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Bi-directionally protective communication between neurons and astrocytes under ischemia.

ABSTRACT: The extensive existing knowledge on bi-directional communication between astrocytes and neurons led us to hypothesize that not only ischemia-preconditioned (IP) astrocytes can protect neurons but also IP neurons protect astrocytes from lethal ischemic injury. Here, we demonstrated for the first time that neurons have a significant role in protecting astrocytes from ischemic injury. The cultured medium from IP neurons (IPcNCM) induced a remarkable reduction in LDH and an increase in cell viability in ischemic astrocytes in vitro. Selective neuronal loss by kainic acid injection induced a significant increase in apoptotic astrocyte numbers in the brain of ischemic rats in vivo. Furthermore, TUNEL analysis, DNA ladder assay, and the measurements of ROS, GSH, pro- and anti-apoptotic factors, anti-oxidant enzymes and signal molecules in vitro and/or in vivo demonstrated that IP neurons protect astrocytes by an EPO-mediated inhibition of pro-apoptotic signals, activation of anti-apoptotic proteins via the P13K/ERK/STAT5 pathways and activation of anti-oxidant proteins via up-regulation of anti-oxidant enzymes. We demonstrated the existence of astro-protection by IP neurons under ischemia and proposed that the bi-directionally protective communications between cells might be a common activity in the brain or peripheral organs under most if not all pathological conditions.

SUBMITTER: Wu XM

PROVIDER: S-EPMC5447396 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Bi-directionally protective communication between neurons and astrocytes under ischemia.

Wu Xiao-Mei XM Qian Christopher C Zhou Yu-Fu YF Yan Yick-Chun YC Luo Qian-Qian QQ Yung Wing-Ho WH Zhang Fa-Li FL Jiang Li-Rong LR Qian Zhong Ming ZM Ke Ya Y

Redox biology 20170520

The extensive existing knowledge on bi-directional communication between astrocytes and neurons led us to hypothesize that not only ischemia-preconditioned (IP) astrocytes can protect neurons but also IP neurons protect astrocytes from lethal ischemic injury. Here, we demonstrated for the first time that neurons have a significant role in protecting astrocytes from ischemic injury. The cultured medium from IP neurons (IPcNCM) induced a remarkable reduction in LDH and an increase in cell viabilit ...[more]

PMID: 28551085

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Project description:Methamphetamine (meth) is a central nervous system (CNS) stimulant that results in psychological and physical dependency. The long-term effects of meth within the CNS include neuronal plasticity changes, blood-brain barrier compromise, inflammation, electrical dysfunction, neuronal/glial toxicity, and an increased risk to infectious diseases including HIV. Most of the reported meth effects in the CNS are related to dysregulation of chemical synapses by altering the release and uptake of neurotransmitters, especially dopamine, norepinephrine, and epinephrine. However, little is known about the effects of meth on connexin (Cx) containing channels, such as gap junctions (GJ) and hemichannels (HC). We examined the effects of meth on Cx expression, function, and its role in NeuroAIDS. We found that meth altered Cx expression and localization, decreased GJ communication between neurons and astrocytes, and induced the opening of Cx43/Cx36 HC. Furthermore, we found that these changes in GJ and HC induced by meth treatment were mediated by activation of dopamine receptors, suggesting that dysregulation of dopamine signaling induced by meth is essential for GJ and HC compromise. Meth-induced changes in GJ and HC contributed to amplified CNS toxicity by dysregulating glutamate metabolism and increasing the susceptibility of neurons and astrocytes to bystander apoptosis induced by HIV. Together, our results indicate that connexin containing channels, GJ and HC, are essential in the pathogenesis of meth and increase the sensitivity of the CNS to HIV CNS disease. Methamphetamine (meth) is an extremely addictive central nervous system stimulant. Meth reduced gap junctional (GJ) communication by inducing internalization of connexin-43 (Cx43) in astrocytes and reducing expression of Cx36 in neurons by a mechanism involving activation of dopamine receptors (see cartoon). Meth-induced changes in Cx containing channels increased extracellular levels of glutamate and resulted in higher sensitivity of neurons and astrocytes to apoptosis in response to HIV infection.

Project description:BackgroundHypothermic protection against ischemic stroke has been reported by many studies. Hypothermia is supposed to mitigate the effects of deleterious genes and proteins and promote the activity of protective genes and proteins in the ischemic brain. Metallothionein (MT)-1/2 is thought to be a crucial factor for metal homeostasis, immune function, and apoptosis. This protein was found to exert protective effects in models of brain injury as well. In the present study, we investigated the effect of hypothermia on MT expression and the underlying mechanisms.MethodsCultured bEnd.3 brain endothelial cells were exposed to oxygen glucose deprivation and reperfusion (OGD+R). Reverse transcription PCR and western blot analyses were performed to measure the expression of MT, transcription factors, and methylation regulating factors. Transcription factor binding assays were also performed. Methylation profiles of the promoter area were obtained with pyrosequencing.ResultsHypothermia protected bEnd.3 cells from OGD+R. When the cells were exposed to OGD+R, MT expression was induced. Hypothermia augmented MT levels. While OGD+R-induced MT expression was mainly associated with metal regulatory transcription factor 1 (MTF-1), MT expression promoted by hypothermia was primarily mediated by the signal transducer and activator of transcription 3 (STAT3). Significantly increased STAT3 phosphorylation at Ser727 was observed with hypothermia, and JSI-124, a STAT-3 inhibitor, suppressed MT expression. The DNA demethylating drug 5-aza-2'-deoxycytidine (5-Aza) enhanced MT expression. Some of the CpG sites in the promoter MT=> it should be "the CpG sites in the MT promoter" showed different methylation profiles and some methylation regulating factors had different expressional profiles in the presence of OGD+R and hypothermia.ConclusionsWe demonstrated that hypothermia is a potent inducer of MT gene transcription in brain endothelial cells, and enhanced MT expression might contribute to protection against ischemia. MT gene expression is induced by hypothermia mainly through the STAT3 pathway. DNA methylation may contribute to MT gene regulation under ischemic or hypothermic conditions.

Project description:BackgroundTraumatic spinal cord injury (SCI) is a major clinical concern and a life-changing neurological condition with substantial socioeconomic implications. The initial mechanical force applied to the spinal cord at the time of injury is known as the primary injury. After the primary injury, ischemia and hypoxia induce cell death and autolysis, which are associated with the release of a group of inflammatory factors and biologically active substances, such as superoxide dismutase (SOD), malonaldehyde (MDA), lactate dehydrogenase (LDH), and tumor necrosis factor-α (TNF-α). These processes are called the secondary injury, and may lead to an excess of extracellular glutamate (Glu), which in turn promotes the neuronal injuries. Muscone has been shown to have anti-inflammatory effects in the treatment of brain diseases and other diseases. However, to date, no study has examined the effects of muscone in the treatment of SCI.MethodsAstrocytes were separated and purified by the method of short-term exposure combining with differential sticking wall. Astrocyte was identified by glial fibers acidic protein (GFAP) selecting cell immunochemical staining. A mechanical-chemical damage (MCD) model was established via the primary spinal astrocytes of rats, and treatment was administered with different concentrations of muscone. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (MTT) was detected at 6, 12, 24, 48 and 72 h. SOD, MDA, LDH, TNF-alpha and intracellular calcium was detected at 3, 6 and 12 h. Glu in supernatant was detected respectively at 3, 6 and 12 h by enzyme-linked immunosorbent assay (ELISA) method. Intracellular calcium was detected respectively at 3, 6 and 12 h by flow cytometry method. MRNA expression of excitatory amino acid transporters (EAATs) and GFAP were detected by the quantitative reverse transcription polymerase chain reaction (qRT-PCR) method and protein expression of those by western blot at 6 h.ResultsMuscone reduced the levels of LDH, TNF-α, and MDA after injury, and upregulated the level of SOD. Muscone also reduced the density of extracellular Glu and suppressed the intracellular calcium level. Additionally, it decreased the expression levels of EAATs and GFAPs.ConclusionsMuscone has a protective effect on astrocytes in a MCD and inhibits astrocytes' proliferation.

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Bi-directionally protective communication between neurons and astrocytes under ischemia.

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Bi-directionally protective communication between neurons and astrocytes under ischemia.

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