Role of brain-derived neurotrophic factor and neuronal nitric oxide synthase in stress-induced depression

Dan Wang; Shucheng An

摘要：BACKGROUND: Accumulated evidence indicates an important role for hippocampal dendrite atrophy in development of depression, while brain-derived neurotrophic factor (BDNF) participates in hippocampal dendrite growth. OBJECTIVE: To discuss the role of BDNF and neuronal nitric oxide synthase (nNOS) in chronic and unpredictable stress-induced depression and the pathogenesis of depression.DESIGN, TIME AND SETTING: Randomized, controlled animal experiment. The experiment was carried out from October 2006 to May 2007 at the Department of Animal Physiology, College of Life Science, Shaanxi Normal University.MATERIALS: Thirty-seven male Sprague-Dawley rats weighing 250-300 g at the beginning of the experiment were obtained from Shaanxi Provincial Institute of Traditional Chinese Medicine (Xi'an, China). BDNF antibody and nNOS antibody were provided by Santa Cruz (USA). K252a (BDNF inhibitor) and 7-NI (nNOS inhibitor) were provided by Sigma (USA). METHODS: Animals were randomly divided into five groups: Control group, chronic unpredicted mild stress (CUMS) group, K252a group, K252a+7-NI group and 7-NI+CUMS group. While the Control, K252a and K252a+7-NI groups of rats not subjected to stress had free access to food and water, other groups of rats were subjected to nine stressors randomly applied for 21 days, with each stressor applied 2-3 times. On days 1, 7, 14 and 21 during CUMS, rats received microinjection of 1 μL of physiological saline in the Control and CUMS groups, 1 μL of K252a in the K252a group, 1 μL of K252a and 7-NI in the K252a+7-NI group, and 1 μL of 7-NI in the 7-NI+CUMS group. We observed a variety of alterations in sucrose preference, body weight change, open field test and forced swimming test, and observed the expression of BDNF and nNOS in rat hippocampus by immunohistochemistry;RESULTS: Compared with the Control group, the behavior of the CUMS rats was significantly depressed, the expression of BDNF decreased (P < 0.01) but the expression of nNOS increased (P < 0.01). The behavior of rats given intra-hippocampal injection of BDNF inhibitor was significantly depressed and the expression of nNOS was significantly increased (P < 0.01). Intra-hippocampal injections of an nNOS inhibitor reversed the depression-like behavioral changes induced by CUMS or intra-hippocampal injection of BDNF inhibitor.CONCLUSION: CUMS induced a decrease in expression of BDNF and an increase in expression of NO in the hippocampus, which may lead to depression.