ABSTRACT
The concept of the glial-vascular unit (GVU) was raised recently to emphasize the close associations between brain cells and cerebral vessels, and their coordinated reactions to diverse neurological insults from a "glio-centric" view. GVU is a multicellular structure composed of glial cells, perivascular cells, and perivascular space. Each component is closely linked, collectively forming the GVU. The central roles of glial and perivascular cells and their multi-level interconnections in the GVU under normal conditions and in central nervous system (CNS) disorders have not been elucidated in detail. Here, we comprehensively review the intensive interactions between glial cells and perivascular cells in the niche of perivascular space, which take part in the modulation of cerebral blood flow and angiogenesis, formation of the blood-brain barrier, and clearance of neurotoxic wastes. Next, we discuss dysfunctions of the GVU in various neurological diseases, including ischemic stroke, spinal cord injury, Alzheimer's disease, and major depression disorder. In addition, we highlight the possible therapies targeting the GVU, which may have potential clinical applications.
Subject(s)
Humans , Neuroglia , Nervous System Diseases , Blood-Brain Barrier , Alzheimer Disease , Glymphatic SystemABSTRACT
The glymphatic system plays a pivotal role in maintaining cerebral homeostasis. Chronic cerebral hypoperfusion, arising from small vessel disease or carotid stenosis, results in cerebrometabolic disturbances ultimately manifesting in white matter injury and cognitive dysfunction. However, whether the glymphatic system serves as a potential therapeutic target for white matter injury and cognitive decline during hypoperfusion remains unknown. Here, we established a mouse model of chronic cerebral hypoperfusion via bilateral common carotid artery stenosis. We found that the hypoperfusion model was associated with significant white matter injury and initial cognitive impairment in conjunction with impaired glymphatic system function. The glymphatic dysfunction was associated with altered cerebral perfusion and loss of aquaporin 4 polarization. Treatment of digoxin rescued changes in glymphatic transport, white matter structure, and cognitive function. Suppression of glymphatic functions by treatment with the AQP4 inhibitor TGN-020 abolished this protective effect of digoxin from hypoperfusion injury. Our research yields new insight into the relationship between hemodynamics, glymphatic transport, white matter injury, and cognitive changes after chronic cerebral hypoperfusion.
Subject(s)
Animals , Mice , Brain Ischemia , Carotid Stenosis/drug therapy , Cognitive Dysfunction/etiology , Digoxin , Disease Models, Animal , Mice, Inbred C57BL , White MatterABSTRACT
Objective To explore the expression of nuclear factor-erythroid 2-related factor 2(Nrf2) and the molecular chaperone of cytoplasmic Keap1 in premature newborn rats exposed to hyperoxia.Methods Completely randomized design method was performed,one-day old preterm SD rats were randomly divided into two groups:hyperoxia group and air group.The preterm SD rats in hyperoxia group were continuously exposed to oxygen(oxygen >0.85)and air group in room air.After 1 ,4,7,10,14 days of exposure,the pre-term SD rats of two groups were sacrificed,whole lung of these rats were isolated,the lung histological chan-ges were observed by HE staining.Total lung RNA was extracted,Nrf2 and Keap1 mRNA were detected by RT-PCR.Western-blot was used to detect the changes of Nrf2 protein expression.Results (1 )Compaired with air group,the expression of Nrf2 in lung tissue of hyperoxia group significantly increased after 4,7 days of exposure(4 d:0.314 ±0.064 vs.0.521 ±0.086,7 d:0.440 ±0.121 vs.0.658 ±0.076)(P 0.05),but had a tendency of decreasing after 7 days.On day 10, 14,its expression in hyperoxia group became significantly weak compared with that of air group(10 d:1.325 ±0.464 vs.0.755 ±0.348,14 d:1.662 ±0.474 vs.0.867 ±0.1 15 )(P <0.05 ).Conclusion Oxidation outbreak results in the abnormal expression of Nrf2 and Keap1 in the lung of premature SD rats induced by hyperoxia exposure,which adjusts the levels of oxidative stress in the body,these changes participate in the development of hyperoxia induced lung injury,the activity of Nrf2 may be increased by hyperoxia exposure, and alleviate hyperoxia lung injury in premature rats through antioxidation of Nrf2.