Effects of fluoxetine and pentoxifylline on stress-induced changes in the molecular paradigm of mitochondrial regulation in the hippocampus of male wistar rats / Lobna Hatem Abdelghaphour Khedr ; Supervised Ezzeddin Said Eldenshary , Ahmed M. Abdeltawab , Laila Rashed

Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Previous reports in our lab linked chronic mild stress (CMS), a well-validated model of depression, to impaired hippocampal energy metabolism and mitochondrial dysfunction. Adding repeated lipopolysaccharide (LPS) to CMS was recently proposed as another model of depression. The combined LPS/CMS model highlighted the possible interaction between stress and immune-inflammatory pathways and their impact on disrupting tryptophan metabolism and triggering TNF-Ü induced changes in the hippocampus along with depressive-like behavioral alterations. In the current study, the interplay between mitochondrial biogenesis and toll-like receptor 4 (TLR4) signaling, as a target for LPS, was investigated in a combined LPS/ CMS model. To this end, male Wistar rats were exposed to either LPS (50 og/kg i.p) over 2 weeks, CMS protocol for 4 weeks or LPS over 2 weeks followed by 4 weeks of CMS (LPS/CMS). Another three groups of rats were exposed to LPS/CMS protocol and treated with either pentoxifylline (PTX), fluoxetine (FLX) or a combination of both. Rats were examined for behavioral, neurochemical, gene expression and mitochondrial ultra-structural changes.Animals exposed to LPS/CMS showed perturbation of serum corticosterone (CORT) and {u2018}TNF-Ü{u2019} levels as well as behavioral responses. Interestingly, LPS/CMS attenuated the increased expression of TLR4 and its downstream players; MyD88 adaptor protein, nuclear factor kappa B (NFmB) and hippocampal TNF-Ü, compared to SAL/CMS. Moreover, LPS/CMS abridged the SAL/CMS effects on mitochondrial biogenesis machinery; peroxisome proliferator-activated receptor gamma co-activators1-alpha (PGC1-Ü). Furthermore, the antidepressant (AD) {u2018}FLX{u2019}, the TNF-Ü inhibitor {u2018}PTX{u2019} and their combination engendered a further enhancement in all the aforementioned LPS/CMS-induced changes (figure 1)

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