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1.
Mol Cells ; 37(4): 345-55, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24802057

ABSTRACT

Mitigating secondary delayed neuronal injury has been a therapeutic strategy for minimizing neurological symptoms after several types of brain injury. Interestingly, secondary neuronal loss appeared to be closely related to functional loss and/or death of astrocytes. In the brain damage induced by agonists of two glutamate receptors, N-ethyl-D-aspartic acid (NMDA) and kainic acid (KA), NMDA induced neuronal death within 3 h, but did not increase further thereafter. However, in the KA-injected brain, neuronal death was not obviously detectable even at injection sites at 3 h, but extensively increased to encompass the entire hemisphere at 7 days. Brain inflammation, a possible cause of secondary neuronal damage, showed little differences between the two models. Importantly, however, astrocyte behavior was completely different. In the NMDA-injected cortex, the loss of glial fibrillary acidic protein-expressing (GFAP+) astrocytes was confined to the injection site until 7 days after the injection, and astrocytes around the damage sites showed extensive gliosis and appeared to isolate the damage sites. In contrast, in the KA-injected brain, GFAP+ astrocytes, like neurons, slowly, but progressively, disappeared across the entire hemisphere. Other markers of astrocytes, including S100ß, glutamate transporter EAAT2, the potassium channel Kir4.1 and glutamine synthase, showed patterns similar to that of GFAP in both NMDA- and KA-injected cortexes. More importantly, astrocyte disappearance and/or functional loss preceded neuronal death in the KA-injected brain. Taken together, these results suggest that loss of astrocyte support to neurons may be a critical cause of delayed neuronal death in the injured brain.


Subject(s)
Astrocytes/drug effects , Brain Injuries/drug therapy , Cell Death , Cerebral Cortex/drug effects , Gliosis/drug therapy , Kainic Acid/administration & dosage , N-Methylaspartate/administration & dosage , Animals , Astrocytes/physiology , Biomarkers/metabolism , Cell Communication/drug effects , Cell Death/drug effects , Excitatory Amino Acid Transporter 2/metabolism , Glial Fibrillary Acidic Protein/metabolism , Glutamate-Ammonia Ligase/metabolism , Male , Neurons/drug effects , Neurons/physiology , Potassium Channels, Inwardly Rectifying/metabolism , Rats , Rats, Sprague-Dawley , Receptors, Glutamate/metabolism , S100 Calcium Binding Protein beta Subunit/metabolism
2.
Mol Brain ; 6: 28, 2013 Jun 10.
Article in English | MEDLINE | ID: mdl-23758980

ABSTRACT

Inflammation in injured tissue has both repair functions and cytotoxic consequences. However, the issue of whether brain inflammation has a repair function has received little attention. Previously, we demonstrated monocyte infiltration and death of neurons and resident microglia in LPS-injected brains (Glia. 2007. 55:1577; Glia. 2008. 56:1039). Here, we found that astrocytes, oligodendrocytes, myelin, and endothelial cells disappeared in the damage core within 1-3 d and then re-appeared at 7-14 d, providing evidence of repair of the brain microenvironment. Since round Iba-1+/CD45+ monocytes infiltrated before the repair, we examined whether these cells were involved in the repair process. Analysis of mRNA expression profiles showed significant upregulation of repair/resolution-related genes, whereas proinflammatory-related genes were barely detectable at 3 d, a time when monocytes filled injury sites. Moreover, Iba-1+/CD45+ cells highly expressed phagocytic activity markers (e.g., the mannose receptors, CD68 and LAMP2), but not proinflammatory mediators (e.g., iNOS and IL1ß). In addition, the distribution of round Iba-1+/CD45+ cells was spatially and temporally correlated with astrocyte recovery. We further found that monocytes in culture attracted astrocytes by releasing soluble factor(s). Together, these results suggest that brain inflammation mediated by monocytes functions to repair the microenvironment of the injured brain.


Subject(s)
Astrocytes/pathology , Blood Vessels/pathology , Brain Injuries/blood , Brain Injuries/pathology , Monocytes/metabolism , Myelin Sheath/metabolism , Wound Healing , Animals , Astrocytes/drug effects , Blood Vessels/drug effects , Brain Injuries/physiopathology , Cell Movement/drug effects , Cell Proliferation/drug effects , Endothelial Cells/drug effects , Endothelial Cells/pathology , Inflammation/pathology , Ki-67 Antigen/metabolism , Lipopolysaccharides/pharmacology , Male , Monocytes/drug effects , Neurites/drug effects , Neurites/pathology , Oligonucleotide Array Sequence Analysis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley , Recovery of Function/drug effects , Substantia Nigra/drug effects , Substantia Nigra/pathology , Substantia Nigra/physiopathology , Wound Healing/drug effects
3.
PLoS One ; 5(10): e13756, 2010 Oct 29.
Article in English | MEDLINE | ID: mdl-21060796

ABSTRACT

BACKGROUND: Brain inflammation is accompanied by brain injury. However, it is controversial whether inflammatory responses are harmful or beneficial to neurons. Because many studies have been performed using cultured microglia and neurons, it has not been possible to assess the influence of multiple cell types and diverse factors that dynamically and continuously change in vivo. Furthermore, behavior of microglia and other inflammatory cells could have been overlooked since most studies have focused on neuronal death. Therefore, it is essential to analyze the precise roles of microglia and brain inflammation in the injured brain, and determine their contribution to neuronal damage in vivo from the onset of injury. METHODS AND FINDINGS: Acute neuronal damage was induced by stereotaxic injection of ATP into the substantia nigra pars compacta (SNpc) and the cortex of the rat brain. Inflammatory responses and their effects on neuronal damage were investigated by immunohistochemistry, electron microscopy, quantitative RT-PCR, and stereological counting, etc. ATP acutely caused death of microglia as well as neurons in a similar area within 3 h. We defined as the core region the area where both TH(+) and Iba-1(+) cells acutely died, and as the penumbra the area surrounding the core where Iba-1(+) cells showed activated morphology. In the penumbra region, morphologically activated microglia arranged around the injury sites. Monocytes filled the damaged core after neurons and microglia died. Interestingly, neither activated microglia nor monocytes expressed iNOS, a major neurotoxic inflammatory mediator. Monocytes rather expressed CD68, a marker of phagocytic activity. Importantly, the total number of dopaminergic neurons in the SNpc at 3 h (∼80% of that in the contralateral side) did not decrease further at 7 d. Similarly, in the cortex, ATP-induced neuron-damage area detected at 3 h did not increase for up to 7 d. CONCLUSIONS: Different cellular components (microglia, astrocytes, monocytes, and neutrophils) and different factors (proinflammatory and neurotrophic) could be produced in inflammatory processes depending on the nature of the injury. The results in this study suggest that the inflammatory responses of microglia and monocytes in response to ATP-induced acute injury could not be neurotoxic.


Subject(s)
Adenosine Triphosphate/pharmacology , Brain Injuries/pathology , Cell Death , Inflammation/pathology , Adenosine Triphosphate/administration & dosage , Animals , Base Sequence , DNA Primers , Immunohistochemistry , Microscopy, Electron , Rats , Reverse Transcriptase Polymerase Chain Reaction
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