The anxiolytic effect of salicylic acid is mediated via the GABAergic system in the fear potentiated plus maze behavior in rats.

BACKGROUND: Salicylic acid (SA) is a natural phenolic compound in plants with many beneficial effects for humans. The anxiolytic effect of this compound has been reported in animal models, but its mechanism of action remains unclear. In this study, by using the fear potentiated plus maze test, we evaluated the effect of salicylic acid on the gene expression of the main form of GABA (gamma aminobutyric acid) synthesizing enzyme i.e., the enzyme glutamic acid decarboxylase 67 (GAD67) which is called GAD1, in the ventral subiculum of the hippocampus, one of the main brain structures, in anxiety circuits. Also, the hypnotic effect of Salicylic acid was evaluated. METHODS: Animals were divided into the solvent, (SA) and diazepam treated groups (n = 6). For evaluating the anxiolytic effect of Salicylic acid, animals were subjected to 2 h of isolation, before placing them in the elevated plus maze (EPM). Afterward, the ventral part of the hippocampus was removed for evaluating the change in GAD1 gene expression by the reverse transcription-quantitative polymerase chain reaction (RTqPCR) technique. The hypnotic effect of Salicylic acid was evaluated in the ketamine induced sleeping test. RESULTS: Salicylic acid at 10 and 30 (mg/kg) increased time spent and entries to the open arms in the (EPM) (p < 0.05). (RTqPCR) revealed that 30 mg/kg of Salicylic acid increased GAD1 gene expression (p < 0.001). Salicylic acid (30 and 300 mg/kg) also increased the duration of sleep, in ketamine induced sleeping test (p < 0.05). CONCLUSION: Our results showed that Salicylic acid has anxiolytic and hypnotic effects and it exerts its anxiolytic effect partly, via up the regulation of GAD1 in the ventral part of the hippocampus.

Expression of IGF-1, IL-27 and IL-35 Receptors in Adjuvant Induced Rheumatoid Arthritis Model.

BACKGROUND: IGF-1 and certain other cytokines have been shown to exert inflammatory/anti-inflammatory roles in chronic joint diseases. OBJECTIVE: To assess the effect of IGF-1, IL-27 and IL-35, their interaction and their receptor expression in a rheumatoid arthritis model. METHODS: Freund's adjuvant-induced chronic joint inflammation was operated on 160 male rats. Animals were divided into histopathology and receptor expression groups, each composed of 10 subgroups including; control, vehicle, IGF-1, IL-27, IL-35, their antagonists, IGF-1+IL-27 antagonist and IGF-1+IL-35 antagonist. After two weeks, vehicle or agonist/antagonists were injected into the joint space every other day until day 28 where joint histopathology was performed. The expression of IGF-1, IL-27 and IL-35 receptors were assessed by western blot analysis. RESULTS: IGF-1 did not show pro- or anti- inflammatory functions; endogenous IL-27 and IL-35, on the other hand, exerted inflammatory effects. IL-27 and IL-35 antagonists exerted the highest anti-inflammatory effects. The total inflammation scores were 0.55 ± 0.06, 4.63 ± 0.40, 3.63 ± 0.60, 2.50 ± 0.38 and 1.63 ± 0.40 regarding control, vehicle, IGF-1 Ant., IL-27 Ant. and IL-35 Ant., respectively. IGF-1 receptor expression was reduced in chronic joint inflammation and all three antagonists augmented the IGF-1 receptor expression. IL-27 and IL-35 receptors were up-regulated by chronic joint inflammation. CONCLUSION: Overall, the results demonstrated the pro-inflammatory role of endogenous IL-27 and IL-35 along with the over expression of their receptors in chronic joint inflammation. IL-27 and IL-35 antagonists exerted the most anti-inflammatory effects and increased IGF-1 receptor expression. These two antagonists may be potential agents for new treatment strategies in chronic joint inflammatory diseases.

Investigation of changes in apelin receptor mRNA and protein expression in the myocardium and aorta of rats with two-kidney, one-clip (2K1C) Goldblatt hypertension.

Experimental and clinical evidences suggest that apelin and its receptor APJ are involved in the pathogenesis of cardiovascular complications. However, the role of apelin/APJ in hypertension is not sufficiently understood. Because chronic kidney diseases lead to hypertension and cardiac failure, we investigated the changes in apelin receptor gene expression in the myocardium and aorta of rat models of kidney disease hypertension. Two-kidney, one-clip (2K1C) hypertension was produced by placing a clip around the renal artery. Four and 16 weeks later, blood pressure, left ventricular end-diastolic pressure (LVEDP), serum apelin, and angiotensin II were measured. The messenger RNA (mRNA) and protein of APJ were determined by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. Chronic hypertensive rats had approximately 10 times higher LVEDP (P < 0.001). 2K1C decreased serum apelin from 220 ± 11 to 170 ± 10 pg/mL in 16 weeks (P < 0.05). The mRNA expression of APJ significantly decreased in the heart and aorta at 4 weeks. At 16 weeks, the reduction was not significant in the heart but was significant in the aorta. At 4 weeks, the expression of the APJ protein significantly decreased in the heart but not in the aorta. At 16 weeks, APJ protein was significantly decreased only in the aorta. Reduction of serum apelin and downregulation of apelin receptors in both the heart and aorta may play a role in the pathophysiology of hypertension and cardiac failure in 2K1C hypertensive rats.

Pharmacological blockade of TRPV1 receptors modulates the effects of 6-OHDA on motor and cognitive functions in a rat model of Parkinson's disease.

TRPV1 receptors and cannabinoid system are considered as important modulators of basal ganglia functions, and their pharmacologic manipulation represents a promising therapy to alleviate Parkinson-induced hypokinesia. Recent evidence suggests that the blockade of cannabinoid receptors might be beneficial to alleviate motor deficits observed in Parkinson's disease. In the present study, we have evaluated the effects of AMG9810 , a selective antagonist of TRPV1 receptors, on the motor and cognitive functions in a rat model of Parkinson's disease generated by an intracerebroventricular injection of 6- hydroxydopamine (6-OHDA) (200 µg per animal). The injection of 10 nmol of AMG9810 for a single dose (AMG1) and for 2 weeks (AMG14) partially attenuated the hypokinesia shown by these animals in motor function evaluation tests, whereas chronic administration of AMG had destructive effects on learning and memory in 6-OHDA-treated rats. Animals in the AMG 1 and AMG 14 groups showed an increased latency to fall in rotarod and grasping tests in each trials compared with 6-OHDA-treated rats (P < 0.01) and DMSO 1 and 14 groups (P < 0.05). Our data indicate that pharmacological blockade of TRPV1 receptors by AMG 9810 attenuates the hypokinetic effects of 6-OHDA and that TRPV1 receptors play an important role in 6-OHDA-induced hypokinesia, although elucidation of the neurochemical substrate involved in this process remains a major challenge for the future.

Cardiovascular responses to apelin in two-kidney-one-clip hypertensive rats and its receptor expression in ischemic and non-ischemic kidneys.

BACKGROUND: Apelin and its receptor APJ have been shown to have beneficial effects on cardiovascular function. Apelin was shown to elicit hypotensive effects and also a positive inotropic effect on failing hearts. In this study, we investigated the effect of apelin on blood pressure and cardiac contractility in a two-kidney-one-clip (2K1C) hypertension model. We also assessed the changes in the level of apelin and some other hemodynamically effective hormones in serum and apelin receptor gene expression in nonischemic and ischemic kidneys. METHODS: 2K1C was produced by placing a Plexiglas clip around the left renal artery. Four weeks later, blood pressure (BP) and cardiac indices of contractility were measured by power lab system. The sample venous blood was drawn from the jugular vein for biochemical variable measurements. The mRNA and protein level of APJ were determined in the kidneys by RT-PCR and Western blot methods respectively. RESULTS: The findings showed that, 2K1C increased BP from 116/75 in sham group to 200/140 mmHg in test group. Furthermore, intravenous administration of apelin-13 to hypertensive rats significantly decreased systolic (SBP) and diastolic (DBP) blood pressures in dose of 20 µg/kg with maximal responses within 2 min of injection. This reduction was long lasting and prominent in dose of 40 µg/kg. Apelin at dose of 20 µg/kg increased +LVdp/dt max and -LVdp/dt max. However at dose of 40 µg/kg SBP, DBP, +LVdp/dt max and -LVdp/dt max strongly decreased. All of the observed effects were completely blocked by apelin antagonist F13A. 2K1C did not change serum apelin, aldosterone and arginine-vasopressin levels but significantly increased angiotensin II level. 2K1C hypertension decreased apelin receptor mRNA and protein expression in contra lateral (nonischemic) kidney, but these were not affected in clipped kidney. CONCLUSION: Apelin induces hypotensive and positive inotropic effects in medium doses. However, in higher doses it elicits hypotensive and negative inotropic effects in 2K1C rats. Down regulation of apelin receptor in nonischemic kidney of hypertensive rats may play a role in pathophysiology of renovascular hypertension. Apelin together with renin-angiotensin antagonism may play a useful role in treatment of this type of hypertension.