Non-invasive electrical stimulation restores corneal nerve density and sensory function in diabetic neuropathy via KCNN-dependent mechanism

Corneal nerve, originated from trigeminal ganglia, play an important role in conreal sensation and homeotasis. Under disease conditions when corneal nerves are damaged, such as diabetes, corneal injury, or eye surgury, patients suffer from dry eye, pain, delayed wound healing, or urceration. Current treatments are limited, underscoring the need for a regenerative therapy. Here we show that a non-invasive neural modulation therapy, transcutaneous electrical stimulation (ES), significantly restore the nerve density and sensory function in both streptozotocin-induced diabetes mice and keratectomy model. This transcriptomics analysis of TGs from in vivo ES in keratectomy models aims to find mechanistic insights into the ES-induced corneal reinnervation. The results point to ion transport and Ca2+ signaling alteration, alongside activation of neural regeneration pathways. Consistently, membrane potential recording in TGs shows a rapid hyperpolarization upon ES accompanied by increased [Ca2+]i level. Inhibition of potassium intermediate/small conductance calcium-activated channel (KCNN) abolishes the hyperpolarization and neural regeneration effect, whereas activation of KCNN channel significantly enhances nerve regeneration in the STZ model compared with sham treatment. Overall, ES restores corneal nerve density and function via KCNN activation in a diabetic mouse model, offering a novel, non-invasive, and clinically translatable therapeutic strategy for diabetic neuropathy.