Reduction in TNF alpha and oxidative stress by liraglutide: Impact on ketamine-induced cognitive dysfunction and hyperlocomotion in rats.

BACKGROUND: Diabetes and psychotic disorders are occasionally comorbid. Possible pathophysiologies linking these disorders include inflammation and oxidative stress. Glucagon like peptide-1 (GLP-1) agonists modulate glucose metabolism and may exert neuroprotective effects via central GLP-1 receptors. AIM OF THE WORK: To explore the effects of GLP-1 agonist, liraglutide, on ketamine-induced hyper-locomotion and cognitive dysfunction and the associated inflammation and oxidative stress in normoglycemic and diabetic rats. METHODS: Rats were divided into: Chow fed (non-diabetic) and high fat diet fed/STZ (diabetic) groups: I. non-diabetic/control, non-diabetic/liraglutide, non-diabetic/ketamine, non-diabetic/ketamine/liraglutide groups. II. diabetic/control, diabetic/liraglutide, diabetic/ketamine and diabetic/ketamine/liraglutide groups. Hyperlocomotion and cognitive dysfunction were assessed using open field and water maze tests. Biochemical parameters were measured in serum and hippocampus. RESULTS: Ketamine induced hyperlocomotion and cognitive dysfunction, with hippocampal histopathological changes. Increase in tumour necrosis factor (TNF)-alpha and oxidative stress and reduction in brain-derived neurotrophic factor (BDNF) were noted. These changes were augmented in diabetic compared to non-diabetic rats. Liraglutide significantly improved hyperlocomotion, and cognitive dysfunction and hippocampal histopathological changes in non-diabetic and diabetic rats. Improvement in glucose homeostasis, reduction in TNF alpha and malondialdehyde, and increase in glutathione and BDNF were observed in serum and hippocampus. CONCLUSION: Beneficial effects of liraglutide on ketamine-induced hyperlocomotion and cognitive dysfunction are associated with reduction in TNF alpha and oxidative stress. Since effects of liraglutide occurred in diabetic and non-diabetic rats, glycemic and non-glycemic effects (via central GLP-1 receptors) might be involved. Targeting oxidative stress and inflammation by GLP-1 agonists, may be a promising approach in psychotic patients with diabetes.

Amisulpride alleviates chronic mild stress-induced cognitive deficits: Role of prefrontal cortex microglia and Wnt/ß-catenin pathway.

Accumulating evidence indicates the role of microglial activation and sustained neuroinflammation in the pathogenesis of cognitive dysfunction, a common feature associated with depressive disorders. It also indicates the role of Wnt/ß-catenin pathway in regulation of microglia-mediated neuroinflammation. Amisulpride exhibits antidepressant and pro-cognitive activities in several clinical and experimental studies. Hitherto, the direct effects of amisulpride on Wnt/ß-catenin signaling and microglial activity have not been thoroughly studied. This study aimed at investigating the effects of chronic amisulpride treatment on Wnt/ß-catenin signaling and pro-inflammatory microglial activation and its role in alleviation of depressive-like behavior and cognitive deficits elicited by unpredictable chronic mild stress (UCMS). The effects of amisulpride (3 mg/kg/day) were investigated on behavioral/cognitive deficits, expression of Wnt/ß-catenin pathway and microglial activation in the prefrontal cortex (PFC) of UCMS-exposed male Wistar rats. UCMS induced depressive-like behavior with impairment of performance in novel object recognition test and attentional set-shifting task. These behavioral deficits were associated with decreased total ß-catenin and increased pro-inflammatory microglial activation. Amisulpride improved UCMS-induced behavioral/cognitive deficits, ameliorated Wnt/ß-catenin signaling dysregulation and pro-inflammatory microglial activation. This work highlights the antidepressant and pro-cognitive effects of amisulpride in UCMS-exposed rats that could be mediated by modulation of Wnt/ß-catenin pathway activity and amelioration of pro-inflammatory microglial activation in the prefrontal cortex. This could provide new insights into the putative mechanisms behind the antidepressant and pro-cognitive effects exerted by amisulpride.

Tadalafil versus linaclotide in gastrointestinal dysfunction and depressive behavior in constipation-predominant irritable bowel syndrome.

BACKGROUND: Intestinal GC-C/cGMP pathway may be involved in visceral hypersensitivity and fluid secretion in irritable bowel syndrome (IBS). The guanylcyclase C agonist linaclotide, approved for IBS- constipation, is contraindicated in children as it may cause severe diarrhea. In contrast, drugs increasing cGMP by inhibiting phosphodiesterase 5 (PDE-5) are well tolerated in children with pulmonary hypertension. Accordingly, we investigated whether beneficial effects of linaclotide in IBS might be shared by PDE-5inhibitor tadalafil without the severe diarrhea reported for linaclotide. Since depression is commonly comorbid with IBS and is implicated in its pathophysiology; and since tadalafil is absorbed systemically and crosses blood brain barrier, whereas linaclotide does not, impact of both drugs on behavioral changes in IBS was also investigated. METHODS: 72 rats were divided into 6groups (control naive, control tadalafil, control linaclotide, untreated IBS, IBS tadalafil, and IBS linaclotide-treated). IBS was induced by 0 to 4 °C intragastric saline for 14 days. RESULTS: Both drugs reduced visceral hypersensitivity and colonic C fos. Tadalafil, and to a greater extent, linaclotide increased colonic cGMP, fecal pellets (8.66 ± 4.6 (IBS),versus14.8 ± 3.3(tadalafil), 20 ± 1.2(linaclotide), fecal water content (29.8 ± 5.5 (IBS), versus 47.83 ± 12.6 (tadalafil), 63.58 ± 11.6 (linaclotide) and reduced intestinal transit time (% distance travelled: 29 ± 6.1(IBS), versus 40.58 + 7.5(tadalafil), 51.83 ± 8.3(linaclotide). Tadalafil, but not linaclotide, increased hippocampal cGMP, and improved behavioral tests scores compared to linaclotide (immobility time: 97.3 ± 12.5 s (IBS) versus 68 ± 12.8(tadalafil), 80 ± 17.06 (linaclotide). CONCLUSION: Systemic PDE-5 inhibitors might be alternatives to locally acting guanyl cyclase agonists in IBS, inducing less severe diarrhea and more beneficial effects on the associated behavioral changes.

Modulation of hippocampal TLR4/BDNF signal pathway using probiotics is a step closer towards treating cognitive impairment in NASH model.

BACKGROUND AND AIM: Disturbance of gut microbiota plays a role in induction and progression of non alcoholic steatohepatitis (NASH) and the associated cognitive dysfunction. We supposed that high fat diet (HFD)-induced dysbiosis may lead to NASH/cognitive impairment co-morbidities through hippocampal TLR4/BDNF signaling pathway and the regaining of microbiota balance through probiotics could provide a therapeutic option. METHODOLOGY: Four groups of male Wister rats were used; Naïve, Lactobacillus Plantarum EMCC-1039 (LP EMCC-1039), NASH and NASH+ LP EMCC-1039 groups. After induction of NASH with high fat diet (HFD), LP EMCC-1039 was given daily by oral gavage in the last two weeks of experiment to the treated group. Body weight percentage (BW%) changes, Lee index (LI), liver function tests, expression of BDNF, TLR4 with RT-PCR and quantification of BDNF, TLR4 by ELISA were measured . Histological studies and assessment of cognitive function were also performed. RESULTS: NASH group showed an increase in BW% and LI . It was associated with cognitive deficits, an increase in hepatic, hippocampal TLR4 expression and decline in BDNF expression and protein, all p values were <0.05. Histological examination revealed significant decrease in number of viable cells and shrinking of pyramidal cells in hippocampus (p<0.05). Treatment with LP EMCC-1039 improved all these pathological changes significantly (p<0.05) with negative correlation between NAFLD activity score (NAS) and cognitive measurements. Additionally, hepatic and hippocampal TLR4 expression were decreased and BDNF expression and quantity were increased. CONCLUSIONS: Dysbiosis-induced NASH was associated with cognitive impairment and a probiotic (LP EMCC-1039) supplementation has beneficial effect through modulation of TLR4/BDNF signaling pathway.

Involvement of TLR4/ CXCL9/ PREX-2 pathway in the development of hepatocellular carcinoma (HCC) and the promising role of early administration of lactobacillus plantarum in Wistar rats.

BACKGROUND AND AIM: Improvement of gut microbiota may help in preventing the progression of cirrhosis. We supposed that Lactobacillus Plantarum (L. Plantarum) protects the cirrhotic liver through suppression of TLR4/ CXCL9/ PREX-2. METHODOLOGY: Rats were divided into two groups. Group I, lasts for six weeks and Group II lasts for 12 weeks. Each group was subdivided into: naïve, Lactobacillus Plantarum (L. Plantarum), thioacetamide (TAA) and TAA + L. Plantarum. Liver function tests, α fetoprotein (AFP) levels, CXCL9, PREX-2 and TLR4 expression were assessed. Histological studies were performed. RESULTS: TAA induced significant deterioration in liver functions and increased AFP. There was periportal cirrhosis, vacuolated hepatocytes, decrease hepatocyte parrafin-1 (hep par-1) expression, increase proliferating cell nuclear antigen (PCNA) positive nuclei and cytokeratin AE1/AE3. The PCR results showed significant increase in TLR4, CXCL9 and PREX-2 expression. Early administration of L. Plantarum significantly decreased the expression of TLR4, CXCL9 and PREX-2 together with improvement in liver function and prevented the pathological changes. CONCLUSIONS: The cirrhotic complications induced by TAA are through activation of TLR4/ CXCL9/ PREX-2 pathway and could be prevented by the early administration of L. Plantarum.

Insights into hepatic and renal FXR/DDAH-1/eNOS pathway and its role in the potential benefit of rosuvastatin and silymarin in hepatic nephropathy.

OBJECTIVES: The repression of renal Farnesoid X Receptor (FXR) had been shown to result from lack of bile acid production from cirrhotic liver. We hypothesized that silymarin and rosuvastatin (Rvs) could have a hepatorenal therapeutic effects in hepatic nephropathy through induction of FXR. METHODS: Forty two male Wistar rats were used; naïve (n = 12); six of them were sacrificed after 4 weeks and six continued till the end of the experiment. Thirty rats were treated as follows: Rvs, silymarin, thioacetamide (TAA), TAA + Rvs and TAA + silymarin. Liver and kidney function tests as well as the renal and hepatic expression of transforming growth factor ß1 (TGFß1), FXR, dimethylarginine dimethylaminohydrolase-1 (DDAH-1) and eNOS were performed. Histological and immuno-histochemical studies of liver and kidney were also done. RESULTS: TAA-inducted liver cirrhosis was associated with significant deterioration of liver and renal functions together with increasing expression of hepatic and renal TGFß1 and decreasing expression of hepatic and renal FXR, DDAH-1 and eNOS. Giving silymarin or Rvs induced hepatic and renal improvement which was evidenced biochemically and histologically. Significant positive correlation was detected between all the investigated biomarkers except for the correlation between FXR and TGFß1 which was negative. CONCLUSIONS: In conclusion, liver cirrhosis is associated with deterioration of renal functions. Silymarin and Rvs have a potential hepatorenal therapeutic benefit through simultaneous enhancement of FXR/DDAH-1/eNOS pathway in both organs.

The potential benefit of combined versus monotherapy of coenzyme Q10 and fluoxetine on depressive-like behaviors and intermediates coupled to Gsk-3ß in rats.

As a part of the serotoninergic dysfunction implicated in neurobiology of depression, evidence has focused on serotonin (5-HT) receptors downstream signaling intermediates including glycogen synthase kinase-3ß (GSK-3ß), cAMP response element binding protein (CREB) and brain derived neurotrophic factor (BDNF). Our team previously reported that coenzyme Q10 (CoQ10) exerted antidepressant-like effect in rats exposed to chronic unpredictable mid stress (CUMS) via elevating serotonin levels. However, the effect of CoQ10 has not been elucidated in downstream signaling molecules mediating 5HT receptors' effect involved in depressive disorder hitherto. In the present study, we focused on 5-HT1A and 5-HT2A receptors (activation of 5-HT1A receptor and inhibition of 5-HT2A receptors reduce depressive like-behaviors). We investigated the role of these 5-HT receptors and their linked GSK-3ß signaling intermediates as an underlying mechanism of CoQ10 as monotherapy or combined with fluoxetine, a selective serotonin reuptake inhibitor, to alleviate depressive-like phenotype. Effects of CoQ10 (100mg/kg/day) or/and fluoxetine (10mg/kg/day) were determined on 5-HT1A, 5-HT2A receptors mRNA expression, GSK-3ß and phosphorylated (p)GSK-3ß, CREB, pCREB and BDNF protein expression in rats subjected to CUMS for 6weeks. CUMS rats exhibited obvious depressive-like behaviors (anhedonia-like behavior, negative alterations in social interaction, open field and forced swimming tests) with increased corticosterone and adrenal glands weight, decreased hippocampal levels of pGSK-3ß, pCREB and BDNF protein expressions. Additionally, they exhibited decreased hippocampal 5-HT1A and increased 5-HT2A receptor mRNA expression. CoQ10 or fluoxetine significantly attenuated the behavioral and neurochemical alterations in stressed rats with more significance with combined treatment. These findings imply that CoQ10 or/and fluoxetine attenuated CUMS-induced depressive-like behavior partly through modulating dysfunctional regulation of post-serotonergic receptor signaling pathway focusing on GSK-3ß, CREB and BDNF.

Targeting Oxidative Stress, Cytokines and Serotonin Interactions Via Indoleamine 2, 3 Dioxygenase by Coenzyme Q10: Role in Suppressing Depressive Like Behavior in Rats.

Depression is a major health problem in which oxidative stress and inflammation are inextricably connected in its pathophysiology. Coenzyme Q10 (CoQ10) is an important anti-oxidant compound with anti-inflammatory and neuro-protective properties. This study was designed to investigate the hypothesis that CoQ10 by its anti-oxidant and anti-inflammatory potentials can alleviate depressive- like behavior by restoring the balance of the tryptophan catabolites kynurenine/serotonin toward the serotonin pathway by down-regulation of hippocampal indoleamine 2,3-dioxygenase 1 (IDO-1). Depressive-like behavior was induced by chronic unpredictable mild stress (CUMS) protocol including food or water deprivation, cage tilting, reversed light cycle etc. Male Wistar rats were randomly divided into five groups; Control, CUMS, CUMS and CoQ10 (50,100 and 200 mg/kg/day i.p. respectively) groups. CoQ10 effects on different behavioral and biochemical tests were analyzed. CoQ10 showed significant antidepressant efficacy, as evidenced by significantly decreased stress induced changes to forced swimming challenge and open field test, as well as attenuating raised corticosterone level and adrenal glands weight. The anti-oxidant effect of CoQ10 was exhibited by its ability to significantly reduce hippocampal elevated malondialdehyde and 4-hydroxynonenal levels and elevate the reduced glutathione and catalase levels. CoQ10 significantly reduced different pro-inflammatory cytokines levels including interleukin (IL)-1ß, IL-2, IL-6 and tumor necrosis factor-α. It suppressed hippocampal IDO-1 and subsequent production of kynurenine and enhanced the hippocampal contents of tryptophan and serotonin. Immunohistochemical analysis revealed that CoQ10 was able to attenuate the elevated microglial CD68 and elevate the astrocyte glial fibrillary acidic protein compared to CUMS group. CoQ10 exhibited antidepressant-like effects on rats exposed to CUMS. This could be attributed to its ability to reduce IDO-1 leading to shift the balance of the Kynurenine/ serotonin toward the serotonin pathway.

Potential involvement of JNK1 repression in the hepatic effect of sitagliptin and metformin in rats subjected to high fat diet and chronic mild distress.

BACKGROUND: Depression and non-alcoholic steatohepatitis (NASH) are highly co-morbid, and hepatic JNK pathway may be involved in their relation. AIM: To evaluate the impact of depression on NASH through the involvement of JNK1 and to assess the effect of sitagliptin and metformin on hepatic JNK1 expression in both NASH and NASH associated with depression. METHODS: Eight groups of male Wistar rats were used: naïve rats, non-stressed NASH, non-stressed NASH sitagliptin treated, non-stressed NASH metformin treated, stressed, stressed NASH untreated, stressed NASH sitagliptin treated and stressed NASH metformin treated. Behavioral, biochemical, molecular and histopathological studies were performed. RESULTS: Non-stressed NASH group showed depressive like symptoms, disturbed glucose homeostasis, impairment of liver functions, decrease adiponectin and increase malondialdehyde, which were aggreviated by stress. Sitagliptin produced significant improvement compared to metformin regarding biochemical and histopathological parameters. Furthermore, sitagliptin significantly decreased expression of hepatic JNK1 in both stressed and non-stressed rats. All these changes were accompanied by significant improvement of behavioral changes. CONCLUSIONS: The link between NASH and depression raised the role of JNK activation through increase expression of JNK1. Since sitagliptin was associated with preferable effects than metformin, therefore, it is potentially preferred in the management of either NASH or NASH associated with depression.