LASSBio-1135: A Dual TRPV1 Antagonist and Anti-TNF-Alpha Compound Orally Effective in Models of Inflammatory and Neuropathic Pain

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.

Topical Mannitol Reduces Capsaicin‐Induced Pain: Results of a Pilot‐Level, Double‐Blind, Randomized Controlled Trial

“…The mechanism of action of mannitol in the current study is not clear. Efforts to decrease pain by antagonizing TRPV1 activity are preliminary [33]. Capsaicin and stronger biological analogs are used topically to disable the TRPV1 receptor through unrelenting activation [24].…”

“…Agents from natural products that directly down‐regulate, rather than overstimulate, the TRPV1 receptor may be preferable, but have not been identified [36]. Synthetic pharmaceutical approaches to down‐regulate the TRPV1 receptor have been limited by side effects of hyperthermia, delaying translation to human disease studies [33]. The current study attempts to identify a natural agent that may reduce the painful effects of TRPV1 activation by using the specific TRPV1 receptor agonist, capsaicin [37], as the pain model, and testing an agent that may antagonize the capsaicin‐induced pain.…”

α‐Spinasterol: a COX inhibitor and a transient receptor potential vanilloid 1 antagonist presents an antinociceptive effect in clinically relevant models of pain in mice

“…Therefore, due its multi‐target characteristics, α‐spinasterol could offset the hyperthermic effect induced by blocking TRPV1, by inhibiting COX‐2, which is an enzyme that is known to be involved in the regulation of body temperature (Yun et al, ). This counterbalancing effect on the temperature between targets such as TRPV1 and COX‐2 has also been attributed to another multi‐target agent (Lima et al, ). New approaches using drug combinations or multi‐target compounds to alleviate pain, especially chronic pain such as neuropathic pain, have been tested previously (Lima et al, ).…”

“…Moreover, the antinociceptive effect of α‐spinasterol in traumatic neuropathy can be attributed to its ability to antagonize TRPV1 and inhibit COXs. Although the topical application of a high‐concentration capsaicin patch (8%) is considered as second line of treatment for peripheral neuropathic pain (post‐traumatic painful neuropathies and painful polyneuropathies), TRPV1 antagonists have been shown to reduce the nociception in models of nerve injury‐induced neuropathy (Tributino et al, ; Lima et al, ; Finnerup et al, ).…”

“…Either the direct modulation of TRPV1 or the inhibition of the COX pathway can relieve neuropathic pain (Marwaha et al, ). Therefore, COX inhibitors and TRPV1 antagonists can also reduce the neuropathy induced by trauma or chemotherapy (Guindon and Beaulieu, ; Ito et al, ; Lima et al, ; Li et al, ). Likewise, a TRPV1 antagonist with additional anti‐inflammatory properties would be a promising prototype for the treatment of neuropathies (Sisignano et al, ).…”