CB1 cannabinoid receptors promote oxidative/nitrosative stress, inflammation and cell death in a murine nephropathy model.

Abstract

BACKGROUND AND PURPOSE:

Accumulating recent evidence suggests that cannabinoid-1 (CB(1)) receptor activation may promote inflammation and cell death and its pharmacological inhibition is associated with anti-inflammatory and tissue-protective effects in various preclinical disease models, as well as in humans.

EXPERIMENTAL APPROACH:

In this study, using molecular biology and biochemistry methods, we have investigated the effects of genetic deletion or pharmacological inhibition of CB(1) receptors on inflammation, oxidative/nitrosative stress and cell death pathways associated with a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin.

RESULTS:

Cisplatin significantly increased endocannabinoid anandamide content, activation of p38 and JNK mitogen-activated protein kinases (MAPKs), apoptotic and poly (ADP-ribose)polymerase-dependent cell death, enhanced inflammation (leucocyte infiltration, tumour necrosis factor-alpha and interleukin-1beta) and promoted oxidative/nitrosative stress [increased expressions of superoxide-generating enzymes (NOX2(gp91phox), NOX4), inducible nitric oxide synthase and tissue 4-hydroxynonenal and nitrotyrosine levels] in the kidneys of mice, accompanied by marked histopathological damage and impaired renal function (elevated creatinine and serum blood urea nitrogen) 3 days following its administration. Both genetic deletion and pharmacological inhibition of CB(1) receptors with AM281 or SR141716 markedly attenuated the cisplatin-induced renal dysfunction and interrelated oxidative/nitrosative stress, p38 and JNK MAPK activation, cell death and inflammatory response in the kidney.

CONCLUSIONS AND IMPLICATIONS:

The endocannabinoid system through CB(1) receptors promotes cisplatin-induced tissue injury by amplifying MAPK activation, cell death and interrelated inflammation and oxidative/nitrosative stress. These results also suggest that inhibition of CB(1) receptors may exert beneficial effects in renal (and most likely other) diseases associated with enhanced inflammation, oxidative/nitrosative stress and cell death.

• Authors: Partha Mukhopadhyay, Hao Pan, Mohanraj Rajesh, Sándor Bátkai, Vivek Patel, Judith Harvey-White, Bani Mukhopadhyay, György Haskó, Bin Gao, Ken Mackie, Pál Pacher
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 160 Issue 3 Pg. 657-68 (Jun 2010) ISSN: 1476-5381 [Electronic] England
• PMID: 20590569 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Arachidonic Acids
• Endocannabinoids
• Glycerides
• Morpholines
• Piperidines
• Polyunsaturated Alkamides
• Pyrazoles
• Receptor, Cannabinoid, CB1
• glyceryl 2-arachidonate
• Cisplatin
• Rimonabant
• AM 281
• anandamide

Topics

• Animals
• Arachidonic Acids (metabolism)
• Cell Death (genetics, physiology)
• Cisplatin
• Disease Models, Animal
• Endocannabinoids
• Glycerides (metabolism)
• Inflammation (physiopathology)
• Kidney (drug effects, metabolism, pathology, physiopathology)
• Male
• Mice
• Mice, Knockout
• Morpholines (pharmacology)
• Nephritis (chemically induced)
• Oxidative Stress (physiology)
• Piperidines (pharmacology)
• Polyunsaturated Alkamides (metabolism)
• Pyrazoles (pharmacology)
• Receptor, Cannabinoid, CB1 (antagonists & inhibitors, genetics, physiology)
• Rimonabant
• Signal Transduction (drug effects, physiology)