It is well known that acrolein a metabolite of cyclophospham
It is well known that acrolein, a metabolite of cyclophosphamide, is responsible for the cyclophosphamide-induced cystitis, and that acrolein is capable of activating TRPA1 channels expressed in the capsaicin-sensitive primary afferents , . In this context, it is likely that the early phase of inflammation caused by TRPA1-dependent excitation of the primary afferents is independent of PGE2, but upregulates COX-2 followed by PGE2 formation, resulting in pgp inhibitors pain and some acceleration of the delayed phase of inflammation. This might be the reason why the EP1 antagonist abolished the bladder pain, but had relatively minor antiinflammatory effects (Fig. 3 and Table 1).
The cyclophosphamide-induced cystitis is characterized by the damages to the urothelial cells positive to staining of uroplakin III (Supplementary Fig. 1A), implying that the urothelial barrier functions are impaired, followed by diffusion of urine into the bladder tissue. The urine diffusion might be independent of inflammatory mediators and contribute to the bladder edema and increased bladder weight. This might also be related to our findings that the bladder edema/increased bladder weight was not sensitive to ONO-8130 and diclofenac (Table 1).
In conclusion, the PGE2/EP1 receptor system appears to play a major role in processing of bladder pain, particularly during cyclophosphamide-induced cystitis in mice, and selective EP1 receptor antagonists including ONO-8130 are considered available as therapeutic drugs for treatment of bladder pain.
Conflict of interest statement
Acknowledgement This work was supported in part by the “Antiaging Center Project” for Private Universities from the Ministry of Education, Culture, Sports, Science and Technology, 2008-2012.
Introduction Cyclooxygenase-2 (COX-2) is a rate limiting enzyme for the production of prostanoids (Breyer et al., 2001, Turini and DuBois, 2002). In brain, COX-2 expression is constitutive but is upregulated rapidly by NMDA receptor activation and by injuries such as ischemic stroke (Collaco-Moraes et al., 1996, Miettinen et al., 1997, Nogawa et al., 1997). It is well established that COX-2 activation contributes to ischemic brain injury. Thus, COX-2 gene inactivation or pharmacological inhibition attenuates the infarct and neurological dysfunction in mice subjected to focal cerebral ischemia (Nogawa et al., 1997, Iadecola et al., 2001, Sasaki et al., 2003). The mediator of the neurotoxic effect of COX-2 in cerebral ischemia is prostaglandin E2 (PGE2), and not superoxide, which is also produced by COX-2 (Manabe et al., 2004, Kunz et al., 2007). PGE2 exerts its biological actions through specific G-protein coupled transmembrane receptors (Breyer et al., 2001). Recently, we showed that EP1 receptors are the downstream effectors of COX-2-derived PGE2. Inhibition or genetic inactivation of EP1 receptors counteracts the Ca2+ dysregulation induced by NMDA receptor overactivation and induces neuroprotection (Kawano et al., 2006). However, the downstream molecular events linking the restoration of Ca2+ homeostasis with neuroprotection have not been defined. The serine/theronine kinase AKT/PKB (protein kinase B) is a key component in the survival signaling pathway transducing growth stimuli from growth factors (Manning and Cantley, 2007). In the central nervous system, decreased AKT activity has been linked to the neuronal death induced by NMDA receptor activation, focal ischemia, or hypoxia (Luo et al., 2003, Hirai et al., 2004). On the other hand, increased AKT activity contributes to the neuroprotection induced by hypothermia (Zhao et al., 2005) and to the protection of human cerebral endothelial cells induced by hypoxic preconditioning (Zhang et al., 2007). The activity of AKT depends on the availability of phosphoinisitidylinositol-3,4,5-triphosphate (PIP3), which is generated by the enzyme phosphatidylinositol 3-kinase (PI3K) (Foster et al., 2003). The levels of PIP3 are determined by the activity of a lipid phosphatase, PTEN (phosphatase and tensin homologue deleted on chromosome 10) (Maehama and Dixon, 1998), which dephosphorylates PIP3 and converts it back to PIP2. Therefore, the biological effects of AKT are determined by the balance between the activity of PI3K and PTEN, although the influence of PTEN can be more dominant (Seo et al., 2005).