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.

Background and objectives: Hereditary spastic paraplegia (HSP) is characterized by unsteady gait, motor incoordination, speech impairment, abnormal eye movement, progressive spasticity and lower limb weakness. Spastic paraplegia 75 (SPG75) results from a mutation in the gene that encodes myelin associated glycoprotein (MAG). Only a limited number of MAG variants associated with SPG75 in families of European, Middle Eastern, North African, Turkish and Palestinian ancestry have been documented so far. This study aims to provide further insight into the clinical and molecular manifestations of HSP. Methods: Using whole-exome sequencing, we investigated a consanguineous Pakistani family where three individuals presented with clinical signs of HSP. Sanger sequencing was used to carry out segregation analysis on available family members, and a minigene splicing assay was utilized to evaluate the effect of the splicing variant. Results: We identified a novel homozygous pathogenic splice donor variant in MAG (c.46 + 1G > T) associated with SPG75. RNA analysis revealed exon skipping that resulted in the loss of a start codon for ENST00000361922.8 isoform. Affected individuals exhibited variable combinations of nystagmus, developmental delay, cognitive impairments, spasticity, dysarthria, delayed gait and ataxia. The proband displayed a quadrupedal stride, and his siblings experienced frequent falls and ataxic gait as one of the prominent features that have not been previously reported in SPG75. Conclusions: Thus, the present study presents an uncommon manifestation of SPG75, the first from the Pakistani population, and broadens the spectrum of MAG variants.

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.

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.