Abstract
LASSBio-1135 is an imidazo[1,2-a]pyridine derivative with high efficacy in screening models of nociception and inflammation, presumed as a weak COX-2 inhibitor. In order to tease out its mechanism of action, we investigated others possible target for LASSBio-1135, such as TNF-α and TRPV1, to better characterize it as a multitarget compound useful in the treatment of chronic pain. TRPV1 modulation was assessed in TRPV1-expressing Xenopus oocytes against capsaicin and low pH-induced current. Modulation of TNF-α production was evaluated in culture of macrophages stimulated with LPS. In vivo efficacy of LASSBio-1135 was investigated in carrageenan and partial sciatic ligation-induced thermal hyperalgesia and mechanical allodynia. Corroborating its previous demonstration of efficacy in a model of capsaicin-induced hyperalgesia, LASSBio-1135 blocks capsaicin-elicited currents in a non-competitive way with an IC50 of 580 nM as well as low pH-induced current at 50 µM. As an additional action, LASSBio-1135 inhibited TNF-α release in these cells stimulated by LPS with an IC50 of 546 nM by reducing p38 MAPK phosphorilation. Oral administration of 100 µmol.Kg−1 LASSBio-1135 markedly reduced thermal hyperalgesia induced by carrageenan, however at 10 µmol.Kg−1 only a partial reduction was observed at the 4th h. Neutrophil recruitment and TNF-α production after carrageenan stimulus was also inhibited by the treatment with LASSBio-1135. Modulating TRPV1 and TNF-α production, two key therapeutic targets of neuropathic pain, 100 µmol.Kg−1 LASSBio-1135 was orally efficacious in reversing thermal hyperalgesia and mechanical allodynia produced by partial sciatic ligation 7–11 days after surgery without provoking hyperthermia, a common side effect of TRPV1 antagonists. In conclusion LASSBio-1135, besides being a weak COX-2 inhibitor, is a non-competitive TRPV1 antagonist and a TNF-α inhibitor. As a multitarget compound, LASSBio-1135 is orally efficacious in a model of neuropathic pain without presenting hyperthermia.
Highlights
The pharmacological treatment of patients with chronic pain is a current challenge, since existing drugs have little efficacy and present serious side effects
As previously shown by our group in a pharmacological screening, LASSBio-1135 was orally effective in completely reducing hyperalgesia induced by capsaicin, suggesting the possibility of TRPV1 modulation [2]
We asked whether LASSBio-1135 would interfere with other modalities of TRPV1 activation, the acidic pH, which is found in inflammatory conditions
Summary
The pharmacological treatment of patients with chronic pain is a current challenge, since existing drugs have little efficacy and present serious side effects. Controlling the inflammatory response is essential in inflammatory chronic pain, as pointed by recent studies that have shown the role of inflammation in the development of neuropathic pain and have supported new therapeutic approaches that target immune response [1]. The in vivo pharmacological screening for anti-inflammatory and antinociceptive activities pointed out this compound as one of the most prominent of the series, since LASSBio-1135 reduced the carrageenaninduced paw edema and it completely abrogated capsaicininduced thermal hyperalgesia. In vitro studies regarding its mechanism of action derivative showed that it did not inhibit p38 MAPK activity as planned, but it inhibited weakly COX-2 activity, reducing TXB2 production in whole blood stimulated with lipopolysaccharide (LPS) (IC50 = 18,5 mM) [2]. The robust in vivo actions of this compound were not consistent with the meager in vitro activities, suggesting that other mechanisms might be involved in these actions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
