Current Issue : April - June Volume : 2016 Issue Number : 2 Articles : 6 Articles
Although the anticonvulsant activity of 3-hydroxy-3-ethyl-3-phenylproionamide (HEPP) is well-known, its use is limited by the\npharmacotoxicological profile.We herein tested its fluorinated and chlorinated derivatives (F-HEPP andCl-HEPP) with two seizure\nmodels, maximal electroshock seizures (MES), and intraperitoneal pentylenetetrazole (PTZ) administration. Neurotoxicity was\nexamined via the rotarod test.With in silico methods, binding was probed on possible protein targetsââ?¬â?GABAA receptors and the\nsodium channel Nav1.2. The median effective doses (ED50) of HEPP, F-HEPP, and Cl-HEPP in the MES seizure model were 129.6,\n87.1, and 62.0mg/kg, respectively, and 66.4, 43.5, and in the PTZ seizure model 43.5mg/kg. The HEPP-induced neurotoxic effect,\nwhich occurred at twice the ED50 against MES (...
Resolvin D1 (RvD1) and its aspirin-triggered epimeric form\n(AT-RvD1) are endogenous lipid mediators (derived from\ndocosahexaenoic acid, DHA) that control the duration and\nmagnitude of inflammation in models of complex diseases. Our\nprevious studies demonstrated that RvD1-mediated signaling\npathways are expressed and active in salivary glands from rodents\nand humans. Furthermore, treatment of salivary cells with RvD1\nblocked TNF-�±-mediated inflammatory signals and improved\nepithelial integrity. The purpose of this pilot study was to determine\nthe feasibility of treatment with AT-RvD1 versus dexamethasone\n(DEX) on inflammation (i.e., lymphocytic infiltration, cytokine\nexpression and apoptosis) observed in submandibular glands\n(SMG) from the NOD/ShiLtJ Sj�¶grenâ��s syndrome (SS) mouse\nmodel before experimenting with a larger population. NOD/ShiLtJ\nmice were treated intravenously with NaCl (0.9%, negative control),\nAT-RvD1 (0.01-0.1 mg/kg) or DEX (4.125-8.25 mg/kg) twice a\nweek for 14 weeks beginning at 4 weeks of age. At 18 weeks of\nage, SMG were collected for pathological analysis and detection of\nSS-associated inflammatory genes. The AT-RvD1 treatment alone\ndid not affect lymphocytic infiltration seen in NOD/ShiLtJ mice\nwhile DEX partially prevented lymphocytic infiltration. Interestingly,\nboth AT-RvD1 and DEX caused downregulation of SS-associated\ninflammatory genes and reduction of apoptosis. Results from this\npilot study suggest that a systemic treatment with AT-RvD1 and\nDEX alone attenuated inflammatory responses observed in the\nNOD/ShiLtJ mice; therefore, they may be considered as potential\ntherapeutic tools in treating SS patients when used alone or in\ncombination...
The aims of the present work were to study the effects of chronic NO inhibition on liver cirrhosis and to analyze its relationship\nwith liver and kidney damage markers. Two inhibitors of NO synthesis (inducible NO synthase (iNOS) inhibitor, aminoguanidine\n(AG), and nonselective NOS inhibitor, L-nitroarginine methyl ester (L-NAME)) were administered for 6 weeks to bile duct ligated\n(BDL) rats 3 days after surgery. The present study showed that BDL was associated with liver injury and renal impairment. BDL\nincreased liver NO content and myeloperoxidase (MPO) activity. This was corroborated by increased oxidative stress, TNF-...
Proteinase-activated receptor 2 (PAR2) is a cell surface receptor activated by serine proteinases or specific synthetic compounds.\nInterest in PAR2 as a pharmaceutical target for various diseases is increasing. Here we asked two questions relevant to endothelial\ndysfunction and diabetes: How is PAR2 function affected in blood vessels? What role does PAR2 have in promoting obesity,\ndiabetes, and/or metabolic syndrome, specifically via the endothelium and adipose tissues? We conducted a systematic review of\nthe published literature in PubMed and Scopus (July 2015; search terms: par2, par-2, f2lr1, adipose, obesity, diabetes, and metabolic\nsyndrome). Seven studies focused on PAR2 and vascular function. The obesity, diabetes, or metabolic syndrome animal models\ndiffered amongst studies, but each reported that PAR2-mediated vasodilator actions were preserved in the face of endothelial\ndysfunction. The remaining studies focused on non vascular functions and provided evidence supporting the concept that PAR2\nactivation promoted obesity. Key studies showed that PAR2 activation regulated cellular metabolism, and PAR2 antagonists\ninhibited adipose gain and metabolic dysfunction in rats.We conclude that PAR2 antagonists for treatment of obesity indeed show\nearly promise as a therapeutic strategy; however, endothelial-specific PAR2 functions, which may offset mechanisms that produce\nvascular dysfunction in diabetes, warrant additional study....
Alzheimer�s disease (AD) is characterized by progressive cognitive decline usually beginning with impairment in the ability to form\nrecent memories.Nonavailability of definitive therapeutic strategy urges developing pharmacological targets based on cell signaling\npathways. A great revival of interest in nutraceuticals and adjuvant therapy has been put forward. Tea polyphenols for the ir multiple\nhealth benefits have also attracted the attention of researchers. Tea catechins showed enough potentiality to be used in future as\ntherapeutic targets to provide neuroprotection against AD. This review attempts to present a concise map of different receptor\nsignaling pathways associated with AD with an insight into drug designing based on the proposed signaling pathways, molecular\nmechanistic details of AD pathogenesis, and a scientific rationale for using tea polyphenols as proposed therapeutic agents in AD....
As human life expectancy has improved rapidly in industrialized societies, age-related\ncognitive impairment presents an increasing challenge. Targeting histopathological processes\nthat correlate with age-related cognitive declines, such as neuroinflammation, low levels of\nneurogenesis, disrupted bloodââ?¬â??brain barrier and altered neuronal activity, might lead to\nstructural and functional rejuvenation of the aged brain. Here we show that a 6-week\ntreatment of young (4 months) and old (20 months) rats with montelukast, a marketed\nanti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates\nhippocampal neurogenesis and improves learning and memory in old animals. By using gene\nknockdown and knockout approaches, we demonstrate that the effect is mediated through\ninhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor\nsignalling might represent a safe and druggable target to restore cognitive functions in old\nindividuals and paves the way for future clinical translation of leukotriene receptor inhibition\nfor the treatment of dementias....
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