Polaprezinc attenuates cyclophosphamide-induced cystitis and related bladder pain in mice

Abstract

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.

Sustained relief of ongoing experimental neuropathic pain by a CRMP2 peptide aptamer with low abuse potential

“…Additionally, central blockade of CaV2.2 is effective in treatment of cases of chronic pain that are intractable to other interventions [11]. Other subtypes of calcium channels, such as CaV2.3 (R-type) [54; 72; 81] or CaV3 (T-type)[35; 51; 58], have also been indicated to play important roles in chronic pain. The CaV2.3-selective blocker, SNX-482, has been reported to block the C- and Aδ- fiber neurotransmission in animal models of chronic neuropathic pain [54] and reduce formalin induced paw-flinching and FOS-expression in the ipsilateral spinal cord [81].…”

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

“…Along these lines, hydrogen sulfide induces hyperalgesia via actions on Ca V 3.2 calcium channels (Maeda et al, 2009). In this context, it is interesting to note that administration of polaprezinc can mediate analgesia in a model for interstitial cystitis, presumably through its antioxidant activity (Murakami-Nakayama et al, 2015).…”

Intrarectally administered polaprezinc attenuates the development of dextran sodium sulfate‑induced ulcerative colitis in mice

“…The mechanism of action of PZ may involve the induction of HSPs, inhibition of the inflammatory process, antioxidant functions and cell membrane stabilization (18,(22)(23)(24)(25)(26). It has been reported that intrarectal administration of PZ can effectively protect against subserous injection-induced colitis in rats, and has a beneficial effect on ulcers during the healing stage (27,28) DSS-induced acute colitis is a chemically-induced model of UC. The model is simple and practical, and has many similarities with human UC, thus it is widely used in UC research (29).…”