Search Results (5)

Among the vinca-alkaloid class, vincristine is a potent chemotherapeutic agent with significant neurotoxic effects and is employed to address a wide spectrum of cancer types. Recently, the therapeutic potential of the cholecystokinin type 2 receptor (CCK2R) as a target for vincristine-induced peripheral neuropathy (VIPN) was demonstrated. In this study, the impact of preventive CCK2R blockade using netazepide (Trio Medicines Ltd., London, UK) was investigated in a mouse model of vincristine-induced peripheral neuropathy. Netazepide is a highly selective CCK2R antagonist under development for the treatment of patients with gastric neuroendocrine tumors caused by hypergastrinemia secondary to chronic autoimmune atrophic gastritis. Vincristine-induced peripheral neuropathy was induced by intraperitoneal injections of vincristine at 100 µg/kg/d for 7 days (D0 to D7). Netazepide (2 mg/kg/d or 5 mg/kg/d, per os) was administered one day before vincristine treatment until D7. Vincristine induced a high tactile allodynia from D1 to D7. VIPN was characterized by dorsal root ganglion neuron (DRG) and intraepidermal nerve fiber (IENF) loss, and enlargement and loss of myelinated axons in the sciatic nerve. Netazepide completely prevented the painful symptoms and nerve injuries induced by vincristine. In conclusion, the fact that netazepide protected against vincristine-induced peripheral neuropathy in a mouse model strongly supports the assessment of its therapeutic potential in patients receiving such chemotherapy. Full article

In the cultivation of Mytilus unguiculatus, the broodstock are shade-dried to stimulate sperm and egg production. To identify the functional genes affecting gonad development in M. unguiculatus, the transcriptome of gonads in mussels stimulated by shade-drying and those not stimulated were compared. Differential gene expression analysis revealed that there were 22 differentially expressed genes (DEGs) in the testis and 70 DEGs in the ovary among the experimental groups. KEGG enrichment analysis identified a total of 11 pathways that might be related to environmental stimuli affecting gonadal development. Nicotinic acetylcholine receptors (AChRs), the cholecystokinin A receptor (CCKAR), hypocretin (orexin) receptor 2 (HCRTR2), and gamma-aminobutyric acid type B receptor (GABBR) were highly expressed in the neuroactive ligand-receptor interaction pathway, indicating that these genes might be involved in the transduction of environmental information that stimulates gonadal development. Meanwhile, nuclear receptor co-repressor 2 (NCoR2) was highly expressed in the notch signaling pathway, indicating that NCoR2 might be involved in the regulation of gonad development. To validate the transcriptome data, we selected five DEGs in the KEGG signaling pathway, including AChRs, CCKAR, HCRTR2, GABAB, and NCoR2, for real-time quantitative PCR (RT-qPCR), which produced results consistent with the RNA-Seq data. The transcriptome analysis and gene pathway identification in this study have enhanced our comprehension of the reproductive mechanisms in M. unguiculatus. Full article

Alterations in dopamine neurotransmission are associated with obesity and food preferences. Otsuka Long-Evans Tokushima Fatty (OLETF) rats that lack functional cholecystokinin receptor type-1 (CCK-1R), due to a natural mutation, exhibit impaired satiation, are hyperphagic, and become obese. In addition, compared to lean control Long-Evans Tokushima (LETO) rats, OLETF rats have pronounced avidity for over-consuming palatable sweet solutions, have greater dopamine release to psychostimulants, reduced dopamine 2 receptor (D2R) binding, and exhibit increased sensitivity to sucrose reward. This supports altered dopamine function in this strain and its general preference for palatable solutions such as sucrose. In this study, we examined the relationship between OLETF’s hyperphagic behavior and striatal dopamine signaling by investigating basal and amphetamine stimulated motor activity in prediabetic OLETF rats before and after access to sucrose solution (0.3 M) compared to non-mutant control LETO rats, as well as availability of dopamine transporter (DAT) using autoradiography. In the sucrose tests, one group of OLETF rats received ad libitum access to sucrose while the other group received an amount of sucrose equal to that consumed by the LETO. OLETFs with ad libitum access consumed significantly more sucrose than LETOs. Sucrose exerted a biphasic effect on basal activity in both strains, i.e., reduced activity for 1 week followed by increased activity in weeks 2 and 3. Basal locomotor activity was reduced (−17%) in OLETFs prior to sucrose, compared to LETOs. Withdrawal of sucrose resulted in increased locomotor activity in both strains. The magnitude of this effect was greater in OLETFs and the activity was increased in restricted compared to ad-libitum-access OLETFs. Sucrose access augmented AMPH-responses in both strains with a greater sensitization to AMPH during week 1, an effect that was a function of the amount of sucrose consumed. One week of sucrose withdrawal sensitized AMPH-induced ambulatory activity in both strains. In OLETF with restricted access to sucrose, withdrawal resulted in no further sensitization to AMPH. DAT availability in the nucleus accumbens shell was significantly reduced in OLETF compared with aged-matched LETO. Together, these findings show that OLETF rats have reduced basal DA transmission and a heightened response to natural and pharmacological stimulation. Full article

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. Full article

Over the past decades, accumulating evidence has demonstrated a pivotal role of cholecystokinin type 2 receptor (CCK2R) in pain modulation. The established role of CCK2R activation in directly facilitating nociception has led to the development of several CCK2R antagonists, which have been shown to successfully alleviate pain in several rodent models of pain. However, the outcomes of clinical trials are more modest since they have not demonstrated the expected biological effect obtained in animals. Such discordances of results between preclinical and clinical studies suggest reconsidering our knowledge about the molecular basis of the pharmacology and functioning of CCK2R. This review focuses on the cellular localization of CCK2R specifically in the sensory nervous system and discusses in further detail the molecular mechanisms and signal transduction pathways involved in controlling pain perception. We then provide a comprehensive overview of the most successful compounds targeting CCK2R and report recent advances in pharmacological strategies used to achieve CCK2R modulation. We purposely distinguish between CCK2R benefits obtained in preclinical models and outcomes in clinical trials with different pain etiologies. Lastly, we emphasize the biological and clinical relevance of CCK2R as a promising target for the development of new treatments for pain management. Full article