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Cramer contributes an important article [1] emphasizing the importance of the fluoxetine for motor recovery after acute ischemic stroke (FLAME) trial in providing evidence for the use of fluoxetine in ischemic stroke [2]. In his paper, Cramer highlights many important aspects of the trial but does not discuss possible mechanisms of action for improvements in motor function.

A potential mechanism to explain the findings from the FLAME trial may center on the action of brain-derived neurotrophic factor (BDNF). Brain-derived neurotrophic factor is a neurotrophin that has been implicated in neurogenesis and synaptic plasticity [3] and has been shown to improve recovery from brain ischemia [4]. Given that fluoxetine administration upregulates BDNF, it is intriguing that the effect of fluoxetine in improving motor recovery from ischemic stroke may be related to this mechanism.

Studies have demonstrated that fluoxetine may influence neuronal plasticity through BDNF [5]. In an animal model, both chronic fluoxetine administration and intracortical infusion of BDNF restored ocular dominance plasticity due to monocular deprivation in rats. In addition, fluoxetine administration increased BDNF expression in the visual cortex adding further credence to this claim.

Perhaps more pertinent to the FLAME trial, BDNF may facilitate nervous system repair and improve motor function in animal models of cerebral ischemia. Intraventricular BDNF administration, starting one-day before and finishing seven-days after middle cerebral artery occlusion in the rat, decreased infarct volume, and improved neurological function, as assessed by a motor score assessing posture and circling behavior [6]. Conversely, inhibition of BDNF in similar models of ischemia impeded recovery of reaching [4]. As in the FLAME trial, these animal models implemented robust rehabilitation programs suggesting that BDNF may influence recovery of skilled motor function with the aid of appropriate rehabilitative therapy.

The FLAME trial [2] reported a statistically significant difference in motor function between stroke patients given fluoxetine and placebo only after 90 days of fluoxetine administration, an appropriate timescale for motor recovery mechanisms involving BDNF. Further studies aimed at unraveling the mechanisms by which fluoxetine exerts its positive influence on motor recovery in ischemic stroke are certainly warranted. Brain-derived neurotrophic factor may very well be an important player.

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