Pharmacological interventions targeting Wnt/β-catenin signaling pathway attenuate paclitaxel-induced peripheral neuropathy

• Published in: European journal of pharmacology 2019-12, Vol.864, p.172714, Article 172714
• Main Authors: Resham, Kahkashan, Sharma, Shyam S.
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Depsipeptides - pharmacology; Depsipeptides - therapeutic use; Disheveled; Gene Expression Regulation - drug effects; Male; Neuropathy; Paclitaxel; Paclitaxel - adverse effects; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - drug therapy; Peripheral Nervous System Diseases - pathology; Peripheral Nervous System Diseases - physiopathology; Porcupine; Pyrazines - pharmacology; Pyrazines - therapeutic use; Pyridines - pharmacology; Pyridines - therapeutic use; Rats; Rats, Sprague-Dawley; Sciatic Nerve - drug effects; Sciatic Nerve - metabolism; Sciatic Nerve - physiopathology; Wnt; Wnt Signaling Pathway - drug effects; β-catenin
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2019.172714

Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling pain condition which occurs as a consequence of cancer chemotherapy with anti-cancer agents like paclitaxel, oxaliplatin, etc. Despite immense research in the pathological pathways involved in CIPN, treatment options still remain limited. Recently, pathological involvement of Wnt signaling has been investigated in various neuropathic pain models, however there are no reports as yet on the role of Wnt signaling in CIPN. In the present study, we have investigated the neuroprotective effects of Wnt signaling inhibitors namely LGK974 (Porcupine inhibitor), NSC668036 (Disheveled inhibitor) and PNU76454 (β-catenin inhibitor) in paclitaxel-induced neuropathic pain. Paclitaxel (2 mg/kg, i. p.) was administered to male Sprague Dawley rats on four alternate days. After 21 days, paclitaxel-treated rats showed reduced behavioral pain thresholds (cold allodynia, heat & mechanical hyperalgesia) and nerve functions (nerve conduction velocity and nerve blood flow). Moreover, Wnt signaling proteins (Wnt3a, β-catenin, c-myc and Dvl1), inflammatory marker (matrix metalloproteinase 2) and endoplasmic reticulum stress marker (GRP78) were found to be upregulated in the sciatic nerves of paclitaxel-treated rats accompanied with loss of intraepidermal nerve fiber density as compared to the control rats. Intrathecal administration of Wnt inhibitors (each at dose of 10 and 30 μM) for three consecutive days to paclitaxel-treated rats, significantly improved behavioral pain thresholds and nerve functional parameters by inhibition of Wnt signaling, inflammation, endoplasmic reticulum stress and improvement of intraepidermal nerve fiber density. All these results suggested the neuroprotective potential of Wnt signaling inhibitors in CIPN. [Display omitted] •Wnt signaling activation underlies the pathophysiology of PIPN.•Wnt (porcupine, disheveled and β-catenin) inhibitors were investigated in PIPN.•Wnt signaling inhibitors attenuated neuropathic pain in paclitaxel-treated rats.•Wnt signaling inhibitors reduced inflammation, ER stress and improved IENFD in PIPN.