Polaprezinc attenuates cyclophosphamide-induced cystitis and related bladder pain in mice.
Cav3.2 T-type Ca(2+) channels targeted by H2S, a gasotransmitter, participate in cyclophosphamide-induced cystitis and bladder pain. Given that zinc selectively inhibits Cav3.2 among T-channel isoforms and also exhibits antioxidant activity, we examined whether polaprezinc (zinc-l-carnosine), a medicine for peptic ulcer treatment and zinc supplementation, reveals preventive or therapeutic effects on bladder inflammation and/or pain in the mouse with cyclophosphamide-induced cystitis, a model for interstitial cystitis. Systemic administration of cyclophosphamide caused cystitis-related symptoms including increased bladder weight and vascular permeability, and histological signs of bladder edema, accompanied by bladder pain-like nociceptive behavior/referred hyperalgesia. All these symptoms were significantly attenuated by oral preadministration of polaprezinc at 400 mg/kg. The same dose of polaprezinc also prevented the increased malondialdehyde level, an indicator of lipid peroxidation, and protein upregulation of cystathionine-γ-lyase, an H2S-generating enzyme, but not occludin, a tight junction-related membrane protein, in the bladder tissue of cyclophosphamide-treated mice. Oral posttreatment with polaprezinc at 30-100 mg/kg reversed the nociceptive behavior/referred hyperalgesia in a dose-dependent manner without affecting the increased bladder weight. Together, our data show that zinc supplementation with polaprezinc prevents the cyclophosphamide-induced cystitis probably through the antioxidant activity, and, like T-channel blockers, reverses the established cystitis-related bladder pain in mice, suggesting novel therapeutic usefulness of polaprezinc.
Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka 577-8502, Japan; Section of Clinical Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe 650-8530, Japan.
Masahiro
M
Murakami-Nakayama
Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka 577-8502, Japan.
Maho
M
Tsubota
Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka 577-8502, Japan.
Saki
S
Hiruma
Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka 577-8502, Japan.
Fumiko
F
Sekiguchi
Division of Clinical Pharmacy, Kinki University School of Pharmacy, Higashi-Osaka 577-8502, Japan.
Kenji
K
Matsuyama
Department of Pharmacy, Hyogo College of Medicine Hospital, Nishinomiya 663-8501, Japan.
Takeshi
T
Kimura
Section of Clinical Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe 650-8530, Japan.
Masahiro
M
Moriyama
Division of Pharmacology and Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka 577-8502, Japan. Electronic address: kawabata@phar.kindai.ac.jp.
Atsufumi
A
Kawabata
D060433:Administration, Ophthalmic; D000818:Animals; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants; D020747:Calcium Channels, T-Type; D002336:Carnosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D003520:Cyclophosphamide; D018856:Cystitis, Interstitial / Q000139:chemically induced* / Q000188:drug therapy / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy*; D008815:Mice, Inbred Strains; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001743:Urinary Bladder / Q000187:drug effects; D017967:Zinc Compounds / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use
D000897:Anti-Ulcer Agents; D000975:Antioxidants; D020747:Calcium Channels, T-Type; D009942:Organometallic Compounds; D017967:Zinc Compounds; C061957:polaprezinc; D002336:Carnosine; D003520:Cyclophosphamide
Antioxidant activity; Bladder pain; Cyclophosphamide-induced cystitis; Polaprezinc; T-type Ca(2+) channel