Targeting Neuroinflammation and Neurodegeneration in Parkinson's Disease: Emerging Natural and Synthetic Therapeutic Strategies.

KLF4 in Parkinson’s Disease: Decoding the Molecular Puzzle of Neuroinflammation, Oxidative Stress, and Emerging Therapies

Emerging Advances in Neuropharmacology: Novel Therapeutic Targets for Neurodegenerative Disorders

Neurodegenerative diseases are a heterogeneous group of chronic and progressive disorders, which are characterized by selective neuronal destruction, synaptic malfunction and progressive cognitive and locomotor dysfunction. The major ones are Alzheimer disease, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis which are a formidable and growing global health and socio-economic burden mainly due to demographic aging. Even despite the advances in the symptomatic treatment, predominantly through the cholinergic, dopaminergic, glutamatergic, and GABAergic system, the current treatment regimens are not able to stop the underlying neurodegenerative events or reverse them. There is mounting evidence that convergent pathogenic mechanisms, such as protein misfolding and aggregation, oxidative stress, mitochondrial dysfunction, impaired autophagy-lysosomal pathways, synaptic dysfunction, and chronic neuroinflammation, are convergent mechanisms. These convergent molecular and cellular cascades provide a strong rationale behind the identification of new neuropharmacological targets, which include: kinases, phosphatases, epigenetic regulators, neurotrophic signalling pathways and neuroimmune mediators. Advances in the biomarker discovery, genomics and systems biology have further enabled the use of precision based therapeutic stratification and early-intervention approaches. Genetic, nanotechnology, and RNA-based therapeutics as well as biologics are reconfiguring translational models in neurodegeneration. A mechanism-based, multi-target, precision neuropharmacological approach, as a group, has significant potential in achieving long-term neuroprotection, improved clinical and disease modification in neurodegenerative diseases.

Neuroinflammation in neurodegenerative diseases: pathogenic pathways and emerging pharmacotherapeutic targets in Alzheimer’s and Parkinson’s disease

Therapeutic landscape of Parkinson's disease: Recent advances in saponin-mediated interventions.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic neurons in the substantia nigra, leading to debilitating motor and non-motor symptoms. Current therapeutic strategies, including levodopa, dopamine agonists, monoamine oxidase-B inhibitors, and surgical interventions primarily offer symptomatic relief without halting disease progression. Long-term use of these treatments is often associated with complications such as motor fluctuations, dyskinesia, and systemic side effects, underscoring the urgent need for safer and disease-modifying approaches. In recent years, increasing attention has been directed toward natural products as potential therapeutic agents for PD due to their multi-targeted mechanisms and favourable safety profiles. Among these, plant-derived saponins have emerged as promising candidates owing to their diverse pharmacological properties. Saponins exhibit potent antioxidant, anti-inflammatory, anti-apoptotic, and anti-aggregation activities, enabling them to modulate key pathological pathways involved in PD, including oxidative stress, mitochondrial dysfunction, neuroinflammation, and α-synuclein aggregation. Experimental studies have demonstrated the neuroprotective effects of various saponins such as astragaloside IV, ginsenosides, bacosides, dioscin, and notoginsenosides in animal models of PD. These compounds have been shown to preserve dopaminergic neuronal integrity, enhance mitochondrial function, regulate apoptotic signalling, and promote autophagy. Despite these promising findings, challenges such as poor bioavailability in natural sources and limited access to brain remain significant barriers to clinical translation. This review provides a comprehensive overview of current PD therapies and their limitations, while highlighting the therapeutic potential of plant-derived saponins as multi-target agents. It also discusses recent advances in drug delivery strategies that may enhance their clinical applicability. Overall, saponins represent a promising avenue for the development of novel neuroprotective and disease-modifying therapies for PD.

Mitochondria-Targeted Nanotherapies in Aging Neurodegenerative Disorders: Emerging Prospects and Clinical Potential.

Aging is a significant risk factor of neurodegenerative disorders (NDs) such as Huntington's, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Although several clinical, neuroimaging, and biomarker-based diagnostic approaches are available for NDs, their limited sensitivity for early-stage detection, disease specificity, and prediction of disease progression continue to present significant clinical challenges, often resulting in delayed diagnosis and therapeutic intervention. According to previously published works, the preliminary pathological feature of such disorders is mitochondrial dysfunction. This may lead to elevated oxidative stress, impaired mitophagy, unbalanced mitochondrial function, and bioenergetic failure. This review examines how mitochondria-targeted nanotherapeutic approaches can overcome these pathological barriers and improve therapeutic outcomes in aging-associated neurodegeneration. Targeted delivery of drug-loaded nanocarriers, such as gene-delivery, lipid-based, metallic, and polymeric nanoparticles, has emerged as a potential platform to deliver medication directly to defective mitochondria. It may increase mitochondrial biogenesis, maintain redox balance, and protect against neuronal degeneration. This work incorporates disease-specific mitochondrial pathology with current progress in targeted nanotherapeutics, age-associated delivery barriers, clinical revolution, and emerging artificial intelligence (AI)-enabled precision therapeutic approaches. Mitochondria-targeted nanotherapeutics depict a potential disease-modifying strategy for aging-related NDs. However, further advancements in targeting efficacy, scalable production, long-term safety, and clinical validation can facilitate a successful clinical revolution.

Small molecular therapeutic targets for neurodegenerative diseases.