Pro-ulcer effects of resveratrol in mice with indomethacin-induced gastric ulcers are reversed by L-arginine.
OBJECTIVE
Although resveratrol is currently being evaluated in pre-clinical studies as a potential cancer chemopreventive agent and cardiovascular stress-releasing compound, treatment with resveratrol severely delays healing of pre-existing gastric ulcers. Resveratrol treatment can also induce endothelial NOS (eNOS) expression. Here, we have attempted to modulate NO production via eNOS in order to alleviate the pro-ulcer effects of resveratrol.


METHODS
Gastric ulcers were induced in mice with a single dose of indomethacin. The effects of pretreatment with l-arginine on the pro-ulcer effects of resveratrol in these mice were then assessed. We measured ulcer damage scores (DS), myeloperoxidase (MPO) activity, generation of prostaglandin E(2) (PGE(2)) and NO, along with a gene expression study.


RESULTS
Resveratrol significantly aggravated damage from indomethacin-induced gastric ulcers, and delayed healing, as shown by increased DS and MPO activity. The mRNA for cyclooxygenase (COX)-1, but not that for COX-2, was inhibited by resveratrol treatment, with reduced synthesis of PGE(2) by gastric tissue. However, resveratrol treatment induced eNOS gene expression and shifted the eNOS/iNOS balance. l-Arginine given before resveratrol in mice with indomethacin-induced ulcers significantly increased tissue NO synthesis and improved ulcer healing.


CONCLUSIONS
Exogenous l-arginine increased NO formation via raised levels of eNOS induced by resveratrol and protected against the pro-ulcer effects of resveratrol. Therefore, l-arginine might be useful for alleviation of the pro-ulcer side effects of resveratrol in patients.
Guha
P
P
Department of Biochemistry, Dr. B.C. Roy Post Graduate Institute of Basic Medical Sciences & IPGME&R, Kolkata, India.
Dey
A
A
Chatterjee
A
A
Chattopadhyay
S
S
Bandyopadhyay
S K
SK
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001120:Arginine / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D051545:Cyclooxygenase 1 / Q000378:metabolism / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism / Q000494:pharmacology; D007213:Indomethacin / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000378:metabolism / Q000494:pharmacology; D000077185:Resveratrol; D013267:Stilbenes; D013276:Stomach Ulcer / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D014456:Ulcer / Q000188:drug therapy / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D013267:Stilbenes; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; C077623:Ptgs2 protein, mouse; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000077185:Resveratrol; D007213:Indomethacin