Bortezomib (BTZ), a selective proteasome inhibitor, is a potent antineoplastic drug to treat multiple myeloma. In clinical practice, a significant peripheral sensory neuropathy (PN), generally associated with impairment of Adelta and C type primary afferent fibers, represents the most significant side effect of its administration. However, the mechanisms underlying BTZ harmful effects remain still to be fully clarified. To investigate BTZ-induced neurochemical changes possibly involved in neuropathic pain development, we examined the effects of a single-dose administration of BTZ and a well-established chronic schedule in a rat model of BTZ-induced PN. At the end of treatment, the expression of the neuropeptide calcitonin gene-related peptide (CGRP) was examined in the rat L4-L5 dorsal root ganglia (DRGs) and intraepidermal innervation of hindlimb footpad skin. Mystacial pad skin was also examined in parallel as a territory known to be spared under BTZ treatment. In the DRGs, RT-PCR revealed a decrease of CGRP mRNA relative levels after chronic treatment. Immunohistochemistry showed that CGRP-labelled neurons were mostly small- and medium-sized and that their percent frequency increased after treatment. In the skin, both CGRP and the panneuronal marker PGP9.5 were used to label total cutaneous nerve fibers. On the whole, labelled nerve fibers were distributed in the reticular and papillary dermis and within the epidermal lining. In agreement with the sensory peripheral manifestions of BTZ-induced PN, the quantitative analysis of PGP9.5- and CGRP-labelled intraepidermal nerve fibers revealed that the BTZ treatment induced a statistically significative decrease of the linear density of the sensory innervation. Our findings show that BTZ treatment selectively affects subsets of DRG neurons likely involved in the processing of nociceptive stimuli and that BTZ-induced neurochemical changes may contribute to development and persistence of pain in BTZ-induced PN.
Calcitonine Gene-Related Peptide in dorsal root ganglia and skin of a rat model of Bortezomib-induced neuropathy
BOI, MARIANNA;QUARTU, MARINA;SERRA, MARIA PINA;PODDIGHE, LAURA;MELIS, TIZIANA;PICCI, CRISTINA;
2013-01-01
Abstract
Bortezomib (BTZ), a selective proteasome inhibitor, is a potent antineoplastic drug to treat multiple myeloma. In clinical practice, a significant peripheral sensory neuropathy (PN), generally associated with impairment of Adelta and C type primary afferent fibers, represents the most significant side effect of its administration. However, the mechanisms underlying BTZ harmful effects remain still to be fully clarified. To investigate BTZ-induced neurochemical changes possibly involved in neuropathic pain development, we examined the effects of a single-dose administration of BTZ and a well-established chronic schedule in a rat model of BTZ-induced PN. At the end of treatment, the expression of the neuropeptide calcitonin gene-related peptide (CGRP) was examined in the rat L4-L5 dorsal root ganglia (DRGs) and intraepidermal innervation of hindlimb footpad skin. Mystacial pad skin was also examined in parallel as a territory known to be spared under BTZ treatment. In the DRGs, RT-PCR revealed a decrease of CGRP mRNA relative levels after chronic treatment. Immunohistochemistry showed that CGRP-labelled neurons were mostly small- and medium-sized and that their percent frequency increased after treatment. In the skin, both CGRP and the panneuronal marker PGP9.5 were used to label total cutaneous nerve fibers. On the whole, labelled nerve fibers were distributed in the reticular and papillary dermis and within the epidermal lining. In agreement with the sensory peripheral manifestions of BTZ-induced PN, the quantitative analysis of PGP9.5- and CGRP-labelled intraepidermal nerve fibers revealed that the BTZ treatment induced a statistically significative decrease of the linear density of the sensory innervation. Our findings show that BTZ treatment selectively affects subsets of DRG neurons likely involved in the processing of nociceptive stimuli and that BTZ-induced neurochemical changes may contribute to development and persistence of pain in BTZ-induced PN.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
