Based on accumulating evidence, cholesterol metabolism dysfunction has been suggested to contribute to the pathophysiological process of traumatic brain injury (TBI) and lead to neurological deficits. As a key transporter of cholesterol that efflux from cells, the ATP‐binding cassette (ABC) transporter family exerts many beneficial effects on central nervous system (CNS) diseases. However, there is no study regarding the effects and mechanisms of ABCG1 on TBI. As expected, TBI resulted in the different time‐course changes of cholesterol metabolism‐related molecules in the injured cortex. Considering ABCG1 is expressed in neuron and glia post‐TBI, we generated nestin‐specific Abcg1 knockout ( Abcg1 ‐KO) mice using the Cre/loxP recombination system. These Abcg1 ‐KO mice showed reduced plasma high‐density lipoprotein cholesterol levels and increased plasma lower‐density lipoprotein cholesterol levels under the base condition. After TBI, these Abcg1 ‐KO mice were susceptible to cholesterol metabolism turbulence. Moreover, Abcg1 ‐KO exacerbated TBI‐induced pyroptosis, apoptosis, neuronal cell insult, brain edema, neurological deficits, and brain lesion volume. Importantly, we found that treating with retinoid X receptor (RXR, the upstream molecule of ABCG1) agonist, bexarotene, in Abcg1 ‐KO mice partly rescued TBI‐induced neuronal damages mentioned above and improved functional deficits versus vehicle‐treated group. These data show that, in addition to regulating brain cholesterol metabolism, Abcg1 improves neurological deficits through inhibiting pyroptosis, apoptosis, neuronal cell insult, and brain edema. Moreover, our findings demonstrate that the cerebroprotection of Abcg1 on TBI partly relies on the activation of the RXRalpha/PPARgamma pathway, which provides a potential therapeutic target for treating TBI.

Traumatic brain injury (TBI) is a serious health issue with a high incidence, high morbidity, and high mortality that poses a large burden on society. Further understanding of the pathophysiology and cell death models induced by TBI may support targeted therapies for TBI patients. Ferroptosis, a model of programmed cell death first defined in 2012, is characterized by iron dyshomeostasis, lipid peroxidation, and glutathione (GSH) depletion. Ferroptosis is distinct from apoptosis, autophagy, pyroptosis, and necroptosis and has been shown to play a role in secondary brain injury and worsen long-term outcomes after TBI. This review systematically describes (1) the regulatory pathways of ferroptosis after TBI, (2) the neurobiological links between ferroptosis and other cell death models, and (3) potential therapies targeting ferroptosis for TBI patients.

Stress, which refers to a combination of physiological, neuroendocrine, behavioral, and emotional responses to novel or threatening stimuli, is essentially a defensive adaptation under physiological conditions. However, strong and long-lasting stress can lead to psychological and pathological damage. Growing evidence suggests that patients suffering from mild and moderate brain injuries and diseases often show severe neurological dysfunction and experience severe and persistent stressful events or environmental stimuli, whether in the acute, subacute, or recovery stage. Previous studies have shown that stress has a remarkable influence on key brain regions and brain diseases. The mechanisms through which stress affects the brain are diverse, including activation of endoplasmic reticulum stress (ERS), apoptosis, oxidative stress, and excitatory/inhibitory neuron imbalance, and may lead to behavioral and cognitive deficits. The impact of stress on brain diseases is complex and involves impediment of recovery, aggravation of cognitive impairment, and neurodegeneration. This review summarizes various stress models and their applications and then discusses the effects and mechanisms of stress on key brain regions—including the hippocampus, hypothalamus, amygdala, and prefrontal cortex—and in brain injuries and diseases—including Alzheimer’s disease, stroke, traumatic brain injury, and epilepsy. Lastly, this review highlights psychological interventions and potential therapeutic targets for patients with brain injuries and diseases who experience severe and persistent stressful events.

Neurological dysfunctions commonly occur after mild or moderate traumatic brain injury (TBI). Although most TBI patients recover from such a dysfunction in a short period of time, some present with persistent neurological deficits. Stress is a potential factor that is involved in recovery from neurological dysfunction after TBI. However, there has been limited research on the effects and mechanisms of stress on neurological dysfunctions due to TBI. In this review, we first investigate the effects of TBI and stress on neurological dysfunctions and different brain regions, such as the prefrontal cortex, hippocampus, amygdala, and hypothalamus. We then explore the neurobiological links and mechanisms between stress and TBI. Finally, we summarize the findings related to stress biomarkers and probe the possible diagnostic and therapeutic significance of stress combined with mild or moderate TBI.