Calpain inhibitor I reduces the development of acute and chronic inflammation.
There is limited evidence that inhibition of the activity of the protease calpain I reduces inflammation. Here we investigate the effects of calpain inhibitor I in animal models of acute and chronic inflammation (carrageenan-induced pleurisy and collagen-induced arthritis). We report here for the first time that calpain inhibitor I (given at 5, 10, or 20 mg/kg i.p. in the pleurisy model or at 5 mg/kg i.p every 48 hours in the arthritis model) exerts potent anti-inflammatory effects (eg, inhibition of pleural exudate formation, mononuclear cell infiltration, delayed the development of the clinical signs and histological injury) in vivo. Furthermore, calpain inhibitor I reduced (1) the staining for nitrotyrosine and poly (ADP-ribose) polymerase (immunohistochemistry) and (2) the expression of inducible nitric oxide synthase and cyclooxygenase-2 in the lungs of carrageenan-treated rats and in joints from collagen-treated rats. Thus, prevention of the activation of calpain I reduces the development of acute and chronic inflammation. Inhibition of calpain I activity may represent a novel therapeutic approach for the therapy of inflammation.
Cuzzocrea
S
S
Institute of Pharmacology, University of Messina, Messina, Italy. St. Bartholomew's, and the Royal London School of Medicine and Dentistry, Charterhouse Square, London, United Kingdom. salvator@www.unime.it
McDonald
M C
MC
Mazzon
E
E
Siriwardena
D
D
Serraino
I
I
Dugo
L
L
Britti
D
D
Mazzullo
G
G
Caputi
A P
AP
Thiemermann
C
C
D000208:Acute Disease; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control*; D002351:Carrageenan; D002908:Chronic Disease; D003094:Collagen; D051546:Cyclooxygenase 2; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D006023:Glycoproteins / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008168:Lung / Q000378:metabolism; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D052247:Nitric Oxide Synthase Type II; D010998:Pleurisy / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D011064:Poly Adenosine Diphosphate Ribose / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D011859:Radiography; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013643:Tarsus, Animal / Q000000981:diagnostic imaging; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors
D015853:Cysteine Proteinase Inhibitors; D006023:Glycoproteins; D007527:Isoenzymes; C039304:calpain inhibitors; D011064:Poly Adenosine Diphosphate Ribose; C002744:3-nitrotyrosine; D014443:Tyrosine; D002351:Carrageenan; D003094:Collagen; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases