ArticlePain2018
Orally active Epac inhibitor reverses mechanical allodynia and loss of intraepidermal nerve fibers in a mouse model of chemotherapy-induced peripheral neuropathy.
Article in Pain, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 49 citations in OpenAlex.
- AARS1-catalyzed H4K12 lactylation promotes HCC resistance to targeted therapy by activating RAPGEF3-RAP1 signaling.Cell death & disease · 2026Article
- Epac1 deletion attenuates Müller glial pathological activation and mitigates retinal neurodegeneration in ischemia-induced retinopathy.Journal of advanced research · 2026Article
- Decoding the metabolic cipher of dormant cancer cells: molecular mechanisms and therapeutic potentials.Cell communication and signaling : CCS · 2026Review
- Targeting molecular pathways in neuropathic cancer pain: from mechanisms to novel therapeutics.iScience · 2026Review
- Role of exchange proteins directly activated by cAMP signaling in vascular remodeling.Pharmacological reviews · 2025Review
- Integrative study of lung cancer adeno-to-squamous transition in EGFR TKI resistance identifies RAPGEF3 as a therapeutic target.National science review · 2024Article
- Biochemical pharmacology of adenylyl cyclases in cancer.Biochemical pharmacology · 2024Review
- Role of EPAC1 in chronic pain.Biochemistry and biophysics reports · 2024Review
- Upregulation of NGF/TrkA-Related Proteins in Dorsal Root Ganglion of Paclitaxel-Induced Peripheral Neuropathy Animal Model.Journal of pain research · 2024Article
- Article
- Upregulation of Epac1 Promotes Pericyte Loss by Inducing Mitochondrial Fission, Reactive Oxygen Species Production, and Apoptosis.Investigative ophthalmology & visual science · 2023Article
- Antiallodynic effects of KDS2010, a novel MAO-B inhibitor, via ROS-GABA inhibitory transmission in a paclitaxel-induced tactile hypersensitivity model.Molecular brain · 2022Article
- Epac1 activation by cAMP regulates cellular SUMOylation and promotes the formation of biomolecular condensates.Science advances · 2022Article
- Pharmacological Inhibition of Epac1 Averts Ferroptosis Cell Death by Preserving Mitochondrial Integrity.Antioxidants (Basel, Switzerland) · 2022Article
- The Cannabidiol Analog PECS-101 Prevents Chemotherapy-Induced Neuropathic Pain via PPARγ Receptors.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Article
- Mechanistic insights into the pathogenesis of microtubule-targeting agent-induced peripheral neuropathy from pharmacogenetic and functional studies.Basic & clinical pharmacology & toxicology · 2022Review
- Sex Differences in Protein Kinase A Signaling of the Latent Postoperative Pain Sensitization That Is Masked by Kappa Opioid Receptors in the Spinal Cord.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021Article
- Exchange proteins directly activated by cyclic adenosine monophosphate inhibitor reverses mechanical allodynia via the modification of astrocytes activity in the spinal cord.Annals of translational medicine · 2021Article
- Mini-Review: Mitochondrial dysfunction and chemotherapy-induced neuropathic pain.Neuroscience letters · 2021Review
- Preclinical and Clinical Evidence of Therapeutic Agents for Paclitaxel-Induced Peripheral Neuropathy.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.