Antihypertensive drug amlodipine besylate shows potential in alleviating diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a common diabetic complication with no currently available curative treatments. Here, we demonstrated that the protein level of G-protein-coupled receptor 40 (GPR40) is significantly repressed in the sciatic nerves (SN) of DPN patients, as well as in the peripheral nerves, including dorsal root ganglia (DRG) and SN, of streptozotocin (STZ)-induced type 1 diabetic mice and BKS Cg-m+/+Lepr db/J (db/db) type 2 diabetic mice. We identified that amlodipine besylate (AB), a first-line clinical antihypertensive drug, as a GPR40 agonist capable of alleviating DPN-like pathologies in mice. These pathologies include neurological damage, destruction of myelin sheath structures, vascular injury, loss of intraepidermal nerve fibers, and impaired neurite outgrowth in DRG neurons. To elucidate the underlying mechanisms, we generated the DPN mice with GPR40-specific knockdown in SN and DRG tissues using adeno associated virus 8-GPR40-RNAi. Mechanistically, AB attenuated inflammatory responses via the GPR40/β-arrestin2/NLRP3 pathway and ameliorated mitochondrial dysfunction through the GPR40/LKB1/AMPK/SIRT1/PGC-1α pathway in DPN mice, which were all further validated in primary human Schwann cells. Additionally, AB suppressed the crosstalk between Schwann cells and endothelial cells /DRG neurons in DPN mice. Collectively, our findings highlight the potential of AB for the treatment of DPN.