Targeting prokineticin system counteracts hypersensitivity, neuroinflammation, and tissue damage in a mouse model of bortezomib-induced peripheral neuropathy

Autor: Patrizia Procacci, Gianfranco Balboni, Vincenzo Conte, Giada Amodeo, Roberta Lattanzi, Valentina Onnis, Daniela Maftei, Paola Sacerdote, Silvia Franchi, Alberto E. Panerai, Giorgia Moschetti, Patrizia Sartori
Rok vydání: 2019
Předmět:
Male
0301 basic medicine
Receptors
Peptide
Immunology
Antineoplastic Agents
Pharmacology
lcsh:RC346-429
Receptors
G-Protein-Coupled
neuroinflammation
Gastrointestinal Hormones
Mice
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
medicine
Animals
lcsh:Neurology. Diseases of the nervous system
Neuroinflammation
Inflammation
neuropathic pain
prokineticins
business.industry
Bortezomib
Research
General Neuroscience
Neuropeptides
bortezomib
Peripheral Nervous System Diseases
medicine.disease
Spinal cord
macrophages
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Peripheral neuropathy
Allodynia
medicine.anatomical_structure
Neurology
Hyperalgesia
Neuropathic pain
Sciatic nerve
medicine.symptom
business
030217 neurology & neurosurgery
medicine.drug
Zdroj: Journal of Neuroinflammation, Vol 16, Iss 1, Pp 1-16 (2019)
Journal of Neuroinflammation
ISSN: 1742-2094
DOI: 10.1186/s12974-019-1461-0
Popis: Background Neuropathy is a dose-limiting side effect of many chemotherapeutics, including bortezomib. The mechanisms underlying this condition are not fully elucidated even if a contribution of neuroinflammation was suggested. Here, we investigated the role of a chemokine family, the prokineticins (PKs), in the development of bortezomib-induced peripheral neuropathy (BIPN), and we used a PK receptor antagonist to counteract the development and progression of the pathology. Methods Neuropathy was induced in male C57BL/6J mice by using a protocol capable to induce a detectable neuropathic phenotype limiting systemic side effects. The presence of allodynia (both mechanical and thermal) and thermal hyperalgesia was monitored over time. Mice were sacrificed at two different time points: 14 and 28 days after the first bortezomib (BTZ) injection. At these times, PK system activation (PK2 and PK-Rs), macrophage and glial activation markers, and cytokine production were evaluated in the main station involved in pain transmission (sciatic nerve, DRG, and spinal cord), and the effect of a PK receptors antagonist (PC1) on the same behavioral and biochemical parameters was assessed. Structural damage of DRG during BTZ treatment and an eventual protective effect of PC1 were also evaluated. Results BTZ induces in mice a dose-related allodynia and hyperalgesia and a progressive structural damage to the DRG. We observed a precocious increase of macrophage activation markers and unbalance of pro- and anti-inflammatory cytokines in sciatic nerve and DRG together with an upregulation of GFAP in the spinal cord. At higher BTZ cumulative dose PK2 and PK receptors are upregulated in the PNS and in the spinal cord. The therapeutic treatment with the PK-R antagonist PC1 counteracts the development of allodynia and hyperalgesia, ameliorates the structural damage in the PNS, decreases the levels of activated macrophage markers, and prevents full neuroimmune activation in the spinal cord. Conclusions PK system may be a strategical pharmacological target to counteract BTZ-induced peripheral neuropathy. Blocking PK2 activity reduces progressive BTZ toxicity in the DRG, reducing neuroinflammation and structural damage to DRG, and it may prevent spinal cord sensitization.
Databáze: OpenAIRE
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