Kv7 channel modulation by 4-hydroxycinnamic acid in experimental diabetic neuropathy.

AIMS: This study evaluates the impacts of p-coumaric acid in the challenging condition of diabetic neuropathy, within a focus on Kv7 channel-mediated mechanisms. METHODS: Rats were rendered diabetic by intravenous STZ (50 mg/kg, n = 8). p-Coumaric acid (25, 50, or 100 mg/kg) was given per oral for 28 days. Behavioral testing included von Frey and Hargreaves assays. Blood glucose levels were measured at multiple time points. Primary dorsal root ganglion neurons were collected and utilized for whole-cell patch-clamp recordings to assess M-type (Kv7) K+ currents. RT-PCR was utilized to quantify KCNQ2 and KCNQ5 mRNA expressions. KEY FINDINGS: p-Coumaric acid dose-dependently lowered blood glucose, with the 50  mg/kg group providing optimal effect. All doses significantly altered mechanical and thermal hypersensitivity. At 50  mg/kg, it increased M-type K+ current density and amplitude and enhanced Kv7 activation. RT-PCR revealed increased channel mRNA expressions. CONCLUSIONS: p-Coumaric acid dose-dependently reduces hyperglycemia, alters allodynia and hyperalgesia, and enhances M-type Kv7 function in dorsal root ganglion neurons. By enhancing Kv7 current density, activation, and mRNA expressions, it was associated with changes in Kv7 channel activity that may influence neuronal excitability. These findings suggest that the metabolic and electrophysiological effects of PCA, including its potential modulation of Kv7-related mechanisms, warrant further investigation in diabetic neuropathy. SIGNIFICANCE STATEMENT: This study shows that p-coumaric acid alters diabetic neuropathic pain by enhancing Kv7 channel function in sensory neurons, highlighting Kv7 modulation as a key mechanism in peripheral nerve excitability and a potential therapeutic target.