The antinociceptive effects of the tetracyclic triterpene euphol in inflammatory and neuropathic pain models: The potential role of PKCε.

Evidences suggest protein kinase C epsilon (PKCε) activation is involved in both inflammatory and neuropathic pains. We have previously shown that tetracyclic triterpene euphol produces antinociception in different models of persistent pain, an action associated with its anti-inflammatory properties. Among these properties are the cannabinoid system activation and different PKC isozymes modulation. Herein, we sought to explore the potential role of PKCε modulation on euphol antinociceptive effect, in inflammatory and neuropathic pain models, in rodents. Also, we investigated further mechanisms associated with euphol effects. Oral treatment with euphol (30 mg/kg) prevented the putative effect of PGE2-induced acute and persistent mechanical hypersensitivity in mice and rats, respectively. In the PGE2-induced acute mechanical hypersensitivity euphol promoted an inhibitory effect similar to a PKCε inhibitor peptide. Likewise, in rats it prevented the mechanical hypersensitivity induced by a PKCε activator. Conversely, euphol effectiveness was not observed in a cAMP/PKA-induced mechanical hypersensitivity in mice. Single (1h prior) or repeated (twice daily during 3 or 13 days) treatments with euphol ameliorated painful peripheral neuropathy induced by paclitaxel and also the mechanical hypersensitivity induced by B16F10 melanoma cells injection, in mice. Additionally, in both inflammatory and neuropathic pain models, euphol consistently prevented PKCε up-regulation, as well as, inhibited the up-regulation of PKCε-activated intracellular pathways; namely nuclear factor-κB (NF-κB), cyclic AMP response element binding protein (CREB) and cyclo-oxygenase-2 (COX-2). The present results suggest the antinociceptive effect on persistent pain caused by euphol is likely dependent on the inhibition of pro-inflammatory mediators modulated by PKCε.

The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats.

BACKGROUND AND PURPOSE: Resolution of inflammation is mediated by endogenous molecules with anti-inflammatory and pro-resolving activities and they have generated new possibilities for the treatment of inflammatory diseases. Here, we have investigated the possible anti-hyperalgesic effects of two lipids, aspirin-triggered resolvin D1 (AT-RvD1) and its precursor, 17(R)-hydroxy-4Z,7Z,10Z,13Z,15E,17R,19Z-docosahexaenoic acid (17(R)HDoHE). EXPERIMENTAL APPROACH: The anti-hyperalgesic effects of both lipid mediators were evaluated, using mechanical and thermal stimuli, at different time-points in adjuvant-induced arthritis in rats. Cytokine levels were measured, and immunohistochemistry and real-time PCR for pro-inflammatory mediators were also performed. KEY RESULTS: The precursor of resolvin D series, 17(R)HDoHE, given systemically, inhibited the development and the maintenance of mechanical hyperalgesia in acute inflammation. Such effects were likely to be associated with modulation of both NF-κB and COX-2 in dorsal root ganglia and spinal cord. 17(R)HDoHE was also effective against sub-chronic pain. Unexpectedly, repeated treatment with 17(R)HDoHE did not modify paw and joint oedema in the sub-chronic model, while joint stiffness was prevented. Notably, AT-RvD1 exhibited marked anti-hyperalgesic effects in acute inflammation when given systemically. The efficacy of long-term treatment with either 17(R)HDoHE or AT-RvD1 was partly related to decreased production of TNF-α and IL-1ß in rat hind paw. CONCLUSIONS AND IMPLICATIONS: Our findings provide fresh evidence for the anti-hyperalgesic properties of 17(R)HDoHE and its pro-resolution metabolite AT-RvD1. Such lipid mediators might be useful for treating pain associated with acute or chronic inflammation. LINKED ARTICLE This article is commented on by Xu and Ji, pp. 274-277 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01348.x.

Weight gain post-renal transplantation and its association with glomerular filtration rate.

OBJECTIVE: Obesity may be a risk factor for renal graft loss. The purpose of this study was to assess weight gain and its association with glomerular filtration rate after kidney transplant. METHODS: This retrospective analysis of 152 adult renal transplant outpatients (77 males, 75 females; mean age, 45.6 +/- 10.1 years) with at least 6 months posttransplantation (post-tx) included body weight and creatinine clearance (CrCl) measured pretransplantation (pre-tx) as well as at 6 months (post-tx1), 1 year (post-tx2), 5 years (post-tx3), 10 years (post-tx4), 15 years (post-tx5), and 20 years (post-tx6) post-tx. Weight gain was determined by subtracting patient preoperative weight from the post-tx weights. RESULTS: The weight gain post-tx versus pre-tx was progressive and significant (P < .001) post-tx1, 8.7 +/- 10.9% (n = 152); post-tx2, 12.4 +/- 11.5% (n = 150); post-tx3, 16.6 +/- 14.8% (n = 102); post-tx4, 20.1 +/- 18.1% (n = 47); post-tx5, 20.8 +/- 19.8% (n = 17); and post-tx6, 21.0 +/- 32.5% (n = 11). There was a positive and significant correlation between weight gain and CrCl during most times post-tx: post-tx2 (r = 0.32; P < .000); post-tx3 (r = 0.54; P < .0001); post-tx4 (r = 0.47; P = .01); and post-tx6 (r = 0.92; P < .001). CONCLUSIONS: There was a great increase in body weight after kidney transplantation. The excessive body weight gain was associated with a better glomerular filtration rate.

Prevalence of risk factors for cardiovascular disease in Brazilian renal transplant recipients.

OBJECTIVE: Cardiovascular disease (CVD) is the major cause of death in renal transplant recipients. The aim of this study was to assess the prevalence of CVD risk factors among Brazilian adult renal transplant recipients. METHODS: This cross-sectional study included 192 cases in which the evaluated CVD risk factors were hypertension, diabetes mellitus, impaired fasting glucose, obesity, overweight, abdominal obesity, metabolic syndrome, and dyslipidemia. RESULTS: Hypertension, abdominal obesity, and hypercholesterolemia were the highest prevalent risk factors among the total population with prevalences of approximately 60%. The prevalence of obesity was significantly higher (P < .001) in recipients with normal graft function (28%) than in those with impaired graft function (7%). Abdominal obesity was also higher (P = .02) in the normal graft function group (77%) than in recipients with creatinine clearance (CrCl) values <60 mL/min (61%). There were positive, significant correlations between CrCl and body mass index (BMI) (r = 0.47; P < .001) and between CrCl and waist circumference (WC) (r = 0.44; P < .001). BMI (r = 0.31; P < .001) and WC (r = 0.27; P < .001) were also positively associated with triglyceride levels. There were negative associations of high-density lipoprotein (HDL)-cholesterol (HDL-c) with BMI (r = -0.28; P < .01) and WC (r = -0.32; P < .01). CONCLUSIONS: The high prevalence of CVD risk factors among renal transplant recipients emphasizes the importance of taking appropriate therapeutic measures to reduce modifiable risk factors, reducing CVD and its consequences.