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The repair mechanisms following sciatic nerve injury involve complex signaling interactions between neurons and microglia. Recent studies have demonstrated that neurons activate microglia by releasing chemokines, glutamate, and neurotrophic factors. In turn, microglia regulate neuronal survival and regeneration via phagocytosis, phenotypic switching, and secretion of growth factors. However, the spatiotemporal diversity of signaling pathways, metabolic regulation of the microenvironment, and barriers to clinical application remain inadequately addressed. This review provides a comprehensive analysis of morphological and functional changes in neuronal cell bodies and of the activation and regulatory mechanisms of microglia after sciatic nerve injury. It highlights the dynamic interaction network encompassing the ATP-P2X7 signaling pathway, the CX3CL1- CX3CR1 pathway, the CCL2-CCR2 chemokine axis, the BDNF-TrkB pathway, and inflammatory mediators, offering novel insights into precision therapeutic strategies targeting neuron-glial interactions. Show less

This research evaluated the efficacy of Withaferin A-conjugated mesoporous silica nanoparticles (WA-MSNs) in accelerating the restoration of neural tissue and improving the recovery of sensory and motor functions following a sciatic nerve injury (SNI) in male Wistar rats. WA-MSNs were evaluated for encapsulation efficiency, drug release, particle size, surface charge, and molecular interactions. A rat SNI model was created, and subjects were treated with WA-MSNs, free WA, unloaded MSNs, or received no treatment. The sham group was also included for comparison. Regeneration was measured through the sciatic functional index (SFI), Hargreaves test, and electrophysiology (CMAP and NCV). Complementary assessments included sciatic nerve histomorphometry, assessment of gastrocnemius muscle mass, and Enzyme-Linked Immunosorbent Assay (ELISA) for inflammatory cytokines and neurotrophic factors. WA-MSNs achieved a 74.6% encapsulation efficiency and provided sustained drug release over 72 h. DLS analysis showed a monodisperse colloidal system, with an average hydrodynamic diameter of approximately 198 nm and a zeta potential of -22.4 mV. WA-MSN-treated rats exhibited significantly faster motor and sensory recovery compared to controls (p < 0.001), with electrophysiological parameters approaching those of sham-treated rats. Histological analysis revealed improved axonal morphology, myelination, and recovery of gastrocnemius muscle mass. ELISA results showed modulation of cytokine profiles, characterized by a marked reduction in (IL-1β, IL-6, TNF-α), and substantial elevation in the levels of (IL-10, TGF-β), and elevated neurotrophic factors (NGF, BDNF, NT-3). WA-MSNs significantly promote functional and histological nerve regeneration after SNI by modulating inflammation and enhancing neurotrophic support. These findings support WA-MSNs as a promising therapeutic approach for clinical peripheral nerve repair. Show less

Physical exercise is widely recognized for reducing neuropathic pain. However, the interaction between the immune and opioidergic systems in supraspinal structures is still not fully understood. To evaluate the impact of opioid receptor blockade on the effects of low-intensity exercise on the sensory, cognitive, and emotional aspects of neuropathic pain after sciatic nerve injury. Male Swiss mice (2 months old) were submitted to sciatic nerve crush and divided into sedentary or exercised groups. The exercised groups performed treadmill running for two weeks, with or without naloxone pre-treatment to block opioid receptors. Sensory responses were assessed using the von Frey test, while cognitive and emotional-like behaviors were evaluated through the Mechanical Conflict-Avoidance System (MCAS) and open field test, respectively. Cytokine levels (IL-4, IL-10) and brain-derived neurotrophic factor (BDNF) were quantified in the brainstem and prefrontal cortex by ELISA. Exercise reduced mechanical hypersensitivity and improved performance in cognitive and exploratory tasks. These effects were prevented by naloxone administration. Exercise also increased IL-4, IL-10, and BDNF levels in supraspinal regions, while naloxone reversed these changes, indicating the involvement of μ-opioid receptors in exercise-induced immunomodulation. Low-intensity exercise promotes analgesia and neuroimmune regulation in neuropathic pain through supraspinal μ-opioid receptor activation. The blockade of these receptors abolishes the beneficial effects of exercise, reinforcing the interaction between opioidergic and immune systems in pain modulation. Show less