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Therapeutic potential of endoplasmic reticulum stress inhibitors in the treatment of diabetic peripheral neuropathy

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Abstract

Endoplasmic stress response, the unfolded protein response (UPR), is a homeostatic signaling pathway comprising transmembrane sensors that get activated upon alterations in ER luminal environment. Studies suggest a relation between activated UPR pathways and several disease states such as Parkinson, Alzheimer, inflammatory bowel disease, tumor growth, and metabolic syndrome. Diabetic peripheral neuropathy (DPN), a common microvascular complication of diabetes-related chronic hyperglycemia, causes chronic pain, loss of sensation, foot ulcers, amputations, allodynia, hyperalgesia, paresthesia, and spontaneous pain. Factors like disrupted calcium signaling, dyslipidemia, hyperglycemia, inflammation, insulin signaling, and oxidative stress disturb the UPR sensor levels manifesting as DPN. We discuss new effective therapeutic alternatives for DPN that can be developed by targeting UPR pathways like synthetic ER stress inhibitors like 4-PhenylButyric acid (4-PBA), Sephin 1, Salubrinal and natural ER stress inhibitors like Tauroursodeoxycholic acid (TUDCA), Cordycepin, Proanthocyanidins, Crocin, Purple Rice extract and cyanidin and Caffeic Acid Phenethyl Ester (CAPE).

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Authors and Affiliations

  1. Department of Pharmacology, Bombay College of Pharmacy, Kalina, Mumbai, 400098, India

    Shivangi Patel, Arnika Pangarkar, Sakshi Mahajan & Anuradha Majumdar

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  1. Shivangi Patel
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  2. Arnika Pangarkar
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  3. Sakshi Mahajan
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  4. Anuradha Majumdar
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Contributions

Study Conception and design-Shivangi Patel; Material preparation and data collection- Shivangi Patel, Arnika Pangarkar, Sakshi Mahajan. The first draft of the manuscript was written by Shivangi Patel and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Anuradha Majumdar.

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Highlights

• Numerous factors such as disrupted calcium signaling, dyslipidemia, hyperglycemia, inflammation, insulin signaling, and oxidative stress alter the levels of ER stress response signaling molecules, further leading to diabetic peripheral neuropathy (DPN).

• In this review, we suggest that synthetic ER stress inhibitors such as 4-phenylbutyric acid, sephin-1, salubrinal and natural ER stress inhibitors such as tauroursodeoxycholic acid, cordycepin, proanthocyanidins, crocin, purple rice extracts, and caffeic acid phenethyl ester might serve as potential treatment options for DPN by interacting with the ER stress response signaling chaperones.

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Patel, S., Pangarkar, A., Mahajan, S. et al. Therapeutic potential of endoplasmic reticulum stress inhibitors in the treatment of diabetic peripheral neuropathy. Metab Brain Dis 38, 1841–1856 (2023). https://doi.org/10.1007/s11011-023-01239-x

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