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Abstract Background: There is now evidence that inflammatory and neurodegenerative processes might play an important role in the pathophsiology of depression. The present work examined the effect of exposure of Wistar rats to repeated intraperitoneal injection (i.p.) of lipopolysaccharide (LPS) and to chronic mild stress (a well established model of depression) either alone or in combination, on the behavioral and structural changes, in the hippocampus, in a trial to develop a new animal model of depression. Methods: One hundred sixty male Wistar rats weighing 200-300 gm, were divided into the following groups: group I (control, saline injected), group II (LPS injected rats with 50 μg/kg i.p. for 2 weeks then examined), group III (LPS injected rats with 50 μg/kg i.p. for 2 weeks, left undisturbed for 4 weeks then examined), group IV (rats exposed to the CMS protocol for 4 weeks then examined), group V (LPS injected rats for 2 weeks then exposed to the CMS protocol for 4 weeks then examined), group VI (LPS injected rats for 2 weeks in concomitant with CMS protocol for 4 weeks then examined), group VII (LPS injected rats for 2 weeks then exposed to the CMS protocol for 4 weeks, while treated with imipramine, a tricyclic antidepressant) and group VIII (LPS injected rats for 2 weeks then exposed to the CMS protocol for 4 weeks, while treated with pentoxifylline, an anti-TNF-α). Rats were examined for the behavioral, histological, immunohistochemical and ultrastructural changes in the hippocampus. Results: Animals exposed to LPS then CMS model elaborated depressive-like symptoms detected in the behavioral tests, as increased immobility time in the forced swimming, compared to other schemes. Histologically, these animals showed a significant decrease in the number of the normal pyramidal neurons together with a significant increase in the percentage of dark neurons in both the CA1 and the CA3 regions of the hippocampus, compared to the control group. In addition, there was a significant decrease in the Nissl granules content of the pyramidal cells of the CA1 and the CA3 regions as well as of the granule cells of the DG. The pyramidal cells of the CA3 region of the hippocampus showed distorted outlines with retraction of their dendrites as seen in Golgi-Cox stained sections. The GFAP immuno-stained sections showed a significant increase in the number and the area percentage of astrocytes in the CA1, the CA3 and the DG of the hippocampus. Furthermore, TNFα immuno-stained sections showed a significant increase in the optical density of TNFα within the pyramidal cells of the CA3 region of the hippocampus. At the ultrastructural level, the CA3 hippocampal pyramidal neurons showed several neuro-degenerative signs, both in the nuclei and in the cytoplasm. The nuclei possessed irregular nuclear membrane which formed deep invaginations inside the nucleus, containing parts of the cytoplasm. While the cytoplasm showed vacuoles as well as swollen vacuolated mitochondria. Chronic treatment with imipramine or pentoxifylline ameliorated the behavioral changes induced by LPS then CMS model as shown by a decrease in the immobility time in forced swimming test, compared to the untreated group. Histologically, treatment of rats with imipramine or pentoxiphylline, while exposing them to LPS then CMS model markedly improved the neuro-degenerative changes, as compared to that of the non treated group (group V). There was a significant increase in the number of the normal pyramidal cells as well as a significant decrease in the percentage of dark neurons in the CA1 and the CA3 regions of the hippocampus. In addition, there was a significant increase in the Nissl granules content of the pyramidal cells of the CA1 and the CA3 regions as well as of the granule cells of the DG. The pyramidal neurons of the CA3 region of the hippocampus possessed slightly irregular outlines with the reappearance of parts of the axons and the dendrites of these neurons as seen in Golgi-Cox stained sections. A significant decrease in the number and the area percentage of the astrocytes was noticed in the CA1, the CA3 and the DG in GFAP immuno-stained sections. Moreover, a significant decrease in the optical density of TNFα, in the cytoplasm of the pyramidal neurons of the CA3 region of the hippocampus was noticed. At the ultrastuctural level, imipramine or pentoxiphylline treatment improved LPS then CMS model-induced neurodegerative changes, observed in the nuclei of the CA3 pyramidal cells of the hippocampus, compared to the non-treated rats. On the other hand, the neurodegerative changes, induced by this model were still detected in the cytoplasm of the CA3 pyramidal neurons. Conclusion: This study highlights the possible interaction between stress and immune-inflammatory pathways in the pathogenesis of depression and suggests an animal model that addresses these pathways. Key words: hippocampus, chronic mild stress, LPS, GFAP, TNFα. |