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

Singhmar, Poojaa; Huo, XiaoJiaoa; Li, Yanb; Dougherty, Patrick, M.b; Mei, Fangc; Cheng, Xiaodongc; Heijnen, Cobi, J.a; Kavelaars, Annemiekea,*

doi: 10.1097/j.pain.0000000000001160
Research Paper

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.

Epac-inhibitor ESI-09 reverses paclitaxel-induced mechanical allodynia and associated hallmarks of chemotherapy-induced peripheral neuropathy in rodents including spinal cord astrocyte activation, loss of intraepidermal nerve fibers, and spontaneous neuronal discharges.

aLaboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

bDepartments of Anesthesia and Pain Medicine Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

cDepartment of Integrative Biology and Pharmacology, The University of Texas Health Science Center, Houston, TX, USA

Corresponding author. Address: Laboratory of Neuroimmunology, Department of Symptom Research, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 384, Houston, TX 77030, USA. Tel.: (713) 794-5297. E-mail address: akavelaars@mdanderson.org (A. Kavelaars).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

P. Singhmar and X. Huo contributed equally to this study.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painjournalonline.com).

Received May 22, 2017

Received in revised form December 18, 2017

Accepted January 08, 2018

© 2018 International Association for the Study of Pain
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