Changes in Autophagy after Traumatic Brain Injury

Abstract

Autophagy is the chief machinery for bulk degradation of superfluous or aberrant cytoplasmic components. This study used the rat moderate fluid percussion injury model to investigate whether the autophagy pathway plays a key role after traumatic brain injury (TBI). Induction of autophagy is manifested by accumulation of autophagosomes (APs), observable under transmission electron microscopy (EM). Two hallmarks of autophagy, i.e., the microtubule-associated protein light chain 3 (LC3)-II and the autophagy-related gene (ATG)12-ATG5 conjugates, were explored by biochemical and confocal microscopic analyses of brain tissues. Under EM, both APs and autolysosomes were markedly accumulated in neurons from 4 h onward after TBI. Western blot analysis showed that ATG12-ATG5 conjugate was markedly redistributed during 5 to 15 days in brain tissues after TBI. LC3-II conjugate was initially unchanged but was drastically upregulated from 24 h onward in the pre-AP-containing fraction after TBI. LC-3 immunostaining was mainly located in living neurons under confocal microscopy. These results clearly show that the autophagy pathway is persistently activated after TBI. Because the autophagy pathway is the chief machinery for bulk elimination of aberrant cell components, we propose that activation of this pathway serves as a protective mechanism for maintaining cellular homeostasis after TBI.

Moderate Hypothermia Significantly Decreases Hippocampal Cell Death Involving Autophagy Pathway after Moderate Traumatic Brain Injury

“…SNG, sham injury with normothermia group; SHG, sham injury with hypothermia group; TNG, TBI with normothermia group; THG, TBI with hypothermia group. 9 Zhang and colleagues studied changes of autophagy post-TBI in the controlled cortical injury system and demonstrated that autophagy was elevated in the early stage post-TBI and lasted for at least 32 days thereafter. 12 Viscomi and colleagues used rapamycin, which could enhance autophagy by inactivating mammalian target of rapamycin and demonstrated that autophagy serves as a protective mechanism for maintaining cellular homeostasis after TBI.…”

“…[9][10][11][12][13][14]26,27 The first study investigating the association between autophagy and TBI was conducted by Diskin and colleagues. 11 In that study, it was demonstrated that Beclin-1 level dramatically increased near the site of injury in the closed-head injury model in mice.…”

“…4 Recently, a series of studies has reported the increase of autophagy in subarachnoid hemorrhage, intracerebral hemorrhage, hypoxia-ischemia, neurodegenerative disease, and TBI. [5][6][7][8][9][10] However, the function of autophagy in TBI remains controversial. Some studies have proposed that activation of the autophagy pathway serves as a protective mechanism for maintaining cellular homeostasis post-TBI whereas other studies suggested that inhibition of the autophagy pathway may attenuate traumatic damage and functional outcome deficits.…”

“…Some studies have proposed that activation of the autophagy pathway serves as a protective mechanism for maintaining cellular homeostasis post-TBI whereas other studies suggested that inhibition of the autophagy pathway may attenuate traumatic damage and functional outcome deficits. [9][10][11][12][13][14] Several clinical and experimental studies have shown the neuroprotective effects of mild-to-moderate hypothermia, including inhibition of neurological injury, reduction of infarct size, and improvement of neurological outcome. [15][16][17][18] In our previous studies, we found that post-traumatic moderate hypothermia significantly attenuated cell death within the hippocampus after fluid percussion TBI.…”

Genetic Manipulation of Cell Death and Neuroplasticity Pathways in Traumatic Brain Injury

“…In penumbral regions where cells undergo delayed neurodegeneration, other mechanisms can dominate, including apoptosis, which is a programmed cell death cascade regulated by effector proteins and caspase protease activation [9,10], and autophagy, which is the lysosomal degradation of components within the cell [11][12][13]. These pathways are often mediated by a specific sequence of intracellular protein activation and have been heavily studied in the context of physiological cell function and also in trauma.…”