Axons in the peripheral nervous system have the ability to repair themselves after damage, whereas axons in the central nervous system are unable to do so. A common and important characteristic of damage to the spinal cord, brain, and peripheral nerves is the disruption of axonal regrowth. Interestingly, intrinsic growth factors play a significant role in the axonal regeneration of injured nerves. Various factors such as proteomic profile, microtubule stability, ribosomal location, and signalling pathways mark a line between the central and peripheral axons’ capacity for self-renewal. Unfortunately, glial scar development, myelin-associated inhibitor molecules, lack of neurotrophic factors, and inflammatory reactions are among the factors that restrict axonal regeneration. Molecular pathways such as cAMP, MAPK, JAK/STAT, ATF3/CREB, BMP/SMAD, AKT/mTORC1/p70S6K, PI3K/AKT, GSK-3β/CLASP, BDNF/Trk, Ras/ERK, integrin/FAK, RhoA/ROCK/LIMK, and POSTN/integrin are activated after nerve injury and are considered significant players in axonal regeneration. In addition to the aforementioned pathways, growth factors, microRNAs, and astrocytes are also commendable participants in regeneration. In this review, we discuss the detailed mechanism of each pathway along with key players that can be potentially valuable targets to help achieve quick axonal healing. We also identify the prospective targets that could help close knowledge gaps in the molecular pathways underlying regeneration and shed light on the creation of more powerful strategies to encourage axonal regeneration after nervous system injury.

The human brain's billions of neurons rely on glial cells for repair, maintenance, and protection. Disruption in glia–neuron communication drives chronic neurodegenerative disorders (NDs) such as Alzheimer's and Parkinson's, marked by protein aggregates, neuronal loss, and functional decline. Conventional therapies are costly, have side effects, and often lack efficacy, highlighting the need for novel approaches. Natural bioactive compounds—such as alkaloids (caffeine, berberine), terpenoids (limonene, ginkgolides), and polyphenols (quercetin, resveratrol, curcumin)—exert antioxidant, anti-inflammatory, and neuroprotective effects, thereby modulating neuroglial function. Medicinal plants (Withania somnifera, Curcuma longa, Bacopa monnieri) and agents like cannabinoids, β-asarone, and pergolide show promise in improving cognition, mood, and neurological outcomes. Targeting neuroglia with these compounds offers a complementary, effective, and safer approach to managing CNS disorders.

Neurodegenerative and neurological disorders act as a serious global public health problem. These conditions result in oxidative stress, neuronal loss, neuroinflammation, synaptic dysfunction, and mitochondrial impairment. Polyphenolic compounds such as flavonoids, phenolic acids, stilbenes, and lignans have gained attention due to their antioxidant, antinflammatory, cardioprotective, and neuroprotective properties. The underlying mechanism of neuroprotection of these compounds involves inhibiting the activation of cyclin-dependent kinase-5 and GSK3β, activating the PI3K/AKT pathway, increasing antioxidant enzymes, reducing the generation of oxidative species, inhibiting the NF-κB, and activating the NLRP3 pathway. Additionally, they regulate neurotransmitters (dopamine, glutamate), increase neurotrophic factors to support neuronal growth and plasticity, prevent misfolded proteins, and neurotoxicity for neuronal survival. This chapter will discuss the neuroprotective potential of these polyphenols and the current understanding of their neuroprotective mechanism.

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.