Prokineticin Receptor Inhibition With PC1 Protects Mouse Primary Sensory Neurons From Neurotoxic Effects of Chemotherapeutic Drugs in vitro

Abstract

Neurotoxicity is a common side effect of chemotherapeutics that often leads to the development of chemotherapy-induced peripheral neuropathy (CIPN). The peptide Prokineticin 2 (PK2) has a key role in experimental models of CIPN and can be considered an insult-inducible endangering mediator. Since primary afferent sensory neurons are highly sensitive to anticancer drugs, giving rise to dysesthesias, the aim of our study was to evaluate the alterations induced by vincristine (VCR) and bortezomib (BTZ) exposure in sensory neuron cultures and the possible preventive effect of blocking PK2 signaling. Both VCR and BTZ induced a concentration-dependent reduction of total neurite length that was prevented by the PK receptor antagonist PC1. Antagonizing the PK system also reduced the upregulation of PK2, PK-R1, TLR4, IL-6, and IL-10 expression induced by chemotherapeutic drugs. In conclusion, inhibition of PK signaling with PC1 prevented the neurotoxic effects of chemotherapeutics, suggesting a promising strategy for neuroprotective therapies against the sensory neuron damage induced by exposure to these drugs.

Pathological Mechanisms of Bortezomib-Induced Peripheral Neuropathy

“…To elucidate mechanisms of and discover novel therapeutics for bortezomib-induced axonal degeneration, many studies have employed cell culture models that reflect in vivo observations. Most cell culture models utilized the PC12 cell line (rat pheochromocytoma 12) [ 13 , 34 ], SH-SY5Y cell line (human neuroblastoma) [ 35 , 36 ], or primary cultures of DRG neurons from rats or mice [ 26 , 37 , 38 ]. All culture models display reduced lengths of neurite outgrowth in response to bortezomib.…”

Interplay between Prokineticins and Histone Demethylase KDM6A in a Murine Model of Bortezomib-Induced Neuropathy

“…Neuroinflammation represents one of the main mechanisms underlying BTZ-induced neuropathic pain, and chemokines are emerging as important mediators in this pathway. In particular, among chemokines, we recently suggested a role of the prokineticins- PKs [ 11 , 12 , 31 ], demonstrating their role in sustaining neuroinflammation in peripheral nerves and DRG. We also showed that PK system activation in peripheral nervous system (PNS) is important for promoting spinal cord activation and central sensitization [ 11 , 31 ].…”

“…In addition, a role for the immune system in neuroinflammatory processes in this pathological condition has also been indicated [ 8 , 9 , 10 ] . In this regard, we have recently described the involvement of a newly discovered chemokine, the prokineticin 2 (PK2), in the development of BTZ-induced neuropathy [ 11 , 12 ]. The prokineticin family is composed of two proteins: PK1 and PK2 and by the two cognate G protein coupled receptors PKR1 and PKR2, which are widely distributed in pain stations like peripheral nerves, dorsal root ganglia (DRG), and spinal cord [ 13 , 14 ].…”

Evidence-Based View of Safety and Effectiveness of Prokineticin Receptors Antagonists during Pregnancy

“…Although the doses and the mode of delivery of the therapeutic agents via systemic delivery/subcutaneous injections have proven tolerance and preservation of the gestation, one of the major limitations on the dosage and the mode of delivery of the antagonists agents is that they have not been delivered specifically in the placenta. Nevertheless, the doses and duration of the treatment used in this study were based on strong previous studies from other groups who used either PROKR1 or PROKR2 antagonists to treat pain and inflammatory reactions that were reported to be associated with an increase in the circulating or local levels of prokineticins (PROK1 or PROK2) and their receptors [ 15 , 16 , 25 , 28 , 36 , 37 , 44 , 45 , 62 ].…”

“…Both antagonists were used at a concentration of 1 µM. This concentration was chosen according to previous reports on the use of PROKR1 or PROKR2 antagonists in vitro [ 28 , 44 , 45 ].…”