L H Khedr1, N N Nassar2, Laila Rashed3, E D El-Denshary2, A M Abdel-Tawab4. 1. Departmment of Pharmacology, Faculty of Pharmacy, Misr International University, Cairo, Egypt. Electronic address: lobna.hatem@miuegypt.edu.eg. 2. Department of Pharmacology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. 3. Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt. 4. Department of Pharmacology, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
Abstract
AIM: The addition of repeated lipopolysaccharide (LPS) to chronic mild stress was recently proposed in our lab as an alternative model of depression, highlighting the possible interaction between stress and immune-inflammatory pathways in predisposing depression. Given that CMS-induced depressive behavior was previously related to impaired hippocampal energy metabolism and mitochondrial dysfunction, our current study aimed to investigate the interplay between toll-like receptor 4 (TLR4) signaling and peroxisome proliferator-activated receptor gamma coactivators-1-alpha (PGC1-α) as a physiological regulator of energy metabolism and mitochondrial biogenesis in the combined LPS/CMS model. MAIN METHODS: Male Wistar rats were exposed to either LPS (50 μg/kg i.p.) over 2 weeks, CMS protocol for 4 weeks or LPS over 2 weeks followed by 4 weeks of CMS (LPS/CMS). Three additional 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. KEY FINDINGS: LPS/CMS increased the expression of TLR4 and its downstream players; MyD88, NFκB and TNF-α along with an escalation in hippocampal-energy metabolism and p-AMPK. Simultaneously LPS/CMS attenuated the expression of PGC1-α/NRF1/Tfam and mt-DNA. The antidepressant (AD) 'FLX', the TNF-α inhibitor 'PTX' and their combination ameliorated the LPS/CMS-induced changes. Interestingly, all the aforementioned changes induced by the LPS/CMS combined model were significantly less than those induced by CMS alone. SIGNIFICANCE: Blocking the TLR4/NFκB signaling enhanced the activation of the PGC1-α/NRF1/Tfam and mt-DNA content independent on the activation of the energy-sensing kinase AMPK.
AIM: The addition of repeated lipopolysaccharide (LPS) to chronic mild stress was recently proposed in our lab as an alternative model of depression, highlighting the possible interaction between stress and immune-inflammatory pathways in predisposing depression. Given that CMS-induced depressive behavior was previously related to impaired hippocampal energy metabolism and mitochondrial dysfunction, our current study aimed to investigate the interplay between toll-like receptor 4 (TLR4) signaling and peroxisome proliferator-activated receptor gamma coactivators-1-alpha (PGC1-α) as a physiological regulator of energy metabolism and mitochondrial biogenesis in the combined LPS/CMS model. MAIN METHODS: Male Wistar rats were exposed to either LPS (50 μg/kg i.p.) over 2 weeks, CMS protocol for 4 weeks or LPS over 2 weeks followed by 4 weeks of CMS (LPS/CMS). Three additional 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. KEY FINDINGS: LPS/CMS increased the expression of TLR4 and its downstream players; MyD88, NFκB and TNF-α along with an escalation in hippocampal-energy metabolism and p-AMPK. Simultaneously LPS/CMS attenuated the expression of PGC1-α/NRF1/Tfam and mt-DNA. The antidepressant (AD) 'FLX', the TNF-α inhibitor 'PTX' and their combination ameliorated the LPS/CMS-induced changes. Interestingly, all the aforementioned changes induced by the LPS/CMS combined model were significantly less than those induced by CMS alone. SIGNIFICANCE: Blocking the TLR4/NFκB signaling enhanced the activation of the PGC1-α/NRF1/Tfam and mt-DNA content independent on the activation of the energy-sensing kinase AMPK.