Co-administration of α-lipoic acid and cyclosporine aggravates colon ulceration of acetic acid-induced ulcerative colitis via facilitation of NO/COX-2/miR-210 cascade.
In this work, α-lipoic acid and cyclosporine demonstrated significant protection against acetic acid-induced ulcerative colitis in rats. We proposed that α-lipoic acid and cyclosporine co-administration might modulate their individual effects. Induction of ulcerative colitis in rats was performed by intra-rectal acetic acid (5% v/v) administration for 3 consecutive days. Effects of individual or combined used of α-lipoic acid (35 mg/kg ip) or cyclosporine (5mg/kg sc) for 6 days starting 2 days prior to acetic acid were assessed. Acetic acid caused colon ulceration, bloody diarrhea and weight loss. Histologically, there was mucosal atrophy and inflammatory cells infiltration in submucosa, associated with depletion of colon reduced glutathione, superoxide dismutase and catalase activities and elevated colon malondialdehyde, serum C-reactive protein (C-RP) and tumor necrosis factor-α (TNF-α). Colon gene expression of cyclooxygenase-2 and miR-210 was also elevated. These devastating effects of acetic acid were abolished upon concurrent administration of α-lipoic acid. Alternatively, cyclosporine caused partial protection against acetic acid-induced ulcerative colitis. Cyclosporine did not restore colon reduced glutathione, catalase activity, serum C-RP or TNF-α. Unexpectedly, co-administration of α-lipoic acid and cyclosporine aggravated colon ulceration. Concomitant use of α-lipoic acid and cyclosporine significantly increased nitric oxide production, cyclooxygenase-2 and miR-210 gene expression compared to all other studied groups. The current findings suggest that facilitation of nitric oxide/cyclooxygenase-2/miR-210 cascade constitutes, at least partially, the cellular mechanism by which concurrent use of α-lipoic acid and cyclosporine aggravates colon damage. Collectively, the present work highlights the probable risk of using α-lipoic acid/cyclosporine combination in ulcerative colitis patients.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt. Electronic address: dr_Hanan_el_gowali@hotmail.com.
Hanan M
HM
El-Gowelli
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.
Evan I
EI
Saad
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.
Abdel-Galil A
AG
Abdel-Galil
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.
Einas R
ER
Ibrahim
D019342:Acetic Acid / Q000009:adverse effects*; D000818:Animals; D002097:C-Reactive Protein / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000503:physiopathology*; D003106:Colon / Q000187:drug effects* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000008:administration & dosage / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013482:Superoxide Dismutase / Q000378:metabolism; D008063:Thioctic Acid / Q000008:administration & dosage / Q000009:adverse effects*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
C546388:MIRN210 microRNA, rat; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C546082:mirn21 microRNA, rat; C467498:vascular endothelial growth factor A, rat; D009569:Nitric Oxide; D008315:Malondialdehyde; D008063:Thioctic Acid; D016572:Cyclosporine; D002097:C-Reactive Protein; D002374:Catalase; D051546:Cyclooxygenase 2; C489691:Ptgs2 protein, rat; D013482:Superoxide Dismutase; D005978:Glutathione; D019342:Acetic Acid
Alpha-lipoic acid; Cyclooxygenase-2; Cyclosporine; MicroRNA; Nitric oxide; Ulcerative colitis