Rolipram, a specific type-4 phosphodiesterase inhibitor, inhibits cyclophosphamide-induced haemorrhagic cystitis in rats.
OBJECTIVE
To investigate the protective roles of type 4 phosphodiesterase (PDE4) inhibitor in cyclophosphamide (CYP)-induced haemorrhagic cystitis, as the PDE4 inhibitor has anti-inflammatory effects but its characterization is still unknown in urinary tract diseases.


METHODS
In female Sprague-Dawley rats, CYP was administered intraperitoneally and bladders were harvested 24 h after CYP injection. In another group, rolipram as a PDE4 inhibitor was administered before CYP treatment. The effects and mechanisms of CYP with/without rolipram pretreatment were evaluated by microscopic features, bladder wet weight, myeloperoxidase (MPO) activity, nitric oxide (NO)-metabolite production and expression levels of inflammation-related genes.


RESULTS
CYP injection resulted in severe cystitis. Pretreatment with rolipram significantly reduced the increase in bladder wet weight and MPO activity, and ameliorated histological inflammatory changes caused by CYP. The levels of inflammation-related transcripts including inducible NO synthase (iNOS), interleukin-1beta and tumour necrosis factor-alpha, induced by CYP, were down-regulated significantly by pretreatment with rolipram. Also, rolipram reduced the NO-metabolite production and iNOS protein expression in the immunohistochemical examination.


CONCLUSIONS
These results indicate that rolipram can attenuate the development of CYP-induced cystitis in rats by suppressing cytokine production and iNOS induction. Thus, treatment with PDE4 inhibitor has potential clinical implications of the prevention of bladder inflammatory diseases.
Sakura
Mizuaki
M
Department of Urology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Masuda
Hitoshi
H
Matsuoka
Yoh
Y
Yokoyama
Minato
M
Kawakami
Satoru
S
Kihara
Kazunori
K
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects*; D003520:Cyclophosphamide / Q000009:adverse effects*; D003556:Cystitis / Q000139:chemically induced / Q000517:prevention & control*; D005260:Female; D053583:Interleukin-1beta / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D053583:Interleukin-1beta; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D003520:Cyclophosphamide; D009195:Peroxidase; D020889:Rolipram