Neuroprotection by corticotropin releasing factor during hypoxia in rat brain

Background and Purpose: Corticotropin releasing factor is an endogenous neuropeptide released by the hypothalamus that activates the pituitary-adrenocortical system in response to stressful stimuli. It has been demonstrated that corticotropin releasing factor increases the excitability of hippocampal neurons in both in vitro and in vivo studies, which may contribute to neurological injury during hypoxia. The purpose of this study was to determine the effects of corticotropin releasing factor and its synthetic competitive antagonist, α-CRF, on neuronal synaptic recovery after a hypoxic insult using the hippocampal slice. Methods: Wistar rat hippocampal brain slices (n=120) were treated with various concentrations (10⁻⁶ to 10⁻¹¹) of corticotropin releasing factor or its synthetic antagonist during a 10-minute hypoxic episode. Extracellular recording of population spikes was used during and after the hypoxic insult to assess neuronal recovery. Results: Corticotropin releasing factor provided dose-dependent neuronal protection with maximum recovery (37.95 ±8.71%) occurring at 10 concentrations. The competitive antagonist α-CRF provided a similar degree of recovery at 10⁻⁶ concentration, whereas 10⁻⁹ molar concentration of competitive antagonist resulted in 16.84 ±7.68% recovery. Conclusions: Corticotropin releasing factor provides moderate protection to hypoxic hippocampal neurons in the brain slice preparation. The mechanism of action is unknown but appears to be a direct neuronal effect. These results support the hypothesis that corticotropin releasing factor may act as an endogenous neuroprotective hormone during hypoxia.