Subject(s)
Anti-Bacterial Agents/adverse effects , Linear IgA Bullous Dermatosis/chemically induced , Vancomycin/adverse effects , Aged , Anti-Bacterial Agents/therapeutic use , Biopsy , Disease Progression , Female , Fluorescent Antibody Technique, Direct , Humans , Linear IgA Bullous Dermatosis/diagnosis , Linear IgA Bullous Dermatosis/pathology , Postoperative Complications/drug therapy , Sepsis/drug therapy , Sepsis/etiology , Vancomycin/therapeutic useABSTRACT
We have previously shown that nicotine, the addictive component of tobacco products, alters the blood-brain barrier (BBB) Na(+),K(+),2Cl(-) cotransporter (NKCC) during in vitro hypoxia-aglycemia exposure. Attenuation of abluminal NKCC suggests that accumulation of ions in the brain extracellular fluid would result in an increase of fluid or cytotoxic edema in the brain during hypoxia-aglycemia or stroke conditions. To further investigate whether nicotine products have the potential to worsen stroke outcome by increasing edema formation, two separate models to mimic stroke conditions were utilized to decipher the effects of short-term and long-term administrations of nicotine products on brain edema following stroke. Oxygen glucose deprivation (OGD) was studied in rat hippocampal slices with short-term or long-term exposure to nicotine and cigarette smoke constituents. During short-term exposure, the presence of nicotine at a concentration mimicking heavy smokers increased water content of hippocampal slices during OGD. Furthermore, long-term 1-week administration of nicotine increased water content in hippocampal slices that could be attenuated with nicotine acetylcholine receptor (nAChR) antagonists, suggesting nicotine increase edema during OGD via nAChRs. A second model of focal ischemia, middle cerebral artery occlusion, showed an increase of infarct size during short-term exposure to nicotine and an increase of edema during both short-term and long-term administration of nicotine, compared with saline controls. These findings support the paradigm that nicotine products not only increase the incidence of stroke but also have the potential to worsen stroke outcome by increased edema formation.
Subject(s)
Brain Edema/pathology , Brain/drug effects , Hippocampus/drug effects , Hypoxia-Ischemia, Brain/pathology , Nicotine/adverse effects , Animals , Blood Gas Analysis , Body Temperature/drug effects , Brain/pathology , Brain Edema/blood , Brain Infarction/blood , Brain Infarction/pathology , Drug Administration Schedule , Female , Hippocampus/pathology , Hypoglycemia/pathology , Hypoxia-Ischemia, Brain/blood , Mice , Mice, Inbred Strains , Motor Activity/drug effects , Nicotine/administration & dosage , Rats , Rats, Sprague-Dawley , Smoke/adverse effects , Nicotiana/adverse effectsABSTRACT
beta1 integrin is a cell surface molecule that is critical for endothelial cell adhesion, migration and survival during angiogenesis. In the present study we employed in vivo and in vitro models to elucidate the role of beta1 integrin in vascular remodelling and stroke outcomes. At 24 h after cerebral ischemia and reperfusion (I/R), the ischemic cortex (ipsilateral area) exhibited modest beta1 integrin immunoreactivity and a robust increase was observed at 72 h. Double-label immunohistochemical analysis for beta1 integrin with neuronal (NeuN), microglial (Iba-1), astrocyte (GFAP), progenitor cell (Ng2) and blood vessel (collagen 4) markers showed that beta1 integrin expression only localized to blood vessels. In vitro studies using cultured endothelial cells and a beta1 integrin blocking antibody confirmed that beta1 integrin is required for endothelial cell migration, proliferation and blood vessel formation. In vivo studies in the cerebral I/R model using the beta1 integrin blocking antibody further confirmed that beta1 integrin signaling is involved in vascular formation and recovery following ischemic stroke. Finally, we found that beta1 integrin is critically involved in functional deficits and survival after a stroke. These results suggest that beta1 integrin plays important roles in neurovascular remodelling and functional outcomes following stroke, and that targeting the beta1 integrin signalling may provide a novel strategy for modulating angiogenesis in ischemic stroke and other pathological conditions.
Subject(s)
Blood Vessels/metabolism , Gene Expression Regulation/physiology , Infarction, Middle Cerebral Artery/metabolism , Infarction, Middle Cerebral Artery/physiopathology , Interferon-beta/metabolism , Neovascularization, Pathologic/metabolism , Animals , Antibodies/pharmacology , Antibodies/therapeutic use , Antigens/metabolism , Brain/pathology , Calcium-Binding Proteins/metabolism , Cell Line , Cell Movement/drug effects , Cell Movement/physiology , Cell Proliferation/drug effects , Cell Proliferation/ethics , Collagen/metabolism , Disease Models, Animal , Endothelial Cells/drug effects , Endothelial Cells/physiology , Glial Fibrillary Acidic Protein/metabolism , Infarction, Middle Cerebral Artery/drug therapy , Infarction, Middle Cerebral Artery/pathology , Interferon-beta/immunology , Male , Mice , Mice, Inbred C57BL , Microfilament Proteins , Neovascularization, Pathologic/drug therapy , Phosphopyruvate Hydratase/metabolism , Proteoglycans/metabolism , Reperfusion Injury/drug therapy , Reperfusion Injury/metabolism , Statistics, NonparametricABSTRACT
Toll-like receptors (TLRs) play important roles in innate immunity. Several TLR family members have recently been shown to be expressed by neurons and glial cells in the adult brain, and may mediate responses of these cells to injury and infection. To address the possibility that TLRs play a functional role in development of the nervous system, we analyzed the expression of TLRs during different stages of mouse brain development and assessed the role of TLRs in cell proliferation. TLR3 protein is present in brain cells in early embryonic stages of development, and in cultured neural stem/progenitor cells (NPC). NPC from TLR3-deficient embryos formed greater numbers of neurospheres compared with neurospheres from wild-type embryos. Numbers of proliferating cells, as assessed by phospho histone H3 and proliferating cell nuclear antigen labeling, were also increased in the developing cortex of TLR3-deficient mice compared with wild-type mice in vivo. Treatment of cultured embryonic cortical neurospheres with a TLR3 ligand (polyIC) significantly reduced proliferating (BrdU-labeled) cells and neurosphere formation in wild type but not TLR3(-/-)-derived NPCs. Our findings reveal a novel role for TLR3 in the negative regulation of NPC proliferation in the developing brain.
Subject(s)
Brain/cytology , Gene Expression Regulation, Developmental , Neurons/metabolism , Stem Cells/metabolism , Toll-Like Receptor 3/physiology , Animals , Brain/embryology , Cell Proliferation/drug effects , Cells, Cultured , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/cytology , Poly I-C/pharmacology , Signal Transduction/drug effects , Signal Transduction/physiology , Spheroids, Cellular/cytology , Stem Cells/cytology , Stem Cells/drug effects , Toll-Like Receptor 3/drug effects , Toll-Like Receptor 3/geneticsABSTRACT
The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We recently found that neurons express several TLRs, and that the levels of TLR2 and TLR4 are increased in neurons in response to energy deprivation. Here we report that TLR4 expression increases in neurons when exposed to amyloid beta-peptide (Abeta1-42) or the lipid peroxidation product 4-hydroxynonenal (HNE). Neuronal apoptosis triggered by Abeta and HNE was mediated by jun N-terminal kinase (JNK); neurons from TLR4 mutant mice exhibited reduced JNK and caspase-3 activation and were protected against apoptosis induced by Abeta and HNE. Levels of TLR4 were decreased in inferior parietal cortex tissue specimens from end-stage AD patients compared to aged-matched control subjects, possibly as the result of loss of neurons expressing TLR4. Our findings suggest that TLR4 signaling increases the vulnerability of neurons to Abeta and oxidative stress in AD, and identify TLR4 as a potential therapeutic target for AD.
Subject(s)
Alzheimer Disease/metabolism , Apoptosis , Lipid Peroxidation , Nerve Degeneration/metabolism , Oxidative Stress , Toll-Like Receptor 4/metabolism , Aged , Aged, 80 and over , Aldehydes/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/pathology , Amyloid beta-Peptides/metabolism , Amyloid beta-Peptides/toxicity , Animals , Apoptosis/drug effects , Brain/metabolism , Brain/pathology , Caspase 3/drug effects , Caspase 3/metabolism , Female , Humans , JNK Mitogen-Activated Protein Kinases/drug effects , JNK Mitogen-Activated Protein Kinases/metabolism , Male , Membrane Lipids/metabolism , Mice , Mice, Knockout , Nerve Degeneration/chemically induced , Nerve Degeneration/pathology , Oxidative Stress/drug effects , Peptide Fragments/metabolism , Peptide Fragments/toxicity , Signal Transduction/drug effects , Toll-Like Receptor 4/geneticsABSTRACT
BACKGROUND: Intravenous immunoglobulin (IVIG) is a therapeutic modality approved for the treatment of autoimmune disorders. OBJECTIVE: This review discusses how IVIG can prevent brain damage following ischemic stroke and discuss the potential mechanisms of action. METHODS: Medline and the world wide web were searched and the relevant literature was classified under the following categories: IVIG, IVIG mechanism of action, and ischemic stroke injury mechanisms. RESULTS/CONCLUSION: Brain ischemia induces an inflammatory response that contributes to neuronal cell death. Because of its ability to block multiple molecular events, IVIG may have particularly strong neuroprotective action against ischemic brain injury. In light of the extensive clinical experience with IVIG for other indications, development of clinical trials to evaluate the use of IVIG in human stroke patients are warranted.