Kaempferol-3-O-Rutinoside (K3R) Promotes Functional Rehabilitation by Modulating S100β and Inflammation Following Induced Traumatic Injury to Sciatic Nerve in Mouse Model

Background: Peripheral nerve injury causes substantial functional impairment and represents a major health concern worldwide. Peripheral nerve injuries are sequelae of iatrogenic injuries, occupational trauma, and motor vehicle crashes. The available therapeutic approaches, including pharmacological treatment, surgical repair, and rehabilitation, are mostly management therapies rather than curative treatments. Consequently, functional recovery is never achieved. There is a dire need for new therapeutic approaches to facilitate functional restoration. Kaempferol-3-O-rutinoside (K3R) is a plant-derived flavonoid glycoside known for its potent anti-inflammatory and antioxidant properties. Flavonoids may promote tissue recovery following injury by modulating inflammatory responses and reducing oxidative stress. However, the effect of K3R on functional recovery following peripheral nerve injury has not yet been investigated. Therefore, this study aimed to evaluate the effects of K3R on early functional recovery following sciatic nerve crush injury in mice. Methods: Twenty-four BALB/c mice were equally allocated to three groups (n = 8): (1) Sham, (2) Ctrl (Control), and (3) K3R treatment group. K3R (2.5 mg/kg) was dissolved in DMSO and administered intraperitoneally once a day from the time of sciatic nerve injury until the conclusion of the experiment. The Ctrl and sham groups received an equal volume of DMSO according to the same dosing schedule. Sensorimotor function recovery was assessed using behavioral tests, including grip strength, pinprick, sciatic functional index (SFI), and hot plate tests. Hematological and biochemical assays were performed to assess total blood count and oxidative stress markers. Muscle fiber morphology was evaluated by morphometric analysis. Proinflammatory cytokines (TNF-α and IL-6) were measured as indicators of the systemic inflammatory response, whereas S100β protein levels were measured as a marker associated with neural injury and glial responses following sciatic nerve injury. Results: K3R treatment significantly enhanced early sensorimotor function recovery compared with the Ctrl group (p < 0.001). Significant differences in oxidative stress markers TAC (p < 0.001), TOS (p < 0.001), MDA (p = 0.003), and CAT (p = 0.007) were observed among the experimental groups. When comparing the K3R-treated group to the Ctrl group, morphometric analysis revealed an increase in the diameter of muscle fibers (p = 0.011). The levels of IL-6 (p = 0.042) and TNF-α (p = 0.005) indicated attenuation of the systemic inflammatory response, while reduced S100β levels (p = 0.002) were observed in the K3R-treated group, consistent with reduced injury-associated changes. Conclusions: Our findings suggest that K3R may facilitate early functional recovery following sciatic nerve injury, potentially by attenuating oxidative stress and systemic inflammatory responses. However, the precise mechanisms underlying this remain to be elucidated. Future studies should therefore focus on identifying the molecular pathways involved in K3R-mediated recovery, as well as axonal regeneration, Schwann cell activity, and remyelination. Long-term investigations incorporating structural, morphometric, and molecular assessments will be essential to understand its regenerative efficacy and translational potential.