Effect of dexamethasone on the expression of brain-derived neurotrophic factor and neurotrophin-3 messenger ribonucleic acids after forebrain ischemia in the rat

Objective: To determine whether a large dose of dexamethasone affected brain damage induced by concurrent cerebral ischemia, we used in situ hybridization to examine the expression of brain-derived neurotrophic factor and neurotrophin-3 messenger ribonucleic acids (mRNAs) in rats with and without dexamethasone administration after transient forebrain ischemia. Design: Prospective experimental study in rats. Setting: Experimental laboratory in a teaching hospital and university. Subjects: Eighty adult rats. Interventions: Twenty minutes of transient forebrain ischemia was induced by occlusion of four vessels in lightly anesthetized rats. Thirty-six animals received dexamethasone (15 mg/kg, intraperitoneally) after initial reperfusion. Thirty-six dexamethasone-control rats were injected with saline, and the remaining animals underwent sham surgery but no ischemia or dexamethasone. Measurements and Main Results: Using in situ hybridization, we determined hippocampal brain-derived neurotrophic factor and neurotrophin-3 mRNA expression 2, 4, 6, 12, and 24 hrs and 2, 3, 4, and 7 days after brain ischemia. Additionally, hippocampal CA₁ region cell death was measured with Nissl stains. Both brain-derived neurotrophic factor and neurotrophin-3 mRNA exhibited a biphasic response after ischemia. Brain-derived neurotrophic factor mRNA showed two peaks of 4.07-fold and 2.84-fold increases relative to sham operation at 6 hrs and 2 days, respectively. Neurotrophin-3 mRNA initially decreased to 59% of sham levels at 4 hrs and then increased to 146% at 3 days before it returned to basal levels. When the ischemic rats were treated with dexamethasone, the elevation of brain-derived neurotrophic factor mRNA and the reduction of neurotrophin-3 mRNA level were prevented within the first 24 hrs, and hippocampal CA₁ neurons were protected from ischemia-induced cell loss 7 days after brain ischemia. The protein levels of both brain-derived neurotrophic factor and neurotrophin-3 in general correspond to the mRNA levels in the hippocampal region. Conclusions: Dexamethasone modulates the intriguing temporal and spatial expression of brain-derived neurotrophic factor and neurotrophin-3 that predominantly supports neuronal innervation at different times after brain ischemia and also may provide specific trophic support for various neurons in the central nervous system.