Optimal dosages of fluoxetine in the treatment of hypoxic brain injury induced by 3-nitropropionic acid: implications for the adjunctive treatment of patients after acute ischemic stroke.

Abstract

The serotonin selective reuptake inhibitor fluoxetine (Flx) has tried to treat patients suffered acute ischemic stroke because of its possible neuroprotective actions. However, besides the neuroprotective effect, Flx at high concentration also induces some actions in contradiction to neuroprotection in the brain. The purpose of this study was to investigate whether Flx presents neuroprotective effect against 3-nitropropionic acid (3-NP)-induced hypoxic brain injury, and what is the most suitable dosage of Flx. Mouse model was established by subacute systemic administration of 3-NP. Rotarod and pole tests were used to evaluate motor deficit. The oxidative stress and oxidative DNA damage were assessed respectively by measuring malondialdehyde and 8-hydroxydeoxyguanosine content in brain homogenates. According to measurements in the rotarod test, 7 days pretreatment plus 5 days treatment of Flx at low (2.5 mg/kg/day) and, to a lesser degree, medium (5 mg/kg/day) doses exerted a rapid and strong protection against the neurotoxicity induced by 3-NP, whereas Flx at high dose (10mg/kg/day) showed a much late and light effect. Similarly, in the pole test, Flx at 2.5 mg/kg/day had the strongest protective effects. Again, only Flx administration at 2.5 mg/kg/day canceled out the enhancement of malondialdehyde and 8-hydroxydeoxyguanosine in striatum following 3-NP neurotoxication. Flx attenuated the motor deficits induced by 3-NP in a dose-dependent manner. In contrary to the high dose, Flx at the lower doses had a more remarkable effect against 3-NP insult, similar to acute ischemic stroke.