Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress, and cell death in nephropathy

Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA
Free Radical Biology and Medicine (Impact Factor: 5.74). 02/2010; 48(3):457-467. DOI: 10.1016/j.freeradbiomed.2009.11.022

ABSTRACT Cisplatin is an important chemotherapeutic agent; however, its nephrotoxicity limits its clinical use. Enhanced inflammatory response and oxidative/nitrosative stress seem to play a key role in the development of cisplatin-induced nephropathy. Activation of cannabinoid-2 (CB2) receptors with selective agonists exerts anti-inflammatory and tissue-protective effects in various disease models. We have investigated the role of CB2 receptors in cisplatin-induced nephrotoxicity using the selective CB2 receptor agonist HU-308 and CB2 knockout mice. Cisplatin significantly increased inflammation (leukocyte infiltration, CXCL1/2, MCP-1, TNFα, and IL-1β levels) and expression of adhesion molecule ICAM-1 and superoxide-generating enzymes NOX2, NOX4, and NOX1 and enhanced ROS generation, iNOS expression, nitrotyrosine formation, and apoptotic and poly(ADP-ribose) polymerase-dependent cell death in the kidneys of mice, associated with marked histopathological damage and impaired renal function (elevated serum BUN and creatinine levels) 3 days after the administration of the drug. CB2 agonist attenuated the cisplatin-induced inflammatory response, oxidative/nitrosative stress, and cell death in the kidney and improved renal function, whereas CB2 knockouts developed enhanced inflammation and tissue injury. Thus, the endocannabinoid system, through CB2 receptors, protects against cisplatin-induced kidney damage by attenuating inflammation and oxidative/nitrosative stress, and selective CB2 agonists may represent a promising novel approach to preventing this devastating complication of chemotherapy.

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    • "The activation of the CB2 receptor seems indeed to be associated with a reduced expression of iNOS [57]. Additionally, CB2 stimulation seems to suppress the release of pro-inflammatory factors such as NO and tumor necrosis factor alpha (TNF-α) in macrophages [58]. "
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    ABSTRACT: Experimental animal models of migraine have suggested the existence of interactions between the endocannabinoid system and pain mediation in migraine. Extensive evidence has demonstrated a role for the cannabinoid-1 (CB1) receptor in antinociception. However, recent research suggests that also CB2 receptors, especially located outside the central nervous system, play a role in the perception of pain. Systemic administration of nitroglycerin (NTG) consistently induces spontaneous-like headache attacks in migraneurs; in the rat, systemic NTG induces a condition of hyperalgesia, probably through the activation of cerebral/spinal structures involved in nociceptive transmission. In this study we evaluated the role of CB2 receptors in two animal models of pain that may be relevant for migraine: the tail flick test and the formalin test performed during NTG-induced hyperalgesia. The study was performed in male Sprague-Dawley rats pre-treated with NTG (10 mg/kg, i.p.) or vehicle (4 hours before) and treated with the CB2 agonist AM1241 o dimethylsulfoxide (DMSO) 60 minutes before both the tail flick test and the formalin test. AM1241 showed a significant analgesic effect in baseline conditions in both tests. Furthermore, when administered 3 hours after NTG administration, AM1241 at both doses significantly reduced the total number of flinches/shakes during phase II of the test. These findings suggest that the pharmacological manipulation of the CB2 receptor may represent a potential therapeutic tool for the treatment of migraine.
    The Journal of Headache and Pain 03/2014; 15(1):14. DOI:10.1186/1129-2377-15-14 · 2.80 Impact Factor
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    • "Reactive oxygen species (ROS), which induce oxidative stress, are important in the pathogenesis of cisplatin-induced renal injury, and NAD(P)H oxidase 4 (NOX4) is one of the major sources of ROS generation in cisplatin-treated kidneys (Mukhopadhyay et al., 2010; 2011). Elevated levels of intracellular ROS lead to the oxidation of several cellular molecules, including proteins and lipids, resulting in cellular stress (Chen et al., 1995). "
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    ABSTRACT: Cisplatin is one of the most potent chemotherapy agents. However, its use is limited due to its toxicity in normal tissues, including the kidney and ear. In particular, nephrotoxicity induced by cisplatin is closely associated with oxidative stress and inflammation. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in the heme metabolism, has been implicated in a various cellular processes, such as inflammatory injury and anti-oxidant/oxidant homeostasis. Capsaicin is reported to have therapeutic potential in cisplatin-induced renal failures. However, the mechanisms underlying its protective effects on cisplatin-induced nephrotoxicity remain largely unknown. Herein, we demonstrated that administration of capsaicin ameliorates cisplatininduced renal dysfunction by assessing the levels of serum creatinine and blood urea nitrogen (BUN) as well as tissue histology. In addition, capsaicin treatment attenuates the expression of inflammatory mediators and oxidative stress markers for renal damage. We also found that capsaicin induces HO-1 expression in kidney tissues and HK-2 cells. Notably, the protective effects of capsaicin were completely abrogated by treatment with either the HO inhibitor ZnPP IX or HO-1 knockdown in HK-2 cells. These results suggest that capsaicin has protective effects against cisplatin-induced renal dysfunction through induction of HO-1 as well as inhibition oxidative stress and inflammation.
    Moleculer Cells 03/2014; 37(3). DOI:10.14348/molcells.2014.2322 · 2.09 Impact Factor
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    • "HO-1 and autophagy has been implicated in protective effect of luteolin and berberine in cisplatin induced kidney injury [14], [15]. Cannabinoids and its receptor have protective effect in cisplatin induced kidney failure where inflammation was found to be key regulator of toxicity and cell death [16], [17], [18]. Sulforaphane, a natural constituent of broccoli, prevents cell death and inflammation in cisplatin induced nephropathy in rats [19]. "
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    ABSTRACT: Oxidative and nitrative stress is a well-known phenomenon in cisplatin-induced nephrotoxicity. The purpose of this work is to study the role of two metalloporphyrins (FeTMPyP and MnTBAP), water soluble complexes, in cisplatin-induced renal damage and their ability to scavenge peroxynitrite. In cisplatin-induced nephropathy study in mice, renal nitrative stress was evident by the increase in protein nitration. Cisplatin-induced nephrotoxicity was also evident by the histological damage from the loss of the proximal tubular brush border, blebbing of apical membranes, tubular epithelial cell detachment from the basement membrane, or intra-luminal aggregation of cells and proteins and by the increase in blood urea nitrogen and serum creatinine. Cisplatin-induced apoptosis and cell death as shown by Caspase 3 assessments, TUNEL staining and DNA fragmentation Cisplatin-induced nitrative stress, apoptosis and nephrotoxicity were attenuated by both metalloporphyrins. Heme oxygenase (HO-1) also plays a critical role in metalloporphyrin-mediated protection of cisplatin-induced nephrotoxicity. It is evident that nitrative stress plays a critical role in cisplatin-induced nephrotoxicity in mice. Our data suggest that peroxynitrite is involved, at least in part, in cisplatin-induced nephrotoxicity and protein nitration and cisplatin-induced nephrotoxicity can be prevented with the use of metalloporphyrins.
    PLoS ONE 01/2014; 9(1):e86057. DOI:10.1371/journal.pone.0086057 · 3.23 Impact Factor
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