Structural improvement of new thiazolidinones compounds with antinociceptive activity in experimental chemotherapy‐induced painful neuropathy

Abstract

Chemotherapy-induced neuropathy is a disabling pain condition resulting from chemotherapy for cancers. Up to now, no drug is available to cure chemotherapy-induced neuropathy. In the present study, we describe the structural design, synthesis, chemical and pharmacological characterization of 15 thiazolidinones, a class of potential analgesic compounds. The synthesis of new thiazolidinones was achieved by using the thiazolidinone heterocyclic as main structural pharmacophoric group and varying the substituents attached to the phenyl near to the iminic bond. The analgesic potential of the compounds was investigated in a mice model of oxaliplatin-induced neuropathic pain, using von Frey, rota-rod and open-field tests. Except for compound 14, these thiazolidinones exhibited antinociceptive property without causing motor impairment. Thiazolidinones 12, 15 and 16 displayed a dose-dependent antinociceptive effect, with similar efficacy and enhanced potency than gabapentin, the gold standard drug used for neuropathic pain. In addition, the antinociceptive activity of 16 lasted longer than gabapentin. The antinociceptive effect of thiazolidinones was prevented by GW9662, a PPARγ antagonist. The main antinociceptive compounds exhibited positive Lipinski's index, predicting their oral bioavailability. In conclusion, the structural design performed here led to the identification of new compounds endowed with potent antinociceptive activity, potentially useful to treat chemotherapy-induced neuropathic pain.

The potent anti-inflammatory effect of Guilu Erxian Glue extracts remedy joint pain and ameliorate the progression of osteoarthritis in mice

“…OA is a chronic progressive disease with complicated mechanisms that include inflammation, periarticular bone response, and cartilage degradation [ 18 – 20 ]. To date, the available pain treatments are limited in their efficacy and known to possess associated toxicities, none of which halts disease progression or regenerates damaged cartilage or bone [ 21 ]. Thus, current therapeutic strategies seek to ameliorate pain, offer chondroprotective or regenerative capability, and increase mobility, thereby representing the critically unmet needs.…”

Reliability of Mouse Behavioural Tests of Anxiety: a Systematic Review and Meta-Analysis on the Effects of Anxiolytics

“…For example, if the response of animals to a compound is tested in both the LDB and the open field, an increase in LDB-light in the absence of a change in locomotor activity in the open field would suggest that the investigated compound has a specific anxiolytic effect, but no sedative effect, which is highly desirable in anxiolytics especially from a translational perspective (82)(83)(84). Upon literature review, we have found as many records in which the open field was performed as a test of locomotor activity (80,81,85,86), as we have found records in which it was performed as a test of anxiety (87)(88)(89)(90). Here, we identify an issue with the continuation of such tests as long-held standards that may not be appropriate, due to the researcher's degree of freedom in the interpretation of the test's meaning (91,92).…”

Gabapentin Increases Intra-Epidermal and Peptidergic Nerve Fibers Density and Alleviates Allodynia and Thermal Hyperalgesia in a Mouse Model of Acute Taxol-Induced Peripheral Neuropathy

“…Therefore, the present study aimed to assess whether treatment with gabapentin can affect IENFs and CGRP density in the mice’ hind paws at a time point that significantly confers an analgesic effect in an experimental TIPN mice model that closely mimics the course of peripheral neuropathy in human patients. To the best of our knowledge, this is the first study showing the decreased density of CGRP and PGP 9.5-positive nerve fibers innervating the paw skin in the TIPN model and their increase after 21 days of gabapentin treatment, justifying gabapentin use as a gold standard reference compound in the preclinical TIPN mouse model [ 31 , 32 , 33 ], as found in a randomized, placebo-controlled, clinical trial [ 34 ]. Present findings refine the TIPN mice model and further support the claim that skin biopsy with quantification of the density of IENF and CGRP, using generally agreed-upon counting rules, is a reliable, efficient, and objective technique, complementary to analgesia, to assess gabapentin effects on peripheral neuropathy both in patients and in animal models of peripheral neuropathy.…”