Changes Of Brain ERK1/2 And Egr-1 In Rats Treated With Chronic Stress And The Effects Of Venlafaxine On Them

Background and objective: Depress ion is a devastating illness, of which the mechanisms underlying the pathogenesis are not well understood. Current momoaminergic hypothesis suggest that depression is not only associated with the intrasynaptic levels of monoamine neurotransmitters, but also likely relate to the intracellular signaling transduction systems which are more important. ERK cascades play a crucial role in the regulation of cell growth .proliferation and differentiation , and might contribute to the regulation of important functions in the adult brain including synaptic plasticity, learning and memory. Previous studies have demonstrated that the dysfunction of ERK signaling pathways is likely to exert important effects on the pathogenesis of stress related disorders. EGR-1 (Early growth response- 1 ) has higher expression in central nervous system and can be activated by phospho-ERK. Studies showed that EGR-1 also involved in the pathogenesis of stress damage. The levels of monoaminergic transmitters raise rapidly after acute administration of antidepressant, but its clinical effects are only observed after chronic administration , which suggests that therapeutic actions of antidepressants may involved in intracellular signaling transduction systems and neuronalplasticity. Thus, in order to further explore the mechanisms of stress damage and therapeutic action of antidepressants, the current study observed the changes of brain ERK1/2 and EGR-1 in rats treated with chronic stress and the effects of venlafaxine on them .Materials and methods : Adult male Sprague dawley(SD) rats were used as experimental subjects. They were divided into 7 groups: normal control group A(CA) , normal control group B (CB), stress group (M), group of stress + venlafaxine 15mg/kd(VD), group of stress + venlafaxine 30mg/kd (VZ), group of stress + venlafaxine 60mg/kd(VG), group of stress + water (MZ). Except control group .others were exposed to unpredicted mild stressors for 21 consecutive days. An open field test was repeated three times to evaluate the depressive-behavior during the experiment. Rat of M group and CB group were sacrificed by decapitation after 21 day stress, other group were sacrificed after venlafaxine treatment. Western blot was used to quant ificationally determine the levels of p-ERKl/2 , ERK1/2 and EGR-1 in hippocampus , prefrontal cortex, hypothalamus and striatum0Results: The results showed that the total scores of open field tests in stress group was significantly reduced after 21 days stress compared with control group iP <0.001 ) , while venlafaxine treatment reversed this effect. After stress, the levels of p-ERKl/2 in prefrontal cortex in M group were lower thanthat in CB group CP <0. 001 ) . After venlafaxine treatment, the levels of p-ERKl in prefrontal cortex in VD, VZ and VG groups markedly increased compared with MZ group (P<0. 001 ) , but without dose-related relations . There were no significant differences of the levels of p-ERK2 in prefrontal cortex in VD, VZ and VG groups compared with MZ group. In other examined regions, the levels of p-ERKl/2 and ERK1/2 were unchanged. The levels of Egr-1 in all examined regions were unchanged after stress and after venalfaxine treatment. Conclusions:1. Depressive-behaviors were induced in rats after 21 days stresses, while venlafaxine treatment could reverse this effect;2. Significant decrease of p-ERKl/2 levels in prefrontal cortex after 21 days stresses suggested that down regulation of ERK signaling pathway may be involved in the mechanisms of stress damage.3. Treatment with chronic venlafaxine could markedly improved activity of stressed rats and increased the levels of p-ERKl levels in prefrontal cortex , which suggested that upregulation of ERK signaling pathway may be involved in mechanisms of therapeutic action of antidepressant.4. Egr-1 may not be involved in the mechanisms of stress damage and the mechanisms of therapeutic action of antidepressant.