Pain Relieving and Neuroprotective Effects of Non-opioid Compound, DDD-028, in the Rat Model of Paclitaxel-Induced Neuropathy

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.

Inhibitors of Mitochondrial Human Carbonic Anhydrases VA and VB as a Therapeutic Strategy against Paclitaxel-Induced Neuropathic Pain in Mice

“…Deepening the mechanisms that lead to paclitaxel-induced neuropathy, it is well accepted the phenomena of ganglionopathy and axonopathy in the peripheral nervous system [ 45 ] but less is known about the central mechanisms involved. Our previous work reported a complex maladaptive plasticity of astrocytes and microglia in the spinal cord as well as in the cerebral area involved in pain control [ 46 ]. These data are in line with evidence reported in other studies that highlight the pivotal role of glial cells in pain development and chronicization [ 47 , 48 ].…”

Transcranial direct current stimulation regulates phenotypic transformation of microglia to relieve neuropathic pain induced by spinal cord injury

“…It is worth noting that recent studies have shown activation of microglia is often accompanied by morphological changes ( Lucarini et al, 2020 ; Micheli et al, 2021 ). In this study, we also found that SCI could cause amoeba-like microglia in related brain regions.…”

N-type calcium channel blockers: a new approach towards the treatment of chronic neuropathic pain

“…The pharmacodynamics and pharmacokinetics affect living cells, and their dosage regimens have been reviewed and studied [81]. This drug is in the final stage of human testing to confirm its efficacy against NP and is one of the non-opioid neuroprotective agents [82]. Moreover, it acts by inhibiting Ca v 2.2 channels [83,84].…”