Publication News 192 - 15 September 2025

Old pill, new target: amlodipine shows promise in attenuating DPN in mice and in human Schwann cells

Aims: G-protein–coupled receptor 40 (GPR40) is a seven-transmembrane protein whose activation attenuates neuro-inflammation, cell apoptosis, mitochondrial dysfunction, and energy metabolic disorders -processes implicated in the pathogenesis of diabetic polyneuropathy (DPN). This study aimed at identifying novel activators of GPR40 and the potential mechanisms by which receptor activation might improve DPN-related parameters.

Methods: Streptozotocin (STZ)-induced type 1 and db/db type 2 diabetic mice with DPN-like features were generated, some of which underwent GPR40-specific knockdown via adeno-associated virus 8-GPR40-RNAi.  Immunostaining and quantitative real-time PCR were employed to quantify GPR40 expression in sural nerves (SN) and dorsal root ganglia (DRG). Among FDA-approved drugs, amlodipine besylate (AB) was identified as a GPR40 agonist and administered daily at doses of 2 or 4 mg/kg for 4 weeks. Nerve conduction studies were performed in DPN and GPR40-knockout mice. Intraepidermal nerve fiber density (IEFD), myelin sheath thickness and structure were evaluated via immunofluorescence-based and Luxol fast blue staining. Primary human Schwann cells (HSCs) from SNs and human umbilical vein endothelial cells (HUVECs) from patients with DPN were extracted to confirm the efficacy of AB on human cell cultures.

Results: Reduced expression of GPR40 was demonstrated in SNs and DRG of DPN mice. The GPR40-activating effect of AB was confirmed to be independent of calcium-channel blockade as nifedipine did not reproduce this effect. AB improved the 50% paw withdrawal threshold, thermal response latency, motor and sensory nerve conduction velocities at both tested dosages in DPN mice (STZ, db/db) and not in GPR40-knockout mice. Likewise, IEFD as well as myelin sheath thickness and structure improved only in DPN mice. Additionally, suppression of neuroinflammation in Schwann cells through the GPR40/ β-arrestin2/NLRP3 pathway and decreased DRG neuronal apoptosis and mitochondrial dysfunction via the GPR40/LKB1/AMPK/SIRT1/PGC-1α pathway occurred both in DPN mice and in HSCs. Amelioration of peripheral vascular dysfunction and endothelial permeability was observed in DPN mice and in high glucose-induced HUVEC. Finally, AB-induced reduction in Schwann cells inflammation was proposed as the mechanism underpinning decreased mitochondrial and endothelial dysfunction in DRG neurons.

Conclusions: AB-mediated activation of GPR40 reduced neuroinflammation, mitochondrial dysfunction and vascular dysfunction underlying DPN in mice and primary human Schwann cells.

Comments. This study reveals the potential of amlodipine to mitigate DPN in mice and human Schwann cells in vitro by targeting critical pathogenetic mechanisms, including inflammation, mitochondrial dysfunction and vascular impairment. While previous clinical studies reported ameliorative effects of antihypertensive agents on DPN, such as manidipine in combination with delapril (Ruggenenti P et al. Hypertension 2011;58:776-83), this study identifies GPR40 underexpression as a key driver of DPN. Moreover, it demonstrates that amlodipine acts as a GPR40 agonist independent of its calcium channel-blocking activity, thereby paving the way for the development of druggable lead compounds targeting this pathway. However, STZ-induced and db/db mouse models with DPN-like characteristics do not fully mirror the complexity of human DPN. Therefore, these findings require confirmation in additional pre-clinical settings before translation to humans.

Pietro Pertile

Reference. Wei Y, Huang Y, Huang R, Ruan Y, Feng T, Zhou F, Zhang W, Lu J, Xie S, Yao Y, Wang J, Ji S, Shen X. Antihypertensive Drug Amlodipine Besylate Shows Potential in Alleviating Diabetic Peripheral Neuropathy. Diabetes. 2025 Jun 1;74(6):983-997. doi: 10.2337/db24-0403. PMID: 40019860; PMCID: PMC12097462.

🔗 https://diabetesjournals.org/diabetes/article/74/6/983/157941/Antihypertensive-Drug-Amlodipine-Besylate-Shows

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