Capsazepine

Capsazepine is a competitive antagonist of vanilloid (capsaicin) receptor with IC50 value of 562 nM.[1]

Capsazepine is a synthetic analogue of capsaicin, which activates the TRPV1 ion channel, thereby, blocks the painful sensation of heat caused by capsaicin. Capsazepine blocked voltage-activated calcium currents in adult rat dorsal root ganglion neurons with EC50 value of 7.7±1.4 μM.[2] Capsazepine was also able to block the response of TRPM8 to menthol (IC50=18±1.1 μM).[3] Capsazepine also inhibited nicotinic acetylcholine receptors in rat trigeminal ganglia at 10μM.[4] In human colon cancer cells, capsazepine treatment activated caspase -8, –9, and -3, induced death receptors (DRs) DR5 and DR4, then sensitized the cells to TRAIL-induced apoptosis.[5] Capsazepine is thought to be a tool to study the TRPV1 ion channel.

References:
1. C. S. Walpole, S. Bevan, G. Bovermann, J. J. Boelsterli, R. Breckenridge, J. W. Davies, G. A. Hughes, I. James, L. Oberer, J. Winter and et al., J Med Chem 1994, 37, 1942-1954.
2. R. J. Docherty, J. C. Yeats and A. S. Piper, Br J Pharmacol 1997, 121, 1461-1467.
3. H. J. Behrendt, T. Germann, C. Gillen, H. Hatt and R. Jostock, Br J Pharmacol 2004, 141, 737-745.
4. L. Liu and S. A. Simon, Neurosci Lett 1997, 228, 29-32.
5. B. Sung, S. Prasad, J. Ravindran, V. R. Yadav and B. B. Aggarwal, Free Radic Biol Med 2012, 53, 1977-1987.

The Transient Receptor Potential Vanilloid 1 Antagonist Capsazepine Improves the Impaired Lung Mechanics during Endotoxemia.[Pubmed:27090778]

Basic Clin Pharmacol Toxicol. 2016 Nov;119(5):421-427.

Acute lung injury (ALI) caused by systemic inflammatory response remains a leading cause of morbidity and mortality in critically ill patients. Management of patients with sepsis is largely limited to supportive therapies, reflecting an incomplete understanding of the underlying pathophysiology. Furthermore, there have been limited advances in the treatments for ALI. In this study, lung function and a histological analysis were performed to evaluate the impact of transient receptor potential vanilloid-1 receptor (TRPV1) antagonist (Capsazepine; CPZ) on the lipopolysaccharide (LPS)-induced lung injury in mice. For this, adult mice pre-treated with CPZ or vehicle received intraperitoneal injections of LPS or saline and 24 hr after, the mice were anaesthetized, and lung mechanics was evaluated. The LPS-challenged mice exhibited substantial mechanical impairment, characterized by increases in respiratory system resistance, respiratory system elastance, tissue damping and tissue elastance. The pre-treatment with CPZ prevented the increase in respiratory system resistance and decreased the increase in tissue damping during endotoxemia. In addition, mice pre-treated with CPZ had an attenuated lung injury evidenced by reduction on collapsed area of the lung parenchyma induced by LPS. This suggests that the TRPV1 antagonist Capsazepine has a protective effect on lung mechanics in ALI during endotoxemia and that it may be a target for enhanced therapeutic efficacy in ALI.

Systemic desensitization through TRPA1 channels by capsazepine and mustard oil - a novel strategy against inflammation and pain.[Pubmed:27356469]

Sci Rep. 2016 Jun 30;6:28621.

We demonstrate a novel dual strategy against inflammation and pain through body-wide desensitization of nociceptors via TRPA1. Attenuation of experimental colitis by Capsazepine (CPZ) has long been attributed to its antagonistic action on TRPV1 and associated inhibition of neurogenic inflammation. In contrast, we found that CPZ exerts its anti-inflammatory effects via profound desensitization of TRPA1. Micromolar CPZ induced calcium influx in isolated dorsal root ganglion (DRG) neurons from wild-type (WT) but not TRPA1-deficient mice. CPZ-induced calcium transients in human TRPA1-expressing HEK293t cells were blocked by the selective TRPA1 antagonists HC 030031 and A967079 and involved three cysteine residues in the N-terminal domain. Intriguingly, both colonic enemas and drinking water with CPZ led to profound systemic hypoalgesia in WT and TRPV1(-/-) but not TRPA1(-/-) mice. These findings may guide the development of a novel class of disease-modifying drugs with anti-inflammatory and anti-nociceptive effects.

Capsazepine inhibits JAK/STAT3 signaling, tumor growth, and cell survival in prostate cancer.[Pubmed:27458171]

Oncotarget. 2017 Mar 14;8(11):17700-17711.

Persistent STAT3 activation is seen in many tumor cells and promotes malignant transformation. Here, we investigated whether Capsazepine (Capz), a synthetic analogue of capsaicin, exerts anticancer effects by inhibiting STAT3 activation in prostate cancer cells. Capz inhibited both constitutive and induced STAT3 activation in human prostate carcinoma cells. Capz also inhibited activation of the upstream kinases JAK1/2 and c-Src. The phosphatase inhibitor pervanadate reversed Capz-induced STAT3 inhibition, indicating that the effect of Capz depends on a protein tyrosine phosphatase. Capz treatment increased PTPepsilon protein and mRNA levels. Moreover, siRNA-mediated knockdown of PTPepsilon reversed the Capz-induced induction of PTPepsilon and inhibition of STAT3 activation, indicating that PTPepsilon is crucial for Capz-dependent STAT3 dephosphorylation. Capz also decreased levels of the protein products of various oncogenes, which in turn inhibited proliferation and invasion and induced apoptosis. Finally, intraperitoneal Capz administration decreased tumor growth in a xenograft mouse prostate cancer model and reduced p-STAT3 and Ki-67 expression. These data suggest that Capz is a novel pharmacological inhibitor of STAT3 activation with several anticancer effects in prostate cancer cells.

Capsazepine is a novel activator of the delta subunit of the human epithelial Na+ channel.[Pubmed:15308635]

J Biol Chem. 2004 Oct 22;279(43):44483-9.

The amiloride-sensitive epithelial Na+ channel (ENaC) regulates Na+ homeostasis into cells and across epithelia. So far, four homologous subunits of mammalian ENaC have been isolated and are denoted as alpha, beta, gamma, and delta. The chemical agents acting on ENaC are, however, largely unknown, except for amiloride and benzamil as ENaC inhibitors. In particular, there are no agonists currently known that are selective for ENaCdelta, which is mainly expressed in the brain. Here we demonstrate that Capsazepine, a competitive antagonist for transient receptor potential vanilloid subfamily 1, potentiates the activity of human ENaCdeltabetagamma (hENaCdeltabetagamma) heteromultimer expressed in Xenopus oocytes. The inward currents at a holding potential of -60 mV in hENaCdeltabetagamma-expressing oocytes were markedly enhanced by the application of Capsazepine (> or =1 microM), and the Capsazepine-induced current was mostly abolished by the addition of 100 microM amiloride. The stimulatory effects of Capsazepine on the inward current were concentration-dependent with an EC50 value of 8 microM. Neither the application of other vanilloid compounds (capsaicin, resiniferatoxin, and olvanil) nor a structurally related compound (dopamine) modulated the inward current. Although hENaCdelta homomer was also significantly activated by Capsazepine, unexpectedly, Capsazepine had no effect on hENaCalpha and caused a slight decrease on the hENaCalphabetagamma current. In conclusion, Capsazepine acts on ENaCdelta and acts together with protons. Other vanilloids tested do not have any effect. These findings identify Capsazepine as the first known chemical activator of ENaCdelta.

A capsaicin-receptor antagonist, capsazepine, reduces inflammation-induced hyperalgesic responses in the rat: evidence for an endogenous capsaicin-like substance.[Pubmed:9881874]

Neuroscience. 1998 Sep;86(2):619-26.

In the present study, the presence of an endogenous capsaicin-like substance and the role of capsaicin receptors in nociception during inflammation were assessed using Fos immunohistochemistry and the paw-withdrawal test in rats. Intradermal injection of carrageenan in the hind-paw produced inflammation in the foot pad, increased the number of cells exhibiting Fos-like immunoreactivity in the dorsal horn of the spinal cord, and decreased the paw-withdrawal latency. Intradermal injection of Capsazepine, a capsaicin-receptor antagonist, significantly reduced the number of cells exhibiting Fos-like immunoreactivity, significantly increased the paw-withdrawal latency, but did not decrease inflammation induced by carrageenan injection. Intradermal injection of capsaicin or formalin also increased Fos-positive neurons. Capsaicin- or formalin-induced Fos expression was reduced in both cases by pretreatment of Capsazepine, but to a much lesser extent for formalin. The Capsazepine inhibition of carrageenan inflammation-induced hyperalgesic responses strongly suggests that an endogenous capsaicin-like substance is released in inflamed tissues and produces nociceptive neural impulses by acting on capsaicin receptors present on sensory neurons. Furthermore, our results indicate that capsaicin receptors take part only in generating nociceptive signals in sensory neurons, but not in activating the inflammation-promoting cells.

Selective antagonism of capsaicin by capsazepine: evidence for a spinal receptor site in capsaicin-induced antinociception.[Pubmed:1810591]

Br J Pharmacol. 1991 Dec;104(4):1045-9.

1. Capsazepine has recently been described as a competitive capsaicin antagonist. We have used this compound to test the hypotheses that the in vitro and in vivo effects of capsaicin are due to interactions with a specific receptor. 2. In an in vitro preparation of the neonatal rat spinal cord with functionally connected tail, the activation of nociceptive afferent fibres by the application of capsaicin, bradykinin or noxious heat (48 degrees C) to the tail could be measured by recording a depolarizing response from a spinal ventral root. Application of capsaicin or substance P to the spinal cord also evoked a depolarizing response which was recorded in a ventral root. 3. When Capsazepine (50 nM-20 microM) was administered to the tail or spinal cord it did not evoke any measurable response. However on the tail, Capsazepine reversibly antagonized (IC50 = 254 +/- 28 nM) the responses to capsaicin but not to heat or bradykinin administered to the same site. Similarly Capsazepine administration to the spinal cord antagonized the responses evoked by capsaicin (IC50 = 230 +/- 20 nM) applied to the cord but not responses evoked by substance P on the cord or by noxious heat and capsaicin on the tail. 4. In halothane anaesthetized rats, C-fibre responses evoked by transcutaneous electrical stimulation of the receptive field were recorded from single wide dynamic range neurones located in the spinal dorsal horn. C-fibre evoked discharges were consistently reduced by the systemic administration of capsaicin (20 mumol kg-1, s.c.) and this action of capsaicin was antagonized by Capsazepine (100 mumol kg-1) administered by the same route. In addition the systemic effect of capsaicin was antagonized by a spinal intrathecal administration of Capsazepine (5-50 nmol). 5. Intradermal injections of capsaicin, localized to the peripheral receptive field, usually one toe of the ipsilateral hind-paw, produced a transient increase in C-fibre-evoked activity followed by a prolonged period of localized insensitivity to transcutaneous C-fibre stimulation. These effects of capsaicin were significantly reduced by the concommitant administration of Capsazepine to the same site. 6. These data demonstrate that Capsazepine is a selective antagonist of capsaicin on nociceptive neurones in vitro and in vivo and suggest that the effects of capsaicin were mediated by activation of a specific receptor. Since the antinociceptive effect produced by systemically administered capsaicin was antagonised by spinal intrathecal Capsazepine this further supports the hypothesis that capsaicin exerts its antinociceptive effect by acting on specific receptors localized to sensory nerve fibres in the spinal cord.

Capsazepine is a synthetic analogue of the sensory neurone excitotoxin, and an antagonist of TRPV1 receptor with an IC50 of 562 nM.

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