Abstract
Autophagy is a physiological process that helps maintain a balance between the manufacture of cellular components and breakdown of damaged organelles and other toxic cellular constituents. Changes in autophagic markers are readily detectable in the spinal cord and brain following neurotrauma, including traumatic spinal cord and brain injury (SCI/TBI). However, the role of autophagy in neurotrauma remains less clear. Whether autophagy is good or bad is under debate, with strong support for both a beneficial and detrimental role for autophagy in experimental models of neurotrauma. Emerging data suggest that autophagic flux, a measure of autophagic degradation activity, is impaired in injured central nervous systems (CNS), and interventions that stimulate autophagic flux may provide neuroprotection in SCI/TBI models. Recent data demonstrating that neurotrauma can cause lysosomal membrane damage resulting in pathological autophagosome accumulation in the spinal cord and brain further supports the idea that the impairment of the autophagy–lysosome pathway may be a part of secondary injury processes of SCI/TBI. Here, we review experimental work on the complex and varied responses of autophagy in terms of both the beneficial and detrimental effects in SCI and TBI models. We also discuss the existing and developing therapeutic options aimed at reducing the disruption of autophagy to protect the CNS after injuries.
Highlights
The role of autophagy after the central nervous system (CNS) insults is under perusal, as investigation has begun to determine how autophagy and related pathways contribute to secondary injury and functional recovery following neurotrauma [1,2,3,4,5], including spinal cord injury (SCI) and traumatic brain injury (TBI)
CPLA2-mediated lysosomal damage in turn damage in turn causes the inhibition of autophagy flux and autophagosome accumulation, whichwith are causes the inhibition of autophagy flux and autophagosome accumulation, which are associated associated with neuronal cell death
TBI and SCI mice models, we recently demonstrated that the early administration of cytosolic phospholipase A2 (cPLA2) inhibitor arachidonyl trifluoromethyl ketone (AACOCF3) reduced lysosomal damage, improved autophagy flux, limited neuronal cell death, and improved functional outcomes [110,111]
Summary
The role of autophagy after the central nervous system (CNS) insults is under perusal, as investigation has begun to determine how autophagy and related pathways contribute to secondary injury and functional recovery following neurotrauma [1,2,3,4,5], including spinal cord injury (SCI) and traumatic brain injury (TBI). Several types of targeted autophagy have been described, including mitophagy, which is a selective form of macroautophagy that targets and degrades damaged mitochondria. Macroautophagy involves the formation of a cytoplasmic membrane that engulfs cargo and eventually elongates to form double-membrane vesicles termed autophagosomes. This review explores the current research on the function and mechanisms of autophagy in two models of CNS injury: SCI and TBI. Cell-type specific responses of autophagy are discussed according to different locations, severity, and time windows of traumatic injury. We discuss recent findings suggesting that impairment of the autophagy–lysosomal pathway may be part of the secondary injury processes of SCI/TBI. We review recent studies and novel mechanistic discoveries on cytosolic phospholipase A2 (cPLA2) participation in lysosomal damage, and provide therapeutic options, with an emphasis on the pharmacological modulation of autophagy and lysosomal biogenesis for neuroprotection and the prevention of neuroinflammation after CNS trauma
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