Role of c-Jun N-terminal kinase (JNK) activation in micturition reflexes in cyclophosphamide (CYP)-induced cystitis in female rats.
c-Jun N-terminal kinase (JNK) is member of the mitogen-activated protein kinase (MAPK) family, activated through phosphorylation following cytokine exposure and stress. In this study, phosphorylation of JNK was examined in the urinary bladder with cyclophosphamide (CYP)-induced cystitis and the effects of SP600125, a selective inhibitor of phosphorylation of JNK, on urinary bladder function were assessed using conscious, open outlet, cystometry with continuous instillation of intravesical saline. We induced bladder inflammation in adult female Wistar rats by injecting CYP intraperitoneally to produce acute (150 mg/kg; 4 h), intermediate (150 mg/kg; 48 h), and chronic (75 mg/kg; every third day for 10 days) treatments. Western blotting of urinary bladder demonstrated a significant (p ≤ 0.01) increase (i.e., phosphorylation) in JNK activation with 4- and 48-h CYP-induced cystitis. Immunohistochemistry and image analyses demonstrated a significant (p ≤ 0.01) increase in JNK activation in the urothelium with 4- and 48-h CYP-induced cystitis. Blockade of JNK phosphorylation significantly (p ≤ 0.01) increased bladder capacity and intercontraction void intervals in CYP-treated rats (4 and 48 h). Furthermore, blockade of JNK phosphorylation reduced (p ≤ 0.01) neuropeptide (substance P, calcitonin gene-related peptide) expression in the urinary bladder with CYP-induced cystitis (4 and 48 h). In contrast, blockade of JNK phosphorylation was without effect on bladder function or neuropeptide expression in urinary bladder in control (no inflammation) rats. Blockade of JNK phosphorylation may represent a novel target for improving urinary bladder function with CYP-induced cystitis.
Department of Neurological Sciences, University of Vermont College of Medicine, D405A Given Research Building, Burlington, VT, 05405, USA.
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D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000235:genetics / Q000378:metabolism; D003520:Cyclophosphamide / Q000633:toxicity; D003556:Cystitis / Q000209:etiology / Q000378:metabolism*; D005260:Female; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex; D013373:Substance P / Q000235:genetics / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism; D014554:Urination
D000873:Anthracenes; D047428:Protein Kinase Inhibitors; C432165:pyrazolanthrone; D013373:Substance P; D003520:Cyclophosphamide; D048031:JNK Mitogen-Activated Protein Kinases; D015740:Calcitonin Gene-Related Peptide