Premium
PARP inhibitors attenuate chemotherapy‐induced painful neuropathy
Author(s) -
Brederson JillDesiree,
Joshi Shailen K.,
Browman Kaitlin E.,
Mikusa Joseph,
Zhong Chengmin,
Gauvin Donna,
Liu Xuesong,
Shi Yan,
Penning Thomas D.,
Shoemaker Alex R.,
Giranda Vincent L.
Publication year - 2012
Publication title -
journal of the peripheral nervous system
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 67
eISSN - 1529-8027
pISSN - 1085-9489
DOI - 10.1111/j.1529-8027.2012.00413.x
Subject(s) - vincristine , poly adp ribose polymerase , medicine , peripheral neuropathy , pharmacology , allodynia , neuropathic pain , chemotherapy induced peripheral neuropathy , chemotherapy , chemistry , hyperalgesia , polymerase , cyclophosphamide , diabetes mellitus , endocrinology , enzyme , biochemistry , nociception , receptor
Chemotherapy‐induced peripheral neuropathy (CIPN) is a major toxicity of chemotherapy treatment for which no therapy is approved. Poly(ADP‐ribose) polymerase (PARP)1/2 are nuclear enzymes activated upon DNA damage, and PARP1/2 inhibition provides resistance against DNA damage. A role for PARP inhibition in sensory neurotransmission has also been established. PARP inhibitors attenuate pain‐like behaviors and neuropathy‐associated decreased peripheral nerve function in diabetic models. The hypothesis tested was that PARP inhibition protects against painful neuropathy. The objective of this study was to investigate whether the novel, selective PARP1/2 inhibitors (ABT‐888 and related analogues) would attenuate development of mechanical allodynia in vincristine‐treated rats. PARP inhibitors were dosed for 2 days, and then co‐administered with vincristine for 12 days. Mechanical allodynia was observed in rats treated with vincristine. PARP1/2 inhibition significantly attenuated development of mechanical allodynia and reduced poly ADP‐ribose (PAR) activation in rat skin. The data presented here show that PARP inhibition attenuates vincristine‐induced mechanical allodynia in rats, and supports that PARP inhibition may represent a novel therapeutic approach for CIPN.