Functions and mechanisms of cytosolic phospholipase A2 in central nervous system trauma

Neural Regen Res, 2023 · DOI: 10.4103/1673-5374.346460 · Published: February 1, 2023

Simple Explanation

Central nervous system (CNS) trauma, including traumatic brain injury (TBI) and spinal cord injury (SCI), is a leading cause of long-term disability and death worldwide. Cytosolic phospholipase A2 (cPLA2), a key target of inflammatory response, is involved in neuroinflammation in SCI and TBI. Early studies have proven that it exists in both spinal cord and brain neurons In general, as a rate-limiting step of the inflammatory response, activated cPLA2 will induce the production of more inflammatory factors, creating a cascade effect that promotes the progression of inflammation.

Study Duration

Not specified

Participants

Not specified

Evidence Level

Review

Key Findings

1
cPLA2 is vital for the production of diverse inflammatory mediators: a variety of inflammatory mediators are directly or indirectly involved in the pathogenesis of CNS trauma
2
The barrier capability of lysosomal membranes is damaged under multiple pathological conditions including SCI and TBI, resulting in the release of lysosome contents into the cytosol
3
Autophagy is inhibited after SCI or TBI, thereby contributing to secondary neuronal cell death

Research Summary

Accumulating evidence has proven that acute SCI and TBI can cause a secondary injury by several bioprocesses. cPLA2, the heavyweight component of cellular signal transduction in inflammatory responses, acts as a “trigger” in regulating the production of several major inflammatory mediators. In this review, we provide an overview of the cPLA2 family, together with its upstream signaling pathways. We discussed a series of current studies on cPLA2 in SCI and TBI and analyzed the potential pathogenesis of cPLA2. Among them, we focused on exploring the mechanism of cPLA2 and its metabolites that participate in neuroinflammation, causing an increase in lysosomal membrane permeability and inducing damage to neuronal autophagic flux.

Practical Implications

Therapeutic Potential of cPLA2 Inhibitors

Developing and testing novel, potent, and highly specific inhibitors of cPLA2, such as AX059 and AVX001, could lead to new treatments for CNS trauma.

Combination Therapies

Combining MAPK inhibitors and calcium ion antagonists may thoroughly block cPLA2 activation and produce better curative effects.

Cell-Type Specific Studies

Investigating the roles of cPLA2 in different cell types within the brain and spinal cord could reveal more targeted therapeutic strategies.

Study Limitations

1
The current review mainly focused on cPLA2α in CNS trauma, and further understanding of other cPLA2 subtypes such as cPLA2β and cPLA2γ are also essential.
2
We discussed the effect of cPLA2 on lysosome membrane in nerve cells following TBI and SCI, but its potential roles on other membranous organelles such as the mitochondria and endoplasmic reticulum, should also be elaborated in further studies.
3
To determine the effect of cPLA2 in CNS trauma, pharmacological inhibitors of cPLA2 were commonly used in previous studies. However, these inhibitors are not specific.

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