Pharmacol.  2009 Jun;13(3):257-263. 10.4196/kjpp.2009.13.3.257.

Fluoxetine and Sertraline Attenuate Postischemic Brain Injury in Mice

• Shin TK
• Kang MS
• Lee HY
• Seo MS
• Kim SG
• Kim CD
• Lee WS

• KMID: 2071679
• DOI: http://doi.org/10.4196/kjpp.2009.13.3.257

Abstract

This study aimed to investigate whether selective serotonin reuptake inhibitors (SSRIs) attenuate brain injury and facilitate recovery following photothrombotic cortical ischemia in mice. Male ICR mice were anesthetized and systemically administered Rose Bengal. Permanent focal ischemia was induced in the medial frontal and somatosensory cortices by irradiating the skull with cold light laser. The animals were treated with fluoxetine or sertraline once a day for 14 d starting 1 h after ischemic insult. Treatment with fluoxetine and sertraline significantly reduced the infarct size. 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 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-1alpha (HIF-1alpha) proteins in the ischemic region. These results suggest that SSRIs, such as fluoxetine and sertraline, facilitate recovery following photothrombotic cortical ischemia via enhancement of HO-1 and HIF-1alpha proteins expression, thereby providing a benefit in therapy of cerebral ischemia.

Keyword

Cerebral blood flow autoregulation; Focal cerebral ischemia; Heme oxygenase-1; Hypoxia-inducible factor-1alpha; Selective serotonin reuptake inhibitors

MeSH Terms

Animals
Arterial Pressure
Brain
Brain Injuries
Brain Ischemia
Cold Temperature
Evans Blue
Fluoxetine
Heme Oxygenase-1
Homeostasis
Humans
Ischemia
Light
Male
Mice
Mice, Inbred ICR
Proteins
Rose Bengal
Serotonin Uptake Inhibitors
Sertraline
Skull
Evans Blue
Fluoxetine
Heme Oxygenase-1
Proteins
Rose Bengal
Serotonin Uptake Inhibitors
Sertraline

Figure

• 

  Fig. 1. Study design and drug treatment. rCBF, regional cerebral blood flow.

• 

  Fig. 2. Effects of fluoxetine and sertraline on infarct area (A) and volume (B) in mice. Animals were treated daily with fluoxetine (10 mg/kg, i.p.) or sertraline (20 mg/kg, i.p.) for 14 d. Data are presented as mean±S.E.M. from 6 independent experiments. ∗p<0.05, ∗∗p<0.01, ∗∗∗p<0.001 vs. vehicle group.

• 

  Fig. 3. Evans blue extravasation in cerebral cortex after photothrombotic cortical ischemia in mice. Mice were sacrificed at 1 h after Evans blue injection, at 24 h after drug treatment, and at 14 d after photothrombotic cortical ischemia. The numbers in columns indicate the numbers of animals. ###p<0.001 vs. sham group. ∗∗∗p<0.001 vs. vehicle group.

• 

  Fig. 4. Effects of fluoxetine and sertraline on regional cerebral blood flow (rCBF) response to changes in mean arterial blood pressure (MABP). Animals were treated daily with fluoxetine (10 mg/kg, i.p.) or sertraline (20 mg/kg, i.p.) for 14 d. The numbers in parentheses indicate the numbers of animals.

• 

  Fig. 5. Effects of fluoxetine and sertraline on hypoxia-inducible factor-1α (HIF-1α) and heme oxygense-1 (HO-1) protein expression in photothrombotic ischemic cortex. Animals were treated daily with fluoxetine (10 mg/kg, i.p.) or sertraline (20 mg/kg, i.p.) for 14 d. Data are presented as mean±S.E.M. from 6 independent experiments. ∗p<0.05, ∗∗p<0.01 vs. vehicle, ##p<0.01 vs. sham.

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