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Evaluation of central and peripheral effects of doxepin on acetic acid-induced colitis in rat and the involved mechanisms.

ABSTRACT: Anti-colitis effect of antidepressants has been demonstrated recently. Doxepin, a tricyclic antidepressant drug (TCA), with potent H1, H2, alpha1 adrenergic and muscarinic receptor blocking effects could be a good candidate for investigation for its anti-colitis activity. Moreover high prevalence of depression in patients who suffer from IBD (inflammatory bowel disease), defends this idea that adjuvant therapy with an antidepressant drug which has anti-inflammatory effect, may exert favorable effects in the control of the disease. In this study colitis was induced by acetic acid instillation into rat's colon. Doxepin was injected by intraperitoneal (10, 20, 40 mg/kg, twice daily, i.p.) or intracerebroventricular (50 and 100 microgram/rat, i.c.v.) routes to separate the mechanisms are absolutely exerted centrally or mediated both centrally and peripherally prior to induction of colitis. Dexamethasone (2 mg/kg/day, i.p.) was used as reference drug. All the treatments continued for three successive days. The effectiveness of drug was evaluated by determination of cytokines (TNFα, IL6 and IL1β) and myeloperoxidase (MPO) activity as well as macroscopic scores and histopathological parameters. Doxepin after i.p. administration was effective to reduce colitis severity through reduction in the macroscopic and microscopic colonic parameters, MPO activity and cytokines levels. Intracerebroventricular administration of the drug in contrast, did not show any significant protective effect suggesting no important central mechanisms for anti-colitis activity of doxepin. Doxepin as an ancient antidepressive drug has anti-colitis and anti-inflammatory properties which are mainly exerted peripherally so it could be introduced as a good candidate for depressed people who suffered from IBD disorders.

SUBMITTER: Zabihi M

PROVIDER: S-EPMC5491921 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:Background Fatty-acid-binding proteins (FABPs) are intracellular carriers for endocannabinoids, N-acylethanolamines, and related lipids. Previous work indicates that systemically administered FABP5 inhibitors produce analgesia in models of inflammatory pain. It is currently not known whether FABP inhibitors exert their effects through peripheral or central mechanisms. Here, we examined FABP5 distribution in dorsal root ganglia and spinal cord and examined the analgesic effects of peripherally and centrally administered FABP5 inhibitors. Results Immunofluorescence revealed robust expression of FABP5 in lumbar dorsal root ganglia. FABP5 was distributed in peptidergic calcitonin gene-related peptide-expressing dorsal root ganglia and non-peptidergic isolectin B4-expressing dorsal root ganglia. In addition, the majority of dorsal root ganglia expressing FABP5 also expressed transient receptor potential vanilloid 1 (TRPV1) and peripherin, a marker of nociceptive fibers. Intraplantar administration of FABP5 inhibitors reduced thermal and mechanical hyperalgesia in the complete Freund's adjuvant model of chronic inflammatory pain. In contrast to its robust expression in dorsal root ganglia, FABP5 was sparsely distributed in the lumbar spinal cord and intrathecal administration of FABP inhibitor did not confer analgesic effects. Administration of FABP inhibitor via the intracerebroventricular (i.c.v.) route reduced thermal hyperalgesia. Antagonists of peroxisome proliferator-activated receptor alpha blocked the analgesic effects of peripherally and i.c.v. administered FABP inhibitor while antagonism of cannabinoid receptor 1 blocked the effects of peripheral FABP inhibition and a TRPV1 antagonist blocked the effects of i.c.v. administered inhibitor. Although FABP5 and TRPV1 were co-expressed in the periaqueductal gray region of the brain, which is known to modulate pain, knockdown of FABP5 in the periaqueductal gray using adeno-associated viruses and pharmacological FABP5 inhibition did not produce analgesic effects. Conclusions This study demonstrates that FABP5 is highly expressed in nociceptive dorsal root ganglia neurons and FABP inhibitors exert peripheral and supraspinal analgesic effects. This indicates that peripherally restricted FABP inhibitors may serve as a new class of analgesic and anti-inflammatory agents.

Project description:BACKGROUND: Ulcerative colitis is a chronic inflammatory disease and involves multiple etiological factors. Acetic acid (AA)-induced colitis is a reproducible and simple model, sharing many characteristics with human colitis. N-acetylcysteine (NAC) has been widely used as an antioxidant in vivo and in vitro. NAC can affect several signaling pathways involving in apoptosis, angiogenesis, cell growth and arrest, redox-regulated gene expression, and inflammatory response. Therefore, NAC may not only protect against the direct injurious effects of oxidants, but also beneficially alter inflammatory events in colitis. This study was conducted to investigate whether NAC could alleviate the AA-induced colitis in a porcine model. METHODS: Weaned piglets were used to investigate the effects of NAC on AA-induced colitis. Severity of colitis was evaluated by colon histomorphology measurements, histopathology scores, tissue myeloperoxidase activity, as well as concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon. The protective role of NAC was assessed by measurements of antioxidant status, growth modulator, cell apoptosis, and tight junction proteins. Abundances of caspase-3 and claudin-1 proteins in colonic mucosae were determined by the Western blot method. Epidermal growth factor receptor, amphiregulin, tumor necrosis factor-alpha (TNF-?), and toll-like receptor 4 (TLR4) mRNA levels in colonic mucosae were quantified using the real-time fluorescent quantitative PCR. RESULTS: Compared with the control group, AA treatment increased (P?<?0.05) the histopathology scores, intraepithelial lymphocyte (IEL) numbers and density in the colon, myeloperoxidase activity, the concentrations of malondialdehyde and pro-inflammatory mediators in the plasma and colon, while reducing (P?<?0.05) goblet cell numbers and the protein/DNA ratio in the colonic mucosa. These adverse effects of AA were partially ameliorated (P?<?0.05) by dietary supplementation with NAC. In addition, NAC prevented the AA-induced increase in caspase-3 protein, while stimulating claudin-1 protein expression in the colonic mucosa. Moreover, NAC enhanced mRNA levels for epidermal growth factor and amphiregulin in the colonic mucosa. CONCLUSION: Dietary supplementation with NAC can alleviate AA-induced colitis in a porcine model through regulating anti-oxidative responses, cell apoptosis, and EGF gene expression.

Project description:BackgroundUlcerative colitis is a gut inflammatory disorder due to altered immune response to gut microbiome, with interplay of environmental and genetic factors. TNF-α activates inflammatory response through a cascade of immune responses, augmenting pro-inflammatory mediators and proteases, activating chemotaxis, and infiltration of inflammatory cells, leading to ulceration and haemorrhage through cytotoxic reactive oxygen species. 6-Paradol, a dietary component in several plants belonging to the Zingiberaceae family, has shown anti-inflammatory and antioxidant activities. Current study evaluates the effect of 6-paradol in amelioration of ulcerative colitis in rats for the first time.Methods6-Paradol (95% purity) was obtained from seeds of Aframomum melegueta. Rats were divided randomly into six groups (n = 8). Group one was administered normal saline; group two was treated with the vehicle only; group three, sulfasalazine 500 mg/kg; and groups four, five, and six, were given 6-paradol (50, 100, 200, respectively) mg/kg orally through gastric gavage for 7 days. Colitis was induced on 4th day by intrarectal administration of 2 ml acetic acid (3%), approximately 3 cm from anal verge. On 8th day, rats were sacrificed, and distal one-third of the colon extending proximally up to 4 cm from anal orifice was taken for biochemical and gross examination. Two centimetres of injured mucosal portion was taken for histopathological investigations. SPSS (ver.26) was used for statistical analysis.ResultsColonic and serum glutathione (GSH) levels decreased, while colonic and serum malondialdehyde (MDA), colonic myeloperoxidase (MPO) activity, serum interleukin-6 (IL-6), serum tumour necrosis factor-α (TNF-α) levels, and colon weight to length ratio were increased significantly in the colitis untreated group compared to normal control. Treatment with 6-paradol considerably improved all these parameters, especially at a dose of 200 mg/kg (p < 0.001), revealing non-significant differences with sulfasalazine 500 mg/kg and normal control (p = 0.998). Sulfasalazine and 6-paradol in a dose dependent manner also markedly reversed mucosal oedema, atrophy and inflammation, cryptic damage, haemorrhage, and ulceration. There were non-significant differences between low and medium doses and between medium and high doses of 6-paradol for IL-6 and serum MDA levels.Conclusion6-Paradol demonstrated protection against acetic acid-induced ulcerative colitis, probably by anti-inflammatory and antioxidant actions.

Project description:Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer's disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3β (GSK-3β) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.

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Evaluation of central and peripheral effects of doxepin on acetic acid-induced colitis in rat and the involved mechanisms.

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