الفهرس 
Review of Literature
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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.