Orally active Epac inhibitor reverses mechanical allodynia and loss of intraepidermal nerve fibers in a mouse model of chemotherapy-induced peripheral neuropathy

Pain. 2018 May;159(5):884-893. doi: 10.1097/j.pain.0000000000001160.


Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of cancer treatment that significantly compromises quality of life of cancer patients and survivors. Identification of targets for pharmacological intervention to prevent or reverse CIPN is needed. We investigated exchange protein regulated by cAMP (Epac) as a potential target. Epacs are cAMP-binding proteins known to play a pivotal role in mechanical allodynia induced by nerve injury and inflammation. We demonstrate that global Epac1-knockout (Epac1-/-) male and female mice are protected against paclitaxel-induced mechanical allodynia. In addition, spinal cord astrocyte activation and intraepidermal nerve fiber (IENF) loss are significantly reduced in Epac1-/- mice as compared to wild-type mice. Moreover, Epac1-/- mice do not develop the paclitaxel-induced deficits in mitochondrial bioenergetics in the sciatic nerve that are a hallmark of CIPN. Notably, mice with cell-specific deletion of Epac1 in Nav1.8-positive neurons (N-Epac1-/-) also show reduced paclitaxel-induced mechanical allodynia, astrocyte activation, and IENF loss, indicating that CIPN develops downstream of Epac1 activation in nociceptors. The Epac-inhibitor ESI-09 reversed established paclitaxel-induced mechanical allodynia in wild-type mice even when dosing started 10 days after completion of paclitaxel treatment. In addition, oral administration of ESI-09 suppressed spinal cord astrocyte activation in the spinal cord and protected against IENF loss. Ex vivo, ESI-09 blocked paclitaxel-induced abnormal spontaneous discharges in dorsal root ganglion neurons. Collectively, these findings implicate Epac1 in nociceptors as a novel target for treatment of CIPN. This is clinically relevant because ESI-09 has the potential to reverse a debilitating and long-lasting side effect of cancer treatment.

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects*
  • Astrocytes / drug effects
  • Disease Models, Animal
  • Female
  • Ganglia, Spinal / drug effects
  • Guanine Nucleotide Exchange Factors / antagonists & inhibitors*
  • Guanine Nucleotide Exchange Factors / genetics
  • Hydrazones / pharmacology
  • Hydrazones / therapeutic use
  • Hyperalgesia / drug therapy*
  • Hyperalgesia / etiology
  • Isoxazoles / pharmacology
  • Isoxazoles / therapeutic use
  • Male
  • Mice
  • Mice, Knockout
  • Nerve Fibers / drug effects
  • Paclitaxel / adverse effects*
  • Pain Threshold / drug effects
  • Peripheral Nervous System Diseases / chemically induced
  • Peripheral Nervous System Diseases / drug therapy*
  • Spinal Cord / drug effects


  • 3-(5-tert-butylisoxazol-3-yl)-2-((3-chlorophenyl)hydrazono)-3-oxopropionitrile
  • Antineoplastic Agents
  • Epac protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Hydrazones
  • Isoxazoles
  • Paclitaxel