Blockade of Cholecystokinin Type 2 Receptors Prevents the Onset of Vincristine-Induced Neuropathy in Mice

Abstract

Vincristine (VCR) is responsible for the onset of the VCR-induced peripheral neuropathy (VIPN), associated with neuropathic pain. Several reports have strongly linked the cholecystokinin type 2 receptor (CCK2R) to nociceptive modulation. Thus, our aim was to evaluate the effect of CCK2R blockade on the onset of VIPN, as well as its interaction on VCR anticancer efficacy. VCR was administrated in mice for 8 days (100 µg/kg/d, i.p.). Transcriptomic analysis of the dorsal root ganglia (DRG) was performed at day 7 in VCR and control mice. Proglumide (30 mg/kg/d), a CCK1R and CCK2R antagonist, and Ly225910 (1 mg/kg/d), a selective CCK2R antagonist, were administrated one day before and during VCR treatment. Tactile sensitivity was assessed during treatments. Immunofluorescence and morphological analyses were performed on the skin, DRG and sciatic nerve at day 7. The cytotoxicity of VCR in combination with proglumide/Ly225910 was evaluated in human cancer cell lines. Cck2r was highly upregulated in the DRG of VCR mice. Proglumide accelerated the recovery of normal sensitivity, while Ly225910 totally prevented the onset of allodynia and nerve injuries induced by VCR. Proglumide or Ly225910 in combination with VCR did not affect the cytotoxicity of VCR. Targeting CCK2R could therefore be an effective strategy to prevent the onset of VIPN.

Netazepide, an Antagonist of Cholecystokinin Type 2 Receptor, Prevents Vincristine-Induced Sensory Neuropathy in Mice

“…It is important to notice that a definitive diagnostic protocol is not present in the current literature, especially when the damage is to small fibers, and therapeutic strategies are lacking, especially for small fiber damage. This underscores the importance of developing new drugs [ 13 , 26 , 56 ].…”

“…In our previous study, daily administration of proglumide accelerated the recovery of normal mechanical sensitivity in mice exposed to vincristine and prevented nerve injuries induced by vincristine [ 26 ]. Proglumide is a non-selective antagonist of CCK1R and CCK2R and has already been the subject of clinical trials.…”

“…The mice in each group were further categorized into 2 subgroups: control (Ctrl) or vincristine (VCR), resulting in a total of 6 groups of mice (n = 10 in each group): Veh-Ctrl, NTZ2-Ctrl, NTZ5-Ctrl, Veh-VCR, NTZ2-VCR, and NTZ5-VCR. The number n was calculated according to the variability obtained during the von Frey test in previous studies using the same model [ 26 , 36 ].…”

“…Thus, we believe that CCK2R could be a therapeutic target for CIPN in patients. Recently, we demonstrated overexpression of the cck2r gene in DRG in a mouse model of vincristine-induced peripheral neuropathy [ 26 ]. In that model, preventive treatment with the CCK2R antagonists, proglumide (a non-specific CCK2R antagonist) or Ly225910 (a selective CCK2R antagonist), prevented the painful symptoms of vincristine-induced peripheral neuropathy, but only Ly225910 alleviated the nerve injuries induced by the anticancer agent.…”