Cognitive effects of the GSK-3 inhibitor "lithium" in LPS/chronic mild stress rat model of depression: Hippocampal and cortical neuroinflammation and tauopathy.

Low-dose repeated lipopolysaccharide pre-challenge followed by chronic mild stress (LPS/CMS) protocol has been introduced as a rodent model of depression combining the roles of immune activation and chronic psychological stress. However, the impact of this paradigm on cognitive functioning has not been investigated hitherto. METHODS: This study evaluated LPS/CMS-induced cognitive effects and the role of glycogen synthase kinase-3ß (GSK-3ß) activation with subsequent neuroinflammation and pathological tau deposition in the pathogenesis of these effects using lithium (Li) as a tool for GSK-3 inhibition. RESULTS: LPS pre-challenge reduced CMS-induced neuroinflammation, depressive-like behavior and cognitive inflexibility. It also improved spatial learning but increased GSK-3ß expression and exaggerated hyperphosphorylated tau accumulation in hippocampus and prefrontal cortex. Li ameliorated CMS and LPS/CMS-induced depressive and cognitive deficits, reduced GSK-3ß over-expression and tau hyperphosphorylation, impeded neuroinflammation and enhanced neuronal survival. CONCLUSION: This study draws attention to LPS/CMS-triggered cognitive changes and highlights how prior low-dose immune challenge could develop an adaptive capacity to buffer inflammatory damage and maintain the cognitive abilities necessary to withstand threats. This work also underscores the favorable effect of Li (as a GSK-3ß inhibitor) in impeding exaggerated tauopathy and neuroinflammation, rescuing neuronal survival and preserving cognitive functions. Yet, further in-depth studies utilizing different low-dose LPS challenge schedules are needed to elucidate the complex interactions between immune activation and chronic stress exposure.

Effects of lithium on cytokine neuro-inflammatory mediators, Wnt/ß-catenin signaling and microglial activation in the hippocampus of chronic mild stress-exposed rats.

Microglial in vivo production of pro-inflammatory cytokines is central to the pathogenesis of multiple neurological disorders including depression, with a rising role of Wnt/ß-catenin signaling as potential regulator of microglia-mediated neuro-inflammation. This study aimed at investigating the hippocampal expression of the Wnt/ß-catenin pathway in chronic mild stress (CMS)-exposed rats and the effects of Lithium (Li) on the expression of this pathway as a method to identify a plausible link between exposure to chronic stress, microglial activation, and neuroinflammation. METHODS: The effect of chronic administration of Li was investigated on behavioral changes, hippocampal expression of Wnt-DVL-GSK3ß-ß-catenin signaling pathway, and microglial activation in CMS-exposed male Wistar rats RESULTS: CMS induced a depressive-like behavior associated with increased pro-inflammatory microglial activation and reduced hippocampal expression of the Wnt/ß-catenin signaling pathway. Chronic Li treatment ameliorated stress induced-behavioral changes, reduced microglial activation and enhanced the hippocampal expression of Wnt/ß-catenin signaling pathway. CONCLUSION: This work highlights that Li-induced inhibition of GSK-3ß with subsequent accumulation of ß-catenin could impede pro-inflammatory microglia activation which is a key pathological hallmark associated with depression. Wnt/ß-catenin signaling represents a promising therapeutic target, not only for alleviation of depression, but also for a wide array of neurological disorders.

Potential protective effects of Dapagliflozin in gentamicin induced nephrotoxicity rat model via modulation of apoptosis associated miRNAs.

BACKGROUND: Drug-induced kidney injury (DIKI) can be manifested with progressive chronic kidney diseases or end-stage renal diseases. Understanding the molecular disarrangements caused by DIKI is an attractive point of interest. A class of non-coding RNA called microRNAs (miRNAs) is known to play a major role in regulation of gene expression and signaling pathways making miRNAs excellent targets for new therapeutic agents. AIM OF THE STUDY: We aimed to investigate the role of miRNA 21 and 181a in gentamicin (GNT) induced nephrotoxicity rat model and the protective effect of Dapagliflozin (DAPA) in modulating their expression through studying its effect on renal function as well as renal histopathological changes. MATERIALS AND METHODS: Wistar rats were used and divided into: naïve, DAPA, GNT and DAPA + GNT groups. In all studied groups, kidney function, oxidative stress, apoptosis markers and miRNAs' expression in serum and renal biopsies were investigated in addition to the histopathological studies to identify its early renoprotective effect. RESULTS: DAPA was found to improve kidney function, oxidative stress markers, decrease apoptosis of renal tubular cells and increase miR-21 but decrease the expression of miR-181a with restoration of the renal architecture after 14 days of treatment in GNT induced nephrotoxicity rat model. CONCLUSIONS: DAPA produced significant decrease in renal expression of miR-181a on the other hand it increased the expression of renal miR-21, this may introduce a novel early protective effect of DAPA against GNT-induced nephrotoxicity.

Nitric oxide is involved in ibuprofen preemptive analgesic effect in the plantar incisional model of postsurgical pain in mice.

Control of postoperative pain is far from satisfactory. Yet, non-steroidal anti-inflammatory drugs (NSAIDs) remain an important choice. The production of nitric oxide (NO), which plays an important role in the development and maintenance of inflammatory hyperalgesia, is inhibited by NSAIDs. Monoamines also play a key role in the modulation of nociception. The aim of the present work is to study the involvement of NO and monoamines in the antinociceptive mechanism of ibuprofen in postsurgical pain in mice. Surgical incision resulted in mechanical allodynia and increased spinal NO levels. The nitric oxide synthase inhibitor l-NAME (50mg/kg), administered intraperitoneally (i.p.), 30min before the incision decreased the development of postsurgical mechanical allodynia and reduced spinal NO levels. Ibuprofen (100 and 300mg/kg, i.p.), administered 30min before the incision, dose-dependently decreased both spinal NO levels and the development of mechanical allodynia. Administration of ibuprofen (100mg/kg i.p.), 20min following surgery, did not significantly reduce spinal NO level and resulted in a smaller antiallodynic effect. l-Arginine (600mg/kg i.p.), administered 20min before ibuprofen administration, restored both spinal NO level and mechanical allodynia in ibuprofen-treated mice. The selective alpha-2 adrenoceptor blocker yohimbine (4mg/kg i.p.), administered 30min before ibuprofen, also blocked ibuprofen effect on both mechanical allodynia and spinal NO level. These results suggest that inhibition of NO synthesis is involved in the analgesic activity of ibuprofen in post-surgical pain. Alpha-2 adrenoceptors are also involved in the analgesic activity of ibuprofen and NO may be involved in this mechanism.