Abstract
Chemotherapy-induced neuropathy (CIN) is a major dose-limiting side effect of anticancer therapy that can compel therapy discontinuation. Inadequate analgesic efficacy of current pharmacological approaches requires the identification of innovative therapeutics and, hence, the purpose of this study is to conduct a preclinical evaluation of the efficacy of DDD-028, a versatile pentacyclic pyridoindole derivative, against paclitaxel-induced neuropathic pain. In two separate experiments, DDD-028 was administered per os acutely (1–25 mg kg−1) or repeatedly (10 mg kg−1) in paclitaxel-treated rats. The response to mechanical noxious stimulus (paw pressure) as well as to non-noxious mechanical (von Frey) and thermal (cold plate) stimuli was investigated. Acute administration of DDD-028 induced a dose-dependent anti-neuropathic pain effect in all tests performed. Further, repeated daily treatment for 18 consecutive days (starting the first day of paclitaxel administration) significantly reduced the development of pain over time without the development of tolerance to the anti-hyperalgesic effect. Ex vivo analysis showed that DDD-028 was able to reduce oxidative damage of dorsal root ganglia as evidenced by the increase in the level of carbonylated proteins and the decrease in catalase activity. In the lumbar spinal cord, periaqueductal gray matter, thalamus, and somatosensory cortex 1, DDD-28 significantly prevented the activation of microglia and astrocytes. The pharmacodynamic study revealed that the pain-relieving effects of DDD-028 were fully blocked by both the non-selective nicotinic receptor (nAChR) antagonist mecamylamine and by the selective α7 nAChR antagonist methyllycaconitine. In conclusion, DDD-028 was active in reducing paclitaxel-induced neuropathic pain after single or repeated administrations without tolerance development and displaying a double symptomatic and neuroprotective profile. DDD-028 could represent a valuable candidate for the treatment of CIN.
Highlights
The success of cancer treatments is frequently limited by neuropathies which represent a major health concern [1]
To determine whether neurochemical reorganization in the spinal cord occurs following DDD-028 repeated treatment, we examined the lumbar spinal cord sections by immunohistochemistry using antibodies against glial fibrillary acidic protein (GFAP) and Iba1 to label astrocytes and microglia, respectively, which are nonneuronal cells strongly involved in chemotherapy-induced neuropathic pain [32, 33]
Cancer chemotherapy is beset with iatrogenic adverse effects, and neuropathies [34] are unavoidable toxicity of chemotherapy treatments that are endured by patients in exchange for a life extension offered by these drugs
Summary
The success of cancer treatments is frequently limited by neuropathies which represent a major health concern [1]. Neuropathy resulting from chemotherapy can be disabling, causing a significant functional loss and decreasing the quality of Anatomy and Histology Section, University of Florence, Largo Brambilla 3, 50134 Florence, Italy life. Neuropathy is the predominant reason for dose modification and discontinuation of treatment, and may thereby affect overall survival [1]. Paclitaxel induces sensory peripheral neuropathy characterized by burning pain symptoms, allodynia, hyperalgesia, tingling, and numbness. Neuropathy is positively correlated with increasing number of paclitaxel doses per cycle, total cumulative dose, and duration of infusion and can persist for months or years following the cessation of treatments [2]. Grade 3 or 4 sensory neuropathy occurs in 20–35% of patients receiving 250 mg/m2 paclitaxel every 3 weeks [3]. Several attempts have been made to treat or prevent CIN with various neuroprotective drugs, but the results are contradictory and most of them
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