This review systematically elucidates the core mechanisms of the JAK/STAT pathway in NDDs, including the regulation of microglial and astrocytic reactivity, the impact on blood–brain barrier integrity, and involvement in energy metabolism abnormalities.
Abstract
Neurodegenerative diseases (NDDs) are a major public health concern characterized by the progressive loss of neurons, ultimately leading to neuronal death and causing a sustained decline in brain function or physical motor abilities. Major examples include Alzheimer’s disease (AD) and Parkinson’s disease (PD). Currently, NDDs lack effective curative methods, and their pathological process primarily involves misfolded protein aggregation, oxidative stress, and neuroinflammation. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, as a central hub for cytokine signaling, has recently been found to play a key role in neuroinflammation and immune regulation in NDDs. This review systematically elucidates the core mechanisms of the JAK/STAT pathway in NDDs, including the regulation of microglial and astrocytic reactivity, the impact on blood–brain barrier integrity, and involvement in energy metabolism abnormalities. On this basis, we have reviewed and evaluated various therapeutic strategies targeting this pathway, focusing on small-molecule JAK inhibitors such as baricitinib and tofacitinib, and have analyzed their mechanisms of action, preclinical efficacy, and potential side effects. In addition, this article provides a forward-looking perspective on the future research directions of the JAK/STAT pathway from the perspective of anti-neuroinflammation to promote neuroregeneration therapy, aiming to offer theoretical references and new ideas for the clinical translational research of this pathway.
Overall, this review makes a case for integrative, pathway-based therapeutic models, and multiple approaches may facilitate for drug development, biomarker identification and patient management in Alzheimer's disease.
This review examines RCD as an integrated pathogenic network in major NDs as well as evaluating emerging therapeutic strategies that target cell death crosstalk, restore autophagy lysosomal competence, or improve delivery to the central nervous system.
New knowledge about the protective and detrimental aspects of neuroinflammation in AD and PD is summarized, providing an analysis on these developing prospects for targeted interventions toward slowing or stopping neurodegeneration.
R. Kumar, Kamaljeet, Sourabh Kosey· InflammoPharmacology· 0 citations
The protective and deleterious roles of NETs are investigated and how this knowledge may reveal new therapeutic strategies to modulate neurodegenerative diseases and preserve neural integrity are investigated, offering valuable insights for potential applications in clinical practice.
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.
The molecular mechanisms underlying NLRP3 inflammasome activation in Alzheimer’s disease, its interaction with pro-inflammatory cytokine networks, and the emerging role of inflammasome-related biomarkers in disease characterization are examined.
Hira Shabbir· Scholars International Journ...· 0 citations