European journal of pharmacology
-
Nonalcoholic fatty liver disease (NAFLD) and its progressive form, nonalcoholic steatohepatitis (NASH), are the most common causes of chronic liver disease. In this study, we evaluated the effects of Epigallocatechin gallate (EGCG) on methionine- and choline-deficient (MCD) diet-induced NASH. Our data showed that EGCG significantly prevented MCD diet-induced liver and body weight loss. ⋯ Western blot data showed that EGCG inhibited Smad2 and Smad3 phosphorylation in the liver and LX-2 cells which were involved in TGF-β-induced pathway. Taken together, EGCG attenuated NASH induced by MCD diet associated with ameliorating fibrosis, oxidative stress, and hepatic inflammation. Our results indicate that EGCG has beneficial roles in the development of MCD diet-induced NASH.
-
Systematic reviews of animal studies have revealed serious limitations in internal and external validity strongly affecting the reliability of this research. In addition inter-species differences are likely to further limit the predictive value of animal research for the efficacy and tolerability of new drugs in humans. Important changes in the research process are needed to allow efficient translation of preclinical discoveries to the clinic, including improvements in the laboratory and publication practices involving animal research and early incorporation of human proof-of-concept studies to optimize the interpretation of animal data for its predictive value for humans and the design of clinical trials.
-
Many studies suggest that the substantia nigra, pars reticulata (SNpr), a tegmental mesencephalic structure rich in γ-aminobutyric acid (GABA)- and cannabinoid receptor-containing neurons, is involved in the complex control of defensive responses through the neostriatum-nigral disinhibitory and nigro-tectal inhibitory GABAergic pathways during imminently dangerous situations. The aim of the present work was to investigate the role played by CB1-cannabinoid receptor of GABAergic pathways terminal boutons in the SNpr or of SNpr-endocannabinoid receptor-containing interneurons on the effect of intra-nigral microinjections of cannabidiol in the activity of nigro-tectal inhibitory pathways. GABAA receptor blockade in the deep layers of the superior colliculus (dlSC) elicited vigorous defensive behaviour. ⋯ However, the innate fear induced-antinociception was not significantly changed. The blockade of CB1 endocannabinoid receptor in the SNpr decreased the anti-aversive effect of canabidiol based on the frequency and duration of defensive immobility, the frequency of escape expressed by running, and both the frequency and duration of escape expressed by jumps. These findings suggest a CB1 mediated endocannabinoid signalling in cannabidiol modulation of panic-like defensive behaviour, but not of innate fear-induced antinociception evoked by GABAA receptor blockade with bicuculline microinjection into the superior colliculus, with a putative activity in nigro-collicular GABAergic pathways.
-
Chronic pain is a major public health problem categorized as inflammatory or neuropathic, each involving impaired GABAergic control in the spinal cord of mammals. (+)-Borneol, a bicyclic monoterpene present in the essential oil of plants, is used for analgesia and anesthesia in traditional Chinese medicine. It has been reported that (+)-borneol directly potentiates GABA activity at recombinant human GABAA receptors. Although borneol has antinociceptive effect on acute pain models, little is known about its effect on chronic pain and its mechanism. ⋯ The anti-hyperalgesic effects of (+)-borneol were abolished by a selective GABAA receptor (GABAAR) antagonist bicuculline (i.t., at 30 min after (+)-borneol injection). Furthermore, (+)-borneol (500 mg/kg, p.o. or 60 μg, i.t.) did not influence motor function. These findings suggest that (+)-borneol may ameliorate mechanical hyperalgesia by enhancing GABAAR-mediated GABAergic transmission in the spinal cord, and could serve as a therapeutic for chronic pain.
-
Peripheral receptors may contribute to the effects of systemically administered centrally available analgesics. In the present study, we analysed the effect of local peripheral injection of the nociceptin/orphanin FQ peptide (NOP) receptor agonist Ro65-6570 and compared it to the µ-opioid peptide (MOP) receptor agonist morphine in streptozotocin-induced diabetic polyneuropathy in rats. Ro65-6570 and morphine were injected intraplantarly into the hind paw of diabetic rats, and mechanical withdrawal thresholds were determined in both paws (ipsi- and contralateral to the injection site). ⋯ Both compounds did not induce overt confounding side effects across the tested dose range. The NOP receptor antagonist J-113397 and the MOP receptor antagonist naloxone, intraplantarly co-administered with the respective agonists, selectively and completely prevented the antihyperalgesic action of the respective NOP and MOP receptor agonist. These results indicate that the activation of peripheral NOP and MOP receptors by Ro65-6570 and morphine, respectively, mediated antihyperalgesic effects in rats with diabetic polyneuropathy.