Carbon monoxide reverses diabetic gastroparesis in NOD mice.
Diabetic gastroparesis is associated with increased oxidative stress attributable to loss of upregulation of heme oxygenase-1 (HO1), with resultant damage to interstitial cells of Cajal and delayed gastric emptying. These changes can be reversed by induction of HO1. HO1 catalyzes the breakdown of heme into iron, biliverdin and, carbon monoxide (CO). The aim of this study was to determine whether inhalation of CO can mimic the protective effects of HO1. Nonobese diabetic (NOD) mice with delayed gastric emptying were treated with CO inhalation. Serum malondialdehyde was measured as a marker of oxidative stress. Gastric emptying of solids was measured using a [(13)C]octanoic acid breath test. Kit expression levels were determined in immunoblots of protein extracted from the external muscle layers of the gastric body and antrum. The effect of CO on oxidative stress and gastric emptying was also determined in the presence of HO activity inhibitor chromium mesoporphyrin. CO inhalation reduced oxidative stress, restored Kit expression and reversed delayed gastric emptying in diabetic NOD mice with delayed gastric emptying. CO inhalation maintained this effect in the presence of the HO activity inhibitor, chromium mesoporphyrin, also resulting in restoration of the delay in gastric emptying. CO inhalation mimics the protective effect of upregulation of HO1 and decreased oxidative stress, increased Kit expression, and restored delay in gastric emptying. This effect of CO was independent of HO activity, suggesting that its effects were downstream of HO1. CO represents a potential therapeutic option for treatment of diabetic gastroparesis.
Kashyap
Purna C
PC
Mayo Clinic, 200 First St. SW, Rochester MN 55905, USA.
Choi
Kyoung Moo
KM
Dutta
Nirjhar
N
Linden
David R
DR
Szurszewski
Joseph H
JH
Gibbons
Simon J
SJ
Farrugia
Gianrico
G
D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D048909:Diabetes Complications / Q000188:drug therapy*; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D018589:Gastroparesis / Q000188:drug therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D018384:Oxidative Stress
D002248:Carbon Monoxide