NOV/CCN3 attenuates inflammatory pain through regulation of matrix metalloproteinases-2 and -9

<p>Abstract</p> <p>Background</p> <p>Sustained neuroinflammation strongly contributes to the pathogenesis of pain. The clinical challenge of chronic pain relief led to the identification of molecules such as cytokines, chemokines and more recently matrix metalloproteinases (MMPs) as putative therapeutic targets. Evidence points to a founder member of the matricial CCN family, NOV/CCN3, as a modulator of these inflammatory mediators. We thus investigated the possible involvement of NOV in a preclinical model of persistent inflammatory pain.</p> <p>Methods</p> <p>We used the complete Freund's adjuvant (CFA)-induced model of persistent inflammatory pain and cultured primary sensory neurons for <it>in vitro </it>experiments. The mRNA expression of NOV and pro-inflammatory factors were measured with real-time quantitative PCR, CCL2 protein expression was assessed using ELISA, MMP-2 and -9 activities using zymography. The effect of drugs on tactile allodynia was evaluated by the von Frey test.</p> <p>Results</p> <p>NOV was expressed in neurons of both dorsal root ganglia (DRG) and dorsal horn of the spinal cord (DHSC). After intraplantar CFA injection, NOV levels were transiently and persistently down-regulated in the DRG and DHSC, respectively, occurring at the maintenance phase of pain (15 days). NOV-reduced expression was restored after treatment of CFA rats with dexamethasone. <it>In vitro</it>, results based on cultured DRG neurons showed that siRNA-mediated inhibition of NOV enhanced IL-1β- and TNF-α-induced MMP-2, MMP-9 and CCL2 expression whereas NOV addition inhibited TNF-α-induced MMP-9 expression through β₁integrin engagement. <it>In vivo</it>, the intrathecal delivery of MMP-9 inhibitor attenuated mechanical allodynia of CFA rats. Importantly, intrathecal administration of NOV siRNA specifically led to an up-regulation of MMP-9 in the DRG and MMP-2 in the DHSC concomitant with increased mechanical allodynia. Finally, NOV intrathecal treatment specifically abolished the induction of MMP-9 in the DRG and, MMP-9 and MMP-2 in the DHSC of CFA rats. This inhibitory effect on MMP is associated with reduced mechanical allodynia.</p> <p>Conclusions</p> <p>This study identifies NOV as a new actor against inflammatory pain through regulation of MMPs thus uncovering NOV as an attractive candidate for therapeutic improvement in pain relief.</p

AMELIORATIVE EFFECT OF CYPERUS SQUARROSUS (CYPERACEAE) PLANT EXTRACTS ON DIABETIC CARDIOMYOPATHY AGAINST STREPTOZOTOCININDUCED DIABETES IN WISTAR RATS

Objective: Cyperus squarrosus, belongs to the family Cyperaceae, has been claimed to possess antidiabetic activity in the ethnomedicinal literature in India. Therefore, the present study was to investigate the effects of aqueous and ethanolic extracts of C. squarrosus (EECS) on diabetes and its cardiovascular complications with streptozotocin-induced diabetes in rats. Methods: Wister albino rats of either sex were made diabetic with streptozotocin (65 mg/kg, i.v.). Glibenclamide (5 mg/kg) was taken as standard drug. Treatment of aqueous and EECS (aqueous extract of C. squarrosus and EECS) was given in the dose of 200 and 400 mg/kg/day, p.o for 8 weeks and biochemical (serum glucose, cholesterol, triglycerides, and high-density lipoprotein [HDL]) parameters were recorded. Results: Streptozotocin-treated group produced significant increased levels of serum glucose, cholesterol, triglycerides, HDL, creatine kinase-myocardial band (CK-MB), and lactate dehydrogenase (LDH) levels and all these changes were prevented by the treatment with aqueous and EECS in both doses. Conclusion: As compare with ethanolic extract treated group, aqueous extract treated group exhibits significant (p&lt;0.001) effect on CK-MB and LDH levels. Our result suggests that aqueous and EECS prevents the streptozotocin-induced metabolic abnormalities as well as cardiovascular complications