cyclin-d1 and Brain-Injuries--Traumatic

Primary and secondary traumatic brain injury (TBI) can cause tissue damage by inducing cell death pathways including apoptosis, necroptosis, and autophagy. However, similar pathways can also lead to senescence. Senescent cells secrete senescence-associated secretory phenotype proteins following persistent DNA damage response signaling, leading to cell disorders. TBI initially activates the cell cycle followed by the subsequent triggering of senescence. This study aims to clarify how the mRNA and protein expression of different markers of cell cycle and senescence are modulated and switched over time after TBI. We performed senescence-associated-β-galactosidase (SA-β-gal) staining, immunohistochemical analysis, and real-time PCR to examine the time-dependent changes in expression levels of proteins and mRNA, related to cell cycle and cellular senescence markers, in the cerebrum during the initial 14 days after TBI using a mouse model of controlled cortical impact (CCI). Within the area adjacent to the cerebral contusion after TBI, the protein and/or mRNA expression levels of cell cycle markers were increased significantly until 4 days after injury and senescence markers were significantly increased at 4, 7, and 14 days after injury. Our findings suggested that TBI initially activated the cell cycle in neurons, astrocytes, and microglia within the area adjacent to the hemicerebrum contusion in TBI, whereas after 4 days, such cells could undergo senescence in a cell-type-dependent manner.

Topics: Animals; Apoptosis; Autophagy; beta-Galactosidase; Brain Injuries, Traumatic; Cellular Senescence; Cerebrum; Cyclin D1; Disease Models, Animal; Gene Expression Profiling; Male; Mice; Mice, Inbred C57BL; Neurons; Proliferating Cell Nuclear Antigen; Signal Transduction

Cell cycle activation has been associated with varying types of neurological disorders including brain injury. Cyclin D1 is a critical modulator of cell cycle activation and upregulation of Cyclin D1 in neurons contributes to the pathology associated with traumatic brain injury (TBI). Mitochondrial mass is a critical factor to maintain the mitochondrial function, and it can be regulated by different signaling cascades and transcription factors including NRF1. However, the underlying mechanism of how TBI leads to impairment of mitochondrial mass following TBI remains obscure. Our results indicate that augmentation of CyclinD1 attenuates mitochondrial mass formation following TBI. To elucidate the molecular mechanism, we found that Cyclin D1 interacts with a transcription factor NRF1 in the nucleus and prevents NRF1's interaction with p300 in the pericontusional cortex following TBI. As a result, the acetylation level of NRF1 was decreased, and its transcriptional activity was attenuated. This event leads to a loss of mitochondrial mass in the pericontusional cortex following TBI. Intranasal delivery of Cyclin D1 RNAi immediately after TBI rescues transcriptional activation of NRF1 and recovers mitochondrial mass after TBI.

Topics: Animals; Brain Injuries, Traumatic; Cyclin D1; DNA, Mitochondrial; Male; Mice; Mice, Inbred C57BL; Mitochondria; RNA Interference

Traumatic brain injury (TBI) remains a life-threatening disease. Accumulating evidences have showed that neuroinflammatory response is a critical biological event in the progression of TBI induced astrocyte damage. However, the exact mechanisms are not well understood. In this study, we demonstrated that long non-coding RNA (lncRNA) Gm4419 promoted trauma-induced astrocyte apoptosis by up-regulating the expression of inflammatory cytokine tumor necrosis factor α (TNF-α). We observed that Gm4419 was aberrantly induced after injury on astroglial cells in vitro. Overexpression of Gm4419 in injury-treated astrocytes increased protein expressions of TNF-α, Bax, cleaved caspase-3 and cleaved caspase-9, decreased levels of Bcl-2 and CyclinD1, and significantly led to cellular apoptosis. Mechanically, Gm4419 transcript could function as a sponge for miR-466l and miR-466l could target TNF-α 3' UTR for degradation and translation inhibition. Therefore, Gm4419 could up-regulate TNF-α expression by competitively binding miR-466l and then contribute to inflammatory damage as well as astrocyte apoptosis during TBI. Generally speaking, our findings provide better understandings of the mechanism underlying Gm4419 in trauma-induced neuroinflammation and neurological deficits. Thus, the present study would expand the insight into the novel approaches for TBI therapy.

Topics: Animals; Animals, Newborn; Apoptosis; Astrocytes; Base Sequence; bcl-2-Associated X Protein; Binding Sites; Brain Injuries, Traumatic; Caspase 3; Caspase 9; Cerebral Cortex; Cyclin D1; Gene Expression Regulation; Mice; Mice, Inbred C57BL; MicroRNAs; Models, Biological; Neuroglia; Primary Cell Culture; Proto-Oncogene Proteins c-bcl-2; RNA, Long Noncoding; Signal Transduction; Stress, Mechanical; Tumor Necrosis Factor-alpha

Traumatic brain injury (TBI) is induced by complex primary and secondary mechanisms that give rise to cell death, inflammation, and neurological dysfunction. Understanding the mechanisms that drive neurological damage as well as those that promote repair can guide the development of therapeutic drugs for TBI. Kruppel-like factor 4 (KLF4) has been reported to negatively regulate axon regeneration of injured retinal ganglion cells (RGCs) through inhibition of JAK-STAT3 signaling. However, the role of KLF4 in TBI remains unreported. Reactive oxygen species (ROS)-induced neuronal death is a pathophysiological hallmark of TBI.. In this study, we used H. The results show that H. These findings provide evidence that KLF4 plays an important role in the pathophysiology of TBI. Blocking KLF4 may be a potential therapeutic strategy for the treatment of TBI, either alone or in combination with agents that target complementary mechanisms.

Topics: Animals; Apoptosis; Brain Injuries, Traumatic; Cerebral Cortex; Cyclin D1; Disease Models, Animal; Enzyme Inhibitors; Gene Expression Regulation; Hydrogen Peroxide; Janus Kinases; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Nerve Regeneration; Optic Nerve Injuries; Rats; Rats, Sprague-Dawley; Retinal Ganglion Cells; Signal Transduction; STAT3 Transcription Factor; Tumor Suppressor Protein p53; Tyrphostins

Many victims of blast-induced traumatic brain injury are occupants of military vehicles targeted by land mines. Recently improved vehicle designs protect these individuals against blast overpressure, leaving acceleration as the main force potentially responsible for brain injury. We recently developed a unique rat model of under-vehicle blast-induced hyperacceleration where exposure to acceleration as low as 50G force results in histopathological evidence of diffuse axonal injury and astrocyte activation, with no evidence of neuronal cell death. This study investigated the effects of much higher blast-induced accelerations (1200 to 2800G) on neuronal cell death, neuro-inflammation, behavioral deficits and mortality. Adult male rats were subjected to this range of accelerations, in the absence of exposure to blast overpressure, and evaluated over 28days for working memory (Y maze) and anxiety (elevated plus maze). In addition, brains obtained from rats at one and seven days post-injury were used for neuropathology and neurochemical assays. Sixty seven percent of rats died soon after being subjected to blasts resulting in 2800G acceleration. All rats exposed to 2400G acceleration survived and exhibited transient deficits in working memory and long-term anxiety like behaviors, while those exposed to 1200 acceleration G force only demonstrated increased anxiety. Behavioral deficits were associated with acute microglia/macrophage activation, increased hippocampal neuronal death, and reduced levels of tight junction- and synapse- associated proteins. Taken together, these results suggest that exposure of rats to high underbody blast-induced G forces results in neurologic injury accompanied by neuronal apoptosis, neuroinflammation and evidence for neurosynaptic alterations.

Topics: Acceleration; Animals; Antigens, Differentiation; Blast Injuries; Brain; Brain Injuries, Traumatic; Caspase 3; Cyclin D1; Disease Models, Animal; Disks Large Homolog 4 Protein; Gene Expression Regulation; HSP70 Heat-Shock Proteins; Intracellular Signaling Peptides and Proteins; Male; Maze Learning; Membrane Proteins; Nitric Oxide Synthase Type II; Rats; Rats, Sprague-Dawley; Time Factors; von Willebrand Factor; Zonula Occludens-1 Protein