Therapy of the rat hemorrhagic cystitis induced by cyclophosphamide. Stable gastric pentadecapeptide BPC 157, L-arginine, L-NAME.

Abstract

We focused on the cyclophosphamide-induced hemorrhagic cystitis (100 mg/kg/day intraperitoneally throughout three days) as a particular NO-system disturbance, and therapy possibilities. We demonstrated that it may be attenuated by subsequent administration of the NOS substrate L-arginine (100 mg/kg/day intraperitoneally), aggravated by NOS-blocker L-NAME (5 mg/kg/day intraperitoneally), all influenced by the stable gastric pentadecapeptide BPC 157 (10 μg/kg/day, 10 ng/kg/day, intraperitoneally or perorally, in drinking water). Regularly, cyclophosphamide dose- and time-dependently induced severe hemorrhagic cystitis lesions, gross lesions, and corresponding urothelial necrosis, vesical edema, erosion, hemorrhage, inflammation, and ulceration, microscopically. The bladder wet weight dramatically increased. Functionally, already after first cyclophosphamide administration, there is an increased leak point pressure. Until the second cyclophosphamide administration, L-arginine consistently attenuated regular cyclophosphamide-induced severe hemorrhagic cystitis lesions, grossly and microscopically, but not functionally. L-NAME aggravated these lesions and eradicated beneficial effect of L-arginine when combined. BPC 157 administration after cyclophosphamide, given in either dose or in either regimen markedly attenuated all cyclophosphamide lesions, grossly, microscopically. The increase of the bladder wet weight was consistently attenuated. Functionally, increased leak point pressure was reversed to the values noted in normal rats. The similar findings were noted in rats that received BPC 157 together with L-NAME or L-arginine, given alone or combined. Thus, the lesions are NO-related based on the administration of L-NAME as well as administration of L-arginine, and their mutual interaction, and counteraction by BPC 157 application. Likewise, we reveal new therapeutic possibilities, emphasizing stable gastric pentadecapeptide BPC 157 and L-arginine, versus L-NAME in rats underwent cyclophosphamide-induced cystitis.

• Authors: Mario Sucic, Kresimir Luetic, Ivan Jandric, Domagoj Drmic, Anita Zenko Sever, Lovorka Batelja Vuletic, Zeljka Belosic Halle, Dean Strinic, Antonio Kokot, Ranka Serventi Seiwerth, Ivan Zoricic, Alenka Boban Blagaic, Sven Seiwerth, Predrag Sikiric
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 861 Pg. 172593 (Oct 15 2019) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 31401154 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Anti-Ulcer Agents
• Peptide Fragments
• Proteins
• BPC 157
• Cyclophosphamide
• Arginine
• NG-Nitroarginine Methyl Ester

Topics

• Animals
• Anti-Ulcer Agents (pharmacology, therapeutic use)
• Arginine (pharmacology, therapeutic use)
• Cyclophosphamide (adverse effects)
• Cystitis (complications, drug therapy)
• Female
• Hemorrhage (complications)
• NG-Nitroarginine Methyl Ester (pharmacology, therapeutic use)
• Peptide Fragments (pharmacology, therapeutic use)
• Proteins (pharmacology, therapeutic use)
• Rats
• Rats, Wistar