Effects of Kalanchoe pinnata, exercise, and stimulation on neuroinflammation, redox homeostasis, and neuropathic pain in a Wistar-rat model.

BACKGROUND: Neuropathic pain is a persistent, treatment-resistant condition driven not only by peripheral nerve injury but also by maladaptive neuroplasticity in central pain-regulatory networks. Evidence increasingly points to dysfunction in the prefrontal cortex (PFC), a vital area for top-down control of pain, emotions, and autonomic functions, as a key factor in maintaining pain hypersensitivity. AIM: To examine the combined effects of Kalanchoe pinnata (KP), treadmill exercise, and vagus nerve stimulation (VNS) on neuroinflammation, redox homeostasis, and neuropathic pain in a rat model. METHODS: Neuropathic pain was induced via partial sciatic nerve ligation. KP was administered orally at an effective dose of 100 mg/kg. Rats were assigned to 7 groups: (1) Sham; (2) Partial sciatic nerve ligation-neuropathic pain-induced; (3) Gabapentin; (4) KP alone; (5) KP + exercise; (6) KP + VNS; and (7) KP + exercise + VNS. Pain behaviors were assessed using mechanical allodynia and thermal hyperalgesia tests. Biochemical analysis of the PFC measured oxidative stress markers, pro-inflammatory cytokines [nuclear factor-kappa B, tumor necrosis factor alpha, interleukin (IL)-1β, IL-6], anti-inflammatory cytokine (IL-10), nitric oxide, monoaminergic and cholinergic biomarkers. Molecular analysis measured nuclear factor erythroid 2-related factor 2, heme-oxygenase 1, Kelch-like ECH-associated protein 1, B-cell lymphoma 2 associated X-protein, B-cell lymphoma 2, caspase-3, brain-derived neurotrophic factor, and cAMP response element-binding protein in the PFC. RESULTS: Results showed that treatments significantly (P < 0.05) reduced pain behaviors compared to untreated controls. Treatments also significantly (P < 0.05) decreased lipid peroxidation, lowered pro-inflammatory cytokine levels, increased antioxidant activity, and restored the balance between neuronal and apoptotic processes. The combination therapies produced greater biochemical normalization than KP monotherapy, suggesting enhanced therapeutic responses through multimodal intervention. The triple treatment produced the most notable effects, significantly normalizing multiple inflammatory and redox parameters. CONCLUSION: KP alleviated neuropathic pain, and the enhancement with exercise and VNS highlights the potential of multimodal strategies targeting cortical pain-control networks. This therapeutic approach demonstrates potential as a multimodal preclinical strategy for neuropathic pain management and warrants further investigation.