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

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 a...
Source: Pain - Category: Anesthesiology Tags: Research Paper Source Type: research

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Publication date: Available online 11 November 2019Source: Trends in Pharmacological SciencesAuthor(s): Bushu Dong, Alex M. Jaeger, Dennis J. ThieleThe ability of cancer cells to cope with stressful conditions is critical for their survival, proliferation, and metastasis. The heat shock transcription factor 1 (HSF1) protects cells from stresses such as chemicals, radiation, and temperature. These properties of HSF1 are exploited by a broad spectrum of cancers, which exhibit high levels of nuclear, active HSF1. Functions for HSF1 in malignancy extend well beyond its central role in protein quality control. While HSF1 has be...
Source: Trends in Pharmacological Sciences - Category: Drugs & Pharmacology Source Type: research
Publication date: Available online 11 November 2019Source: International Journal of PharmaceuticsAuthor(s): Mahsa Shahriari, Seyed Mohammad Taghdisi, Khalil Abnous, Mohammad Ramezani, Mona AlibolandiAbstractIn the current research, the synthesis of polysaccharide-based polymersomes for targeted delivery of doxorubicin is reported. To this aim, doxorubicin was encapsulated in aqueous compartment of hyaluronan-polycaprolactone polymersomes via nanoprecipitation method. Then the therapeutic index of the prepared formulation was studied in metastatic breast cancer model in vitro and in vivo.The size of obtained polymersomes wa...
Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research
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Source: International Journal of Pharmaceutics - Category: Drugs & Pharmacology Source Type: research
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Source: Biomedicine and Pharmacotherapy - Category: Drugs & Pharmacology Source Type: research
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Source: Phytomedicine - Category: Drugs & Pharmacology Source Type: research
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Source: Annals of Plastic Surgery - Category: Cosmetic Surgery Tags: Breast Surgery Source Type: research
Conclusions Although both types of flaps offer a satisfactory approach for finger reconstruction with small-to-medium defects, FDUAP flaps are more suitable for such operations because of the better sensory reconstruction and aesthetic results.
Source: Annals of Plastic Surgery - Category: Cosmetic Surgery Tags: Hand Surgery Source Type: research
This article describes ossification of the corresponding vascular pedicle after soft tissue transfer with the lateral upper arm free flap and microsurgical anastomosis in oral cancer treatment. Similar findings in the context of the lateral upper arm free flap have never been reported in the literature; however, it is important for surgeons to know that pedicle ossification can occur. This knowledge may be helpful to avoid erroneous diagnosis of the ossification as a sign of tumor relapse/recurrence as well as to anticipate potential difficulties in the surgical approach in cases requiring reentry of the reconstructed regi...
Source: Annals of Plastic Surgery - Category: Cosmetic Surgery Tags: Microsurgery Source Type: research
This study compares the postoperative pain and opioid use in patients managed for surgery with general anesthesia (GA) with patients who were given combined epidural and general anesthesia (E/GA) with continuing postoperative epidural analgesia. Methods All patients who underwent penile inversion vaginoplasty between May of 2016 and May of 2018 under the care of single surgeon were identified retrospectively, 18 patients of which met the inclusion criteria. A retrospective chart review was conducted. Outcome measures were postoperative pain using visual analog scale, type and dosage of postoperatively administered intra...
Source: Annals of Plastic Surgery - Category: Cosmetic Surgery Tags: Reconstructive Surgery Source Type: research
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Source: Annals of Plastic Surgery - Category: Cosmetic Surgery Tags: Review Paper Source Type: research
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