(E)-3-Furan-2-yl-N-p-tolyl-acrylamide and its Derivative DM489 Decrease Neuropathic Pain in Mice Predominantly by α7 Nicotinic Acetylcholine Receptor Potentiation

Arias, Hugo R.; Ghelardini, Carla; Lucarini, Elena; Tae, Han Shen; Yousuf, Arsalan; Marcovich, Irina; Manetti, Dina; Romanelli, Maria Novella; Elgoyhen, Ana Belén; Adams, David J.; Mannelli, Lorenzo Di Cesare

doi:10.1021/acschemneuro.0c00476

Cited by 17 publications

(35 citation statements)

References 33 publications

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“…[15,16], selective α7 nAchR antagonist methyllycaconitine (MLA; 6 mg kg −1 , i.p.) [17], Kv7 channel blocker XE991 (1 mg kg −1 , i.p.) [18,19], and σ 1-σ 2 agonist (method described below).…”

Section: Ddd-028 Administration and Study Of The Pharmacodynamic Mechanismsmentioning

confidence: 99%

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

Micheli

Rajagopalan²,

Lucarini

et al. 2021

Neurotherapeutics

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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.

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Section: Ddd-028 Administration and Study Of The Pharmacodynamic Mechanismsmentioning

confidence: 99%

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

Micheli

Rajagopalan²,

Lucarini

et al. 2021

Neurotherapeutics

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“…Compelling evidence from our laboratory and others has demonstrated that activation of α7 nAchR could attenuate chronic pain, including neuropathic pain, inflammatory pain, and CIBP (Medhurst et al, 2008;Papke et al, 2015;Arias et al, 2020;Yang et al, 2021). Alsharari et al evaluated pain behaviors in the α7 mutant mice (KO) and α7 hypersensitive mice (KI) expressing the L250T α7 nAChR and their respective WT mice in chronic pain models (Alsharari et al, 2013).…”

Section: The Role Of α Nachr In Chronic Painmentioning

confidence: 99%

“…Moreover, α7 nAChR agonists and allosteric modulators suppressed the release of proinflammatory cytokines in chronic pain models (Loram et al, 2010;Sun et al, 2017). More importantly, α7 nAChR agonists and allosteric modulators have shown potent analgesic effects (Bagdas et al, 2018b;Quadri et al, 2018;Wang et al, 2019;Arias et al, 2020;Han et al, 2020). Therefore, it is plausible that potentiation of the α7 nAChR may be a promising therapeutic strategy for the management of chronic pain.…”

Section: Introductionmentioning

confidence: 99%

Targeting α7 nicotinic acetylcholine receptors for chronic pain

Zhou

Liu²,

Liu³

et al. 2022

Front. Mol. Neurosci.

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Despite rapid advances in the field of chronic pain, it remains extremely challenging in the clinic. Pain treatment strategies have not improved for decades as opioids remain the main prescribed drugs for chronic pain management. However, long-term use of opioids often leads to detrimental side effects. Therefore, uncovering the mechanisms underlying the development and maintenance of chronic pain may aid the discovery of novel therapeutics to benefit patients with chronic pain. Substantial evidence indicates downregulation of α7 nicotinic acetylcholine receptors (α7 nAChR) in the sciatic nerve, dorsal root ganglia, and spinal cord dorsal horn in rodent models of chronic pain. Moreover, our recent study and results from other laboratories demonstrate that potentiation of α7 nAChR attenuates pain behaviors in various murine models of chronic pain. This review summarized and discussed the preclinical evidence demonstrating the therapeutic potential of α7 nAChR agonists and allosteric modulators in chronic pain. This evidence indicates that potentiation of α7 nAChR is beneficial in chronic pain, mostly by alleviating neuroinflammation. Overall, α7 nAChR-based therapy for chronic pain is an area with great promise, but more research regarding its detailed mechanisms is warranted.

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“…LL-00066471, JWX-A0108 (Sun et al, 2019), andJNJ-1930942 (Dinklo et al, 2011) improved acoustic startle reflex or genetic defects believed to be associated with hippocampal auditory gating. PAM2 (Arias et al, 2020), 1-(2',5 0 -dihydroxyphenyl)-3-(2-fluoro-4-hydroxyphenyl)-1-propanone (Perez de Vega et al, 2019), TQS (Abbas et al, 2017), and PNU-120596 (Bagdas et al, 2018b) were effective in models of inflammatory or neuropathic pain. Some PAMs are advancing toward Fig.…”

Section: A7-positive Allosteric Modulatorsmentioning

confidence: 99%