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Cemdomespib Ameliorates Mitochondrial and ER Stress to Improve Diabetic Peripheral Neuropathy
Patel, Sugandha
Patel, Sugandha
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Abstract
Diabetic peripheral neuropathy (DPN) is the most common microvascular complication of diabetes which is characterized by damage to neurons, Schwann cells and blood vessels within the nerve. The pathogenic mechanisms of DPN are complex and not well understood, resulting in poor therapeutic options. Cemdomespib is an orally bioavailable novologue, that alleviates DPN by modulating the expression of heat shock protein 70 (Hsp70) to improve oxidative stress and mitochondrial bioenergetics (mtBE). However, the mechanism of action of cemdomespib other than its Hsp70 dependence remains unknown. Mitochondrial dysfunction and ER stress are two of the mechanisms manifested in the development and progression of DPN. ER stress, caused by the accumulation of misfolded proteins leads to the activation of the unfolded protein response (UPR), to improves cell survival. Several proteins such as PERK, ATF6, and BiP, are involved in the stress response commonly regulating downstream ER chaperones and proteins. To understand the role of ER stress and PERK in Schwann cells, a mouse model with Schwann cell specific PERK deletion (SC-cPERK KO) or control Cre-/- x PERKf/f (SC-PERK+/+) mice were used. Diabetic SC-PERK+/+ and SC-cPERK KO mice developed DPN as depicted by sensory and nerve conduction deficits, however, cemdomespib only improved these deficits in the SC-PERK+/+ mice. Diabetic SC-PERK+/+ and SC-cPERK KO mice both showed decreased mtBE in diabetic neurons, but surprisingly, treatment with cemdomespib improved the mtBE in sensory neurons isolated from SC-PERK+/+ mice but not the SC-cPERK KO mice. Assessment of intra-epidermal nerve fiber density (iENFD), an important clinical measure of DPN, showed a significant decrease in iENFD in non-diabetic SC-cPERK KO compared to SC-PERK+/+ mice. While treatment with cemdomespib improved iENFD in diabetic SC-PERK+/+ mice, the drug was unable to improve the decreased iENFD in the plantar footpads of diabetic SC-cPERK KO mice. In vitro studies using rat Schwann cells, demonstrated that cemdomespib treatment increased Nrf2 activity, an antioxidant protein downstream of PERK. These data suggest a role of ER stress and specifically SC-PERK in the mechanism of action of cemdomespib.
Using a Mito-QC x Parkin KO DPN mouse model, we assessed whether cemdomespib improves mtBE via modulating parkin-mediated mitophagy. Cemdomespib failed to improve sensory behavior and nerve conduction velocity in MQC x Parkin KO mice, underscoring the necessity of parkin in mediating cemdomespib's beneficial effects. Surprisingly, cemdomespib enhanced mitochondrial bioenergetics in parkin KO sensory neurons, indicating a potential parkin-independent pathway. Additionally, our immunohistochemistry results confirmed disrupted mitophagy in the absence of parkin in the DRG neurons. In vitro studies with SHSY5Y cells revealed that cemdomespib ameliorates FCCP-induced mitochondrial dysfunction but does not alter mitophagic flux. This suggests that cemdomespib's therapeutic effects might be mediated through pathways other than mitophagy. Overall, our findings highlight the complex mechanisms underlying cemdomespib's action in DPN and underscore the critical roles of PERK and parkin in modulating mitochondrial function and neuronal health. These insights contribute to the broader understanding of DPN pathophysiology and pave the way for the development of targeted therapies.
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2024-08-31
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University of Kansas
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Pharmacology, Neurosciences, Cemdomespib, ER stress, Heat shock protein, Mitochondria, Tunicamycin