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Promising Molecular Targets in Pharmacological Therapy for Neuronal Damage in Brain Injury
Cristóbal de Los Ríos1,2, Lucía Viejo1, Victoria Jiménez Carretero1
1Department of Pharmacology and Therapeutic and Teófilo Hernando Institute, Faculty of Medicine, University Autónoma de Madrid, C/. Arzobispo Morcillo 4, 28029 Madrid, Spain.
Abstract:
The complex etiopathogenesis of brain injury associated with neurodegeneration has sparked a lot of studies in the last century. These clinical situations are incurable, and the currently available therapies merely act on symptoms or slow down the course of the diseases. Effective methods are being sought with an intent to modify the disease, directly acting on the properly studied targets, as well as to contribute to the development of effective therapeutic strategies, opening the possibility of refocusing on drug development for disease management. In this sense, this review discusses the available evidence for mitochondrial dysfunction induced by Ca2+ miscommunication in neurons, as well as how targeting phosphorylation events may be used to modulate protein phosphatase 2A (PP2A) activity in the treatment of neuronal damage. Ca2+ tends to be the catalyst for mitochondrial dysfunction, contributing to the synaptic deficiency seen in brain injury. Additionally, emerging data have shown that PP2A-activating drugs (PADs) suppress inflammatory responses by inhibiting different signaling pathways, indicating that PADs may be beneficial for the management of neuronal damage. In addition, a few bioactive compounds have also triggered the activation of PP2A-targeted drugs for this treatment, and clinical studies will help in the authentication of these compounds. If the safety profiles of PADs are proven to be satisfactory, there is a case to be made for starting clinical studies in the setting of neurological diseases as quickly as possible.
Insights
Mitochondrial dysfunction from calcium (Ca2+) dysregulation contributes to neurodegeneration. Targeting protein phosphatase 2A (PP2A) with activating drugs shows promise for treating neuronal damage and managing neurological diseases.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Neurodegenerative diseases present complex etiopathogenesis with limited therapeutic options.
- Current treatments for brain injury and neurodegeneration primarily manage symptoms.
- There is a critical need for disease-modifying therapies targeting specific molecular pathways.
Purpose of the Study:
- To review evidence linking calcium (Ca2+) miscommunication to mitochondrial dysfunction in neuronal damage.
- To explore the potential of modulating protein phosphatase 2A (PP2A) activity for treating neurodegeneration.
- To discuss the therapeutic implications of PP2A-activating drugs (PADs) and bioactive compounds.
Main Methods:
- Literature review of studies on mitochondrial dysfunction and Ca2+ signaling in brain injury.
- Analysis of research on protein phosphatase 2A (PP2A) and its role in neuronal pathways.
- Examination of data on PP2A-activating drugs (PADs) and their effects on inflammatory and signaling pathways.
Main Results:
- Calcium (Ca2+) dysregulation is a key factor initiating mitochondrial dysfunction and synaptic deficits in brain injury.
- PP2A-activating drugs (PADs) demonstrate potential by suppressing inflammatory responses via signaling pathway inhibition.
- Bioactive compounds targeting PP2A are emerging as potential therapeutic agents, requiring further clinical validation.
Conclusions:
- Targeting Ca2+-induced mitochondrial dysfunction and PP2A activity offers promising therapeutic avenues for neuronal damage.
- PP2A-activating drugs (PADs) may be beneficial in managing neurological diseases by modulating inflammatory and signaling pathways.
- Further clinical studies are warranted to validate the efficacy and safety of PADs and PP2A-targeting compounds for neurological disorders.
