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CNS & Neurological Disorders - Drug Targets - Volume 24, Issue 11, 2025

Volume 24, Issue 11

Volume 24, Issue 11, 2025

    • The NLRP3-P2X7 Axis and Cytokine Crosstalk in Alzheimer's Disease: Mechanisms, Implications, and Therapeutic Opportunities

      https://doi.org/10.2174/0118715273377780250505115039

      Alzheimer's disease (AD) is the primary cause of dementia in elderly individuals, characterized by progressive memory loss, cognitive decline, and impaired daily functioning. Pathologically, AD is associated with the accumulation of amyloid-β (Aβ) plaques, tau tangles, mitochondrial dysfunction, and chronic neuroinflammation. The activation of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome by Aβ clusters triggers microglial activation, leading to a cascade of inflammatory responses. Similarly, tau tangles stimulate neuronal and glial cells, further amplifying NLRP3 activation and perpetuating a cycle of chronic inflammation. Mitochondrial dysfunction exacerbates this process by increasing oxidative stress and inflammasome activation. Additionally, purinergic receptor P2X7 (P2X7R) activation in microglia plays a crucial role in initiating neuroinflammation, making it a potential therapeutic target. Despite extensive research, current AD therapies remain symptomatic rather than disease-modifying. Targeting the NLRP3 inflammasome offers a promising strategy for mitigating AD progression. Various small-molecule inhibitors, monoclonal antibodies, and repurposed drugs have been explored to inhibit NLRP3 activation and its downstream signaling pathways. Preclinical studies suggest that NLRP3 inhibitors effectively reduce Aβ- and tau-induced neuroinflammation while improving mitochondrial function and overall neuronal survival. This review summarizes NLRP3 inflammasome priming, activation, and the therapeutic potential of its inhibitors in AD, highlighting challenges such as tau pathology, biomarker limitations, and treatment optimization. While NLRP3 remains a promising target, most inhibitors are in the early stages with uncertain long-term efficacy and BBB penetration. Future research should explore genetic variability, sex differences, and alternative approaches to enhance neuroprotective strategies.

    • Exploring LRRK2-dependent Mechanisms in Parkinson’s Disease Therapy

      https://doi.org/10.2174/0118715273377507250320035243

      Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease worldwide and presents as a progressive motor disorder. Gene mutations play a pivotal role in the degeneration of dopaminergic neurons in the substantia nigra region. Mutations in the Leucine rich repeat kinase 2 (LRRK2) gene have been identified as one of the most common genetic causes of PD. LRRK2 is a multi-functional protein involved in several critical cellular processes, including mitochondrial function, autophagy, vesicular trafficking, and immune system regulation. Dysregulation of these processes due to aberrant LRRK2 activity contributes to neuronal degeneration, particularly in dopaminergic neurons, which are most affected in PD. The current review discusses the structure of LRRK2, its function, and pathogenic mutations in the context of PD. However, significant challenges remain, particularly in terms of ensuring drug specificity, minimizing off-target effects, and understanding the long-term safety and efficacy of these treatments. As we advance our understanding of LRRK2 biology, it remains a highly promising target for therapeutic strategies aimed at modifying the course of Parkinson’s disease.

    • Unraveling the Triad: A Bioinformatics Analysis of the Interplay between Prenatal Depression, Inflammation, and the Gut Microbiota

      https://doi.org/10.2174/0118715273371682250421053159
      Introduction

      Prenatal depression is a prevalent mental disorder that affects women during pregnancy. Alterations in the maternal microbiota have been linked to changes in the composition of the intestinal microbiota of foetus, which can have long-term consequences for the child's health. The gut-brain axis, which involves bidirectional communication between the gut and the brain, is believed to play a role in the development of depression.

      Methods

      This study aimed to gather evidence for both the influence of microbiota and immunity on depression during pregnancy, using integrated bioinformatics analysis. A set of 219 differentially expressed genes (DEGs) associated with prenatal depression was established to correlate with gut inflammation. DEG data were collected from different bibliographic sources with fold change >1 and adjusted -value <0.05. Moreover, 205 DEGs were annotated using String software.

      Results

      The protein-protein interaction networks of DEGs obtained were determined by 16 main genes: , and The enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was conducted using SRplot and clusterProfiler. They were significantly involved in prenatal depression and associated with inflammation and gut microbiota.

      Discussion

      The identified genes highlight key molecular interactions between the immune system, microbiota, and brain function during pregnancy. These findings support the involvement of inflammatory and microbial pathways in the development of prenatal depression.

      Conclusion

      This study identified core genes that contribute to the understanding of the molecular mechanisms involved in the development of prenatal depression, which may serve as targets for early diagnosis, prevention, and treatment.

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