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.
Subject(s)
Antineoplastic Agents/toxicity , Bortezomib/toxicity , Gastrointestinal Hormones/antagonists & inhibitors , Nerve Tissue Proteins/antagonists & inhibitors , Neuropeptides/antagonists & inhibitors , Neuroprotective Agents/pharmacology , Neurotoxicity Syndromes/prevention & control , Sensory Receptor Cells/drug effects , Triazines/pharmacology , Vincristine/toxicity , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Down-Regulation , Drug Evaluation, Preclinical , Gastrointestinal Hormones/physiology , Gene Expression Regulation/drug effects , Male , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/physiology , Neurites/drug effects , Neurites/ultrastructure , Neuroimmunomodulation/drug effects , Neuropeptides/physiology , Neuroprotective Agents/therapeutic use , RNA, Messenger/biosynthesis , Sensory Receptor Cells/physiology , Sensory Receptor Cells/ultrastructure , Triazines/therapeutic useABSTRACT
Prokineticin 2 (PK2), a new chemokine, causes mechanical hypersensitivity in the rat hind paw, but little is known about the molecular mechanism. Here, we have found that ionotropic P2X receptor is essential to mechanical allodynia induced by PK2. First, intraplantar injection of high dose (3 or 10 pmol) of PK2 significantly increased paw withdrawal response frequency (%) to innocuous mechanical stimuli (mechanical allodynia). And the mechanical allodynia induced by PK2 was prevented by co-administration of TNP-ATP, a selective P2X receptor antagonist. Second, although low dose (0.3 or 1 pmol) of PK2 itself did not produce an allodynic response, it significantly facilitated the mechanical allodynia evoked by intraplantar injection of α,ß-methylene ATP (α,ß-meATP). Third, PK2 concentration-dependently potentiated α,ß-meATP-activated currents in rat dorsal root ganglion (DRG) neurons. Finally, PK2 receptors and intracellular signal transduction were involved in PK2 potentiation of α,ß-meATP-induced mechanical allodynia and α,ß-meATP-activated currents, since the potentiation were blocked by PK2 receptor antagonist PKRA and selective PKC inhibitor GF 109203X. These results suggested that PK2 facilitated mechanical allodynia induced by α,ß-meATP through a mechanism involved in sensitization of cutaneous P2X receptors expressed by nociceptive nerve endings.
Subject(s)
Adenosine Triphosphate/analogs & derivatives , Gastrointestinal Hormones/pharmacology , Hyperalgesia/chemically induced , Neuropeptides/pharmacology , Adenosine Triphosphate/adverse effects , Adenosine Triphosphate/pharmacology , Animals , Drug Synergism , Ganglia, Spinal/drug effects , Ganglia, Spinal/physiology , Gastrointestinal Hormones/antagonists & inhibitors , Hyperalgesia/physiopathology , Indoles/pharmacology , Male , Maleimides/pharmacology , Membrane Potentials/drug effects , Membrane Potentials/physiology , Neuropeptides/antagonists & inhibitors , Protein Kinase C/antagonists & inhibitors , Purinergic P2X Receptor Antagonists/pharmacology , Rats , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, Peptide/antagonists & inhibitors , Receptors, Purinergic P2X3/drug effects , Receptors, Purinergic P2X3/physiologyABSTRACT
The possible signaling role of prokineticin 2 (PK2) and its receptor, prokineticin receptor 2 (PKR2), on female reproduction was investigated. First, the expression of PKR2 and its co-localization with estrogen receptor (ERα) in the hypothalamus was examined. Sexually dimorphic expression of PKR2 in the preoptic area of the hypothalamus was observed. Compared to the male mice, there was more widespread PKR2 expression in the preoptic area of the hypothalamus in the female mice. The likely co-expression of PKR2 and ERα in the preoptic area of the hypothalamus was observed. The estrous cycles in female PK2-null, and PKR2-null heterozygous mice, as well as in PK2-null and PKR2-null compound heterozygous mice were examined. Loss of one copy of PK2 or PKR2 gene caused elongated and irregular estrous cycle in the female mice. The alterations in the estrous cycle were more pronounced in PK2-null and PKR2-null compound heterozygous mice. Consistent with these observations, administration of a small molecule PK2 receptor antagonist led to temporary blocking of estrous cycle at the proestrous phase in female mice. The administration of PKR2 antagonist was found to blunt the circulating LH levels. Taken together, these studies indicate PK2 signaling is required for the maintenance of normal female estrous cycles.