Title : Caspase inhibition: A trailblazer armament to treat neurodegenerative disorders
Abstract:
Introduction: Apoptosis is a form of programmed cell death, that underlies the wide range of symptoms investigated in neurological disorders from stroke to neurodegenerative diseases such as Alzheimer’s. Caspases are shown to be capable of producing inflammasomes along with aiding axon pruning and synapse elimination resulting in the maturation of the nervous system. Their contribution to synapses and the processing of aggregates provides a key to better understanding neurodegenerative diseases and developing alternative approaches for prevention and treating neurodegenerative disorders as a whole. These neurodegenerative diseases have a distinct presentation, etiopathogenesis and individual clinical manifestations. The current-day treatment options present significant morbidities and are not successful in completely halting the progression of the disease, therefore making caspases considerable novel therapeutic targets. In this review, we have summarized emerging evidence concerning the association of apoptotic caspases with neuronal development and neurodegenerative disorders. In addition, we consider recent evidence of potential treatments targeting caspase inhibition concerning neurodegenerative diseases.
Material and Methods: In this study, a systematic search was done based on the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. A literature search was carried out by key-electronic databases, controlled vocabulary and indexing of trials to evaluate all the relevant studies in both medical subject headings and advanced electronic databases. The protocol was registered in the PROSPERO register with ID CRD42022347466.
Results: From our study, we found out that there are 17 studies regarding Alzheimer’s disease, 10 studies related to Parkinson’s disease, and others related to other neurodegenerative disorders like prion disease, and Huntington's. Among mechanisms leading to neuronal degeneration, most studies have demonstrated the role of caspases in this degenerative process. A total of 11 studies mentioned the involvement of caspase-3 in Alzheimer’s disease. A total of 5 studies mentioned the involvement of caspase-3 in the neuronal degeneration process in Parkinson’s disease, the second most common neurodegenerative disorder. Various other studies discuss the direct involvement of caspase-1, 8, 9, and 12 and their inhibition to treat Parkinson’s disease and Alzheimer’s disease. Each one of the studies included has its diversity regarding demographic factors of the populations as well as the study design and settings. Thirdly, those trials that are undergoing require completion in addition to integrating randomized controlled trials and cohort studies with a greater sample size to reveal the reality regarding the role of various caspases for neuronal degradation.
Conclusion: There is accumulative evidence and an incredible amount of data supports the activation of apoptosis in general, and caspases particularly, as an initial event that may not only lead to neuronal death but also enhance the underlying pathophysiology associated with numerous neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, Huntington’s chorea and ischemic brain injury etc. It is essential to have a better knowledge of the caspase involvement in neuronal death, to come up with therapies that may change the course of the illness and provide symptomatic relief.
Audience Take Away Notes:
- The audience will gain insights into the intricate role of apoptosis, specifically being mediated by caspases, in various neurodegenerative disorders such as Alzheimer’s, Parkinson’s, Huntington’s and ischemic brain injury.
- Understanding the specific caspases involved (caspase-3, -1, -8, -9, -12) and their impact on neuronal death and pathophysiology will be a key learning point.
- Latest treatment modalities being involved in clinical trials employing inhibition of caspases to curate these neurodegenerative disorders
- Brain physiology is an evolving branch of medicine; this study helps provide a deeper understanding of the underlying mechanisms in neurodegenerative disorders and the manipulation of those mechanisms to treat them and develop care.
- Healthcare professionals, researchers, and clinicians can benefit from a more nuanced understanding of caspases' role in neurodegenerative disorders, potentially informing the development of more effective treatment strategies.
- Researchers may find avenues for further investigations and the design of clinical trials targeting specific caspases.
- Other faculty in the field of molecular biology, and related disciplines could use this knowledge for expansion of understanding of apoptotic caspases and their relevance to neurodegenerative diseases. Identification of specific caspases through these studies could lead to discoveries in the study of caspase biology and novel roles for caspases that are relevant to all cell types and not just the central nervous system.
- While the study is more geared towards medical and research professionals, the knowledge gained could potentially inspire the development of targeted therapies, contributing to practical solutions for treating neurodegenerative disorders.
- The findings may encourage the design of experiments and clinical trials exploring caspase inhibition as a therapeutic approach for not only nervous disorders but other systemic disorders too.
- The research has the potential to improve the accuracy of therapeutic designs for neurodegenerative disorders by highlighting the significance of caspases in disease progression.
- The inclusion of a systematic search methodology and a diverse range of neurodegenerative disorders enhances the reliability and applicability of the findings.
