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Abstract
The blood–brain barrier (BBB) forms a protective barrier around the brain, with the important function of maintaining brain homeostasis. Pathways thought to initiate BBB dysfunction include the kinin system, excitotoxicity, neutrophil recruitment, mitochondrial alterations and macrophage/microglial activation, all of which converge on the same point—reactive oxygen species (ROS). Interestingly, ROS also provide a common trigger for many downstream pathways that directly mediate BBB compromise such as oxidative damage, tight junction (TJ) modification and matrix metalloproteinases (MMP) activation. These observations suggest that ROS are key mediators of BBB breakdown and implicate antioxidants as potential neuroprotectants in conditions like stroke and traumatic brain injury (TBI). This review explores some of the pathways both upstream and downstream of ROS that have been implicated in increased BBB permeability and discusses the role of ROS and antioxidants in neuropathology.
| Abbreviations | ||
| 3-NP | = | 3-nitropropionic acid |
| 4-HNE | = | 4-hydroxynonenal |
| AA | = | arachidonic acid |
| ABAD | = | amyloid beta-binding alcohol dehydrogenase |
| AD | = | Alzheimer's disease |
| ALCAM | = | activated leukocyte cell adhesion molecule |
| AMPA | = | α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate |
| ARE | = | antioxidant response element |
| Aβ | = | beta-amyloid |
| BBB | = | blood–brain barrier |
| BMVECs | = | brain microvascular endothelial cells |
| cAMP | = | cyclic adenosine monophosphate |
| cDNA | = | complementary DNA |
| cGMP | = | cyclic guanosine monophosphate |
| CNS | = | central nervous system |
| COX | = | cyclooxygenase |
| DAG | = | diacylglycerol |
| eNOS | = | endothelial NOS |
| EPO | = | erythropoietin |
| ERK | = | extracellular signal-regulated kinase |
| F-actin | = | filamentous actin |
| FAK | = | focal adhesion kinase |
| GSH | = | glutathione |
| H2O2 | = | hydrogen peroxide |
| ICAM | = | intercellular adhesion molecule |
| IFNγ | = | interferon-gamma |
| IL | = | interleukin |
| iNOS | = | inducible NOS |
| IP3 | = | inositol triphosphate |
| JAK | = | Janus kinases |
| Keap1 | = | Kelch-like ECH-associated protein 1 |
| MAP | = | mitogen-activated protein |
| mDIA | = | mammalian diaphanous-related forming |
| MLC | = | myosin light chain |
| MLCK | = | MLC kinase |
| MMP | = | matrix metalloproteinase |
| MS | = | multiple sclerosis |
| Na+/K+-ATPase | = | sodium-potassium ATPase |
| NADPH | = | nicotinamide adenosine dinucleotide phosphate |
| NMDA | = | N-methyl-D-aspartate |
| NO | = | nitric oxide |
| NOS | = | nitric oxide synthase |
| Nrf-2 | = | nuclear factor E2-related factor 2 |
| ONOO− | = | peroxynitrite |
| PECAM | = | platelet endothelial cell adhesion molecule |
| PI3K | = | phosphatidylinositol-3-kinase |
| PIP3 | = | phosphatidylinositol (3,4,5)-triphosphate |
| PKA | = | protein kinase A |
| PKC | = | protein kinase C |
| PKG | = | protein kinase G |
| PLA2 | = | phospholipase A2 |
| PLC | = | phospholipase C |
| PTK | = | protein tyrosine kinase |
| PTP | = | protein tyrosine phosphatase |
| RhoGEF | = | Rho guanine-nucleotide exchange factor |
| ROCK | = | Rho kinase |
| ROS | = | reactive oxygen species |
| SOD | = | superoxide dismutase |
| STAT | = | signal transducers and activators of transcription |
| TBI | = | traumatic brain injury |
| TEER | = | transendothelial electrical resistance |
| TJ | = | tight junction |
| TNFα | = | tumour necrosis factor-alpha |
| VCAM | = | vascular cell adhesion molecule |
| VEGF | = | vascular endothelial growth factor |
| ZO | = | zonulae occludens |
| Abbreviations | ||
| 3-NP | = | 3-nitropropionic acid |
| 4-HNE | = | 4-hydroxynonenal |
| AA | = | arachidonic acid |
| ABAD | = | amyloid beta-binding alcohol dehydrogenase |
| AD | = | Alzheimer's disease |
| ALCAM | = | activated leukocyte cell adhesion molecule |
| AMPA | = | α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate |
| ARE | = | antioxidant response element |
| Aβ | = | beta-amyloid |
| BBB | = | blood–brain barrier |
| BMVECs | = | brain microvascular endothelial cells |
| cAMP | = | cyclic adenosine monophosphate |
| cDNA | = | complementary DNA |
| cGMP | = | cyclic guanosine monophosphate |
| CNS | = | central nervous system |
| COX | = | cyclooxygenase |
| DAG | = | diacylglycerol |
| eNOS | = | endothelial NOS |
| EPO | = | erythropoietin |
| ERK | = | extracellular signal-regulated kinase |
| F-actin | = | filamentous actin |
| FAK | = | focal adhesion kinase |
| GSH | = | glutathione |
| H2O2 | = | hydrogen peroxide |
| ICAM | = | intercellular adhesion molecule |
| IFNγ | = | interferon-gamma |
| IL | = | interleukin |
| iNOS | = | inducible NOS |
| IP3 | = | inositol triphosphate |
| JAK | = | Janus kinases |
| Keap1 | = | Kelch-like ECH-associated protein 1 |
| MAP | = | mitogen-activated protein |
| mDIA | = | mammalian diaphanous-related forming |
| MLC | = | myosin light chain |
| MLCK | = | MLC kinase |
| MMP | = | matrix metalloproteinase |
| MS | = | multiple sclerosis |
| Na+/K+-ATPase | = | sodium-potassium ATPase |
| NADPH | = | nicotinamide adenosine dinucleotide phosphate |
| NMDA | = | N-methyl-D-aspartate |
| NO | = | nitric oxide |
| NOS | = | nitric oxide synthase |
| Nrf-2 | = | nuclear factor E2-related factor 2 |
| ONOO− | = | peroxynitrite |
| PECAM | = | platelet endothelial cell adhesion molecule |
| PI3K | = | phosphatidylinositol-3-kinase |
| PIP3 | = | phosphatidylinositol (3,4,5)-triphosphate |
| PKA | = | protein kinase A |
| PKC | = | protein kinase C |
| PKG | = | protein kinase G |
| PLA2 | = | phospholipase A2 |
| PLC | = | phospholipase C |
| PTK | = | protein tyrosine kinase |
| PTP | = | protein tyrosine phosphatase |
| RhoGEF | = | Rho guanine-nucleotide exchange factor |
| ROCK | = | Rho kinase |
| ROS | = | reactive oxygen species |
| SOD | = | superoxide dismutase |
| STAT | = | signal transducers and activators of transcription |
| TBI | = | traumatic brain injury |
| TEER | = | transendothelial electrical resistance |
| TJ | = | tight junction |
| TNFα | = | tumour necrosis factor-alpha |
| VCAM | = | vascular cell adhesion molecule |
| VEGF | = | vascular endothelial growth factor |
| ZO | = | zonulae occludens |