title: CB1 cannabinoid receptors promote oxidative/nitrosative stress, inflammation and cell death in a murine nephropathy model.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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
  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.affiliation: Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9413, USA.
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Hao
authors.initials: H
authors.lastname: Pan
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Rajesh
authors.forename: Sándor
authors.initials: S
authors.lastname: Bátkai
authors.forename: Vivek
authors.initials: V
authors.lastname: Patel
authors.forename: Judith
authors.initials: J
authors.lastname: Harvey-White
authors.forename: Bani
authors.initials: B
authors.lastname: Mukhopadhyay
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D016923:Cell Death / Q000235:genetics / Q000502:physiology*; D002945:Cisplatin; D004195:Disease Models, Animal; D063388:Endocannabinoids; D005989:Glycerides / Q000378:metabolism; D007249:Inflammation / Q000503:physiopathology*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009393:Nephritis / Q000139:chemically induced*; D018384:Oxidative Stress / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D000077285:Rimonabant; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D009025:Morpholines; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C094503:glyceryl 2-arachidonate; D002945:Cisplatin; D000077285:Rimonabant; C109925:AM 281; C078814:anandamide