Caffeic acid and diabetic neuropathy: Investigating protective effects and insulin-like growth factor 1 (IGF-1)-related antioxidative and anti-inflammatory mechanisms in mice.

Diabetic neuropathy (DN) represents a common and debilitating complication of diabetes, affecting a significant proportion of patients. Despite available treatments focusing on symptom management, there remains an unmet need for therapies that address the underlying pathophysiology. In pursuit of novel interventions, this study evaluated the therapeutic effects of caffeic acid-a natural phenolic compound prevalent in various foods-on diabetic neuropathy using a mouse model, particularly examining its interaction with the Insulin-like Growth Factor 1 (IGF-1) signaling pathway. Caffeic acid was administered orally at two dosages (5 mg/kg and 10 mg/kg), and a comprehensive set of outcomes including fasting blood glucose levels, body weight, sensory behavior, spinal cord oxidative stress markers, inflammatory cytokines, and components of the IGF-1 signaling cascade were assessed. Additionally, to determine the specific contribution of IGF-1 signaling to the observed benefits, IGF1R inhibitor Picropodophyllin (PPP) was co-administered with caffeic acid. Our results demonstrated that caffeic acid, at both dosages, effectively reduced hyperglycemia and alleviated sensory behavioral deficits in diabetic mice. This was accompanied by a marked decrease in oxidative stress markers and an increase in antioxidant enzyme activities within the spinal cord. Significantly lowered microglial activation and inflammatory cytokine expression highlighted the potent antioxidative and anti-inflammatory effects of caffeic acid. Moreover, increases in both serum and spinal levels of IGF-1, along with elevated phosphorylated IGF1R, implicated the IGF-1 signaling pathway as a mediator of caffeic acid's neuroprotective actions. The partial reversal of caffeic acid's benefits by PPP substantiated the pivotal engagement of IGF-1 signaling in mediating its effects. Our findings delineate the capability of caffeic acid to mitigate DN symptoms, particularly through reducing spinal oxidative stress and inflammation, and pinpoint the integral role of IGF-1 signaling in these protective mechanisms. The insights gleaned from this study not only position caffeic acid as a promising dietary adjunct for managing diabetic neuropathy but also highlight the therapeutic potential of targeting spinal IGF-1 signaling as part of a strategic treatment approach.