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Astrocyte Proliferation (astrocyte + proliferation)

Distribution by Scientific Domains
Medical Sciences33%

Selected Abstracts

Disruption of the hyaluronan-based extracellular matrix in spinal cord promotes astrocyte proliferation

GLIA, Issue 1 2005
Jaime Struve
Abstract Astrocyte proliferation is tightly controlled during development and in the adult nervous system. In the present study, we find that a high-molecular-weight (MW) form of the glycosaminoglycan hyaluronan (HA) is found in rat spinal cord tissue and becomes degraded soon after traumatic spinal cord injury. Newly synthesized HA accumulates in injured spinal cord as gliosis proceeds, such that high-MW HA becomes overabundant in the extracellular matrix surrounding glial scars after 1 month. Injection of hyaluronidase, which degrades HA, into normal spinal cord tissue results in increased numbers of glial fibrillary acidic protein (GFAP)-positive cells that also express the nuclear proliferation marker Ki-67, suggesting that HA degradation promotes astrocyte proliferation. In agreement with this observation, adding high- but not low-MW HA to proliferating astrocytes in vitro inhibits cell growth, while treating confluent, quiescent astrocyte cultures with hyaluronidase induces astrocyte proliferation. Collectively, these data indicate that high-MW HA maintains astrocytes in a state of quiescence, and that degradation of HA following CNS injury relieves growth inhibition, resulting in increased astrocyte proliferation. © 2005 Wiley-Liss, Inc. [source]

Role of mitogen-activated protein kinase cascades in P2Y receptor-mediated trophic activation of astroglial cells ,

DRUG DEVELOPMENT RESEARCH, Issue 2-3 2001
Joseph T. Neary
Abstract The trophic actions of extracellular nucleotides and nucleosides on astroglial cells in the central nervous system may be important in development as well as injury and repair. Here we summarize recent findings on the signal transduction mechanisms and gene expression that mediate the trophic effects of extracellular ATP on astrocyte cultures, with a particular emphasis on mitogenesis. Activation of ATP/P2Y receptors leads to the stimulation of mitogen-activated protein kinase (MAPK) cascades, which play a crucial role in cellular proliferation, differentiation, and survival. Inhibition of ERK and p38, members of two distinct MAPK cascades, interferes with the ability of extracellular ATP to stimulate astrocyte proliferation, thereby indicating their importance in mitogenic signaling by P2Y receptors. Signaling from P2Y receptors to ERK involves phospholipase D and a calcium-independent protein kinase C isoform, PKC; this pathway is independent of the phosphatidylinositol-phospholipase C / calcium pathway which is also coupled to P2Y receptors. Pharmacological studies suggest that astrocytes may express an as-yet uncloned P2Y receptor that recruits a novel MEK activator in the ERK cascade. Extracellular ATP can also potentiate fibroblast growth factor (FGF)-2-induced proliferation, and studies on interactions between ATP and FGF-2 signaling pathways have revealed that although ATP does not activate cRaf-1, the first protein kinase in the ERK cascade, it can reduce cRaf-1 activation by FGF-2. As intermediate levels of Raf activity stimulate the cell cycle, the partial inhibition of FGF-induced Raf activity by ATP may contribute to the enhancing effect of ATP on FGF-2-induced astrocyte proliferation. Activation of P2Y receptors also leads to nuclear signaling, and the use of DNA arrays has shown that treatment of astrocytes with extracellular ATP results in the up- and downregulation of a number of genes; studies to determine which of these genes are regulated by MAPKs are now in progress. Elucidation of the components of MAPK pathways linked to P2Y receptors and subsequent changes in gene expression may provide targets for a new avenue of drug development aimed at the management of astrogliosis which occurs in many types of neurological disorders and neurodegeneration. Drug Dev. Res. 53:158,165, 2001. Published 2001 Wiley-Liss, Inc. [source]

Pathogenesis of Lyme neuroborreliosis: Borrelia burgdorferi lipoproteins induce both proliferation and apoptosis in rhesus monkey astrocytes

EUROPEAN JOURNAL OF IMMUNOLOGY, Issue 9 2003
Geeta Ramesh
Abstract Brain invasion by Borrelia burgdorferi, the agent of Lyme disease, results in an inflammatory and neurodegenerative disorder called neuroborreliosis. In humans, neuroborreliosis has been correlated with enhanced concentration of glial fibrillary acidic protein in the cerebrospinal fluid, a sign of astrogliosis. Rhesus monkeys infected by us with B.,burgdorferi showed evidence of astrogliosis, namely astrocyte proliferation and apoptosis. We formulated the hypothesis that astrogliosis could be caused by spirochetal lipoproteins. We established primary cultures of rhesus monkey astrocytes and stimulated the cells with recombinant lipidated outer surface protein,A (L-OspA), a model B.,burgdorferi lipoprotein, and tripalmitoyl-S-glyceryl-Cys-Ser-Lys4 -OH (Pam3Cys), a synthetic lipopeptide that mimics the structure of the lipoprotein lipid moiety. L-OspA elicited not only astrocyte proliferation but also apoptosis, two features observed during astrogliosis. Astrocytes produced both IL-6 and TNF-, in response to L-OspA and Pam3Cys. Proliferation induced by L-OspA was diminished in the presence of an excess of anti-IL-6 antibody, and apoptosis induced by this lipoprotein was completely suppressed with anti-TNF-, antibody. Hence, IL-6 contributes to, and TNF-, determines, astrocyte proliferation and apoptosis, respectively, as elicited by lipoproteins. Our results provide proof of the principle that spirochetal lipoproteins could be key virulence factors in Lyme neuroborreliosis, and that astrogliosis might contribute to neuroborreliosis pathogenesis. [source]

Activation of CysLT receptors induces astrocyte proliferation and death after oxygen,glucose deprivation

GLIA, Issue 1 2008
Xiao-Jia Huang
Abstract We recently found that 5-lipoxygenase (5-LOX) is activated to produce cysteinyl leukotrienes (CysLTs), and CysLTs may cause neuronal injury and astrocytosis through activation of CysLT1 and CysLT2 receptors in the brain after focal cerebral ischemia. However, the property of astrocyte responses to in vitro ischemic injury is not clear; whether 5-LOX, CysLTs, and their receptors are also involved in the responses of ischemic astrocytes remains unknown. In the present study, we performed oxygen-glucose deprivation (OGD) followed by recovery to induce ischemic-like injury in the cultured rat astrocytes. We found that 1-h OGD did not injure astrocytes (sub-lethal OGD) but induced astrocyte proliferation 48 and 72 h after recovery; whereas 4-h OGD moderately injured the cells (moderate OGD) and led to death 24,72 h after recovery. Inhibition of phospholipase A2 and 5-LOX attenuated both the proliferation and death. Sub-lethal and moderate OGD enhanced the production of CysLTs that was inhibited by 5-LOX inhibitors. Sub-lethal OGD increased the expressions of CysLT1 receptor mRNA and protein, while moderate OGD induced the expression of CysLT2 receptor mRNA. Exogenously applied leukotriene D4 (LTD4) induced astrocyte proliferation at 1,10 nM and astrocyte death at 100,1,000 nM. The CysLT1 receptor antagonist montelukast attenuated astrocyte proliferation, the CysLT2 receptor antagonist BAY cysLT2 reversed astrocyte death, and the dual CysLT receptor antagonist BAY u9773 exhibited both effects. In addition, LTD4 (100 nM) increased the expression of CysLT2 receptor mRNA. Thus, in vitro ischemia activates astrocyte 5-LOX to produce CysLTs, and CysLTs result in CysLT1 receptor-mediated proliferation and CysLT2 receptor-mediated death. © 2007 Wiley-Liss, Inc. [source]

Disruption of the hyaluronan-based extracellular matrix in spinal cord promotes astrocyte proliferation

GLIA, Issue 1 2005
Jaime Struve
Abstract Astrocyte proliferation is tightly controlled during development and in the adult nervous system. In the present study, we find that a high-molecular-weight (MW) form of the glycosaminoglycan hyaluronan (HA) is found in rat spinal cord tissue and becomes degraded soon after traumatic spinal cord injury. Newly synthesized HA accumulates in injured spinal cord as gliosis proceeds, such that high-MW HA becomes overabundant in the extracellular matrix surrounding glial scars after 1 month. Injection of hyaluronidase, which degrades HA, into normal spinal cord tissue results in increased numbers of glial fibrillary acidic protein (GFAP)-positive cells that also express the nuclear proliferation marker Ki-67, suggesting that HA degradation promotes astrocyte proliferation. In agreement with this observation, adding high- but not low-MW HA to proliferating astrocytes in vitro inhibits cell growth, while treating confluent, quiescent astrocyte cultures with hyaluronidase induces astrocyte proliferation. Collectively, these data indicate that high-MW HA maintains astrocytes in a state of quiescence, and that degradation of HA following CNS injury relieves growth inhibition, resulting in increased astrocyte proliferation. © 2005 Wiley-Liss, Inc. [source]

Role of the Rap1 GTPase in astrocyte growth regulation

GLIA, Issue 3 2003
Anthony J. Apicelli
Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome in which affected individuals develop nervous system abnormalities that might reflect astrocyte dysfunction. The TSC2 gene product, tuberin, encodes a GTPase-activating protein (GAP) domain, which regulates the activity of Rap1 in vitro. To determine whether dysregulated Rap1, resulting from TSC2 inactivation, leads to increased astrocyte proliferation in vivo, we generated transgenic mice expressing activated Rap1G12V specifically in astrocytes. We observed no statistically significant difference in the number of astrocytes between wild-type and GFAP-Rap1G12V littermates in vivo; however, during log-phase growth, we observed a 25% increase in GFAP-Rap1G12V astrocyte doubling times compared to wild-type controls. This decreased proliferation was associated with delayed MAP kinase, but not AKT, activation. Lastly, to determine whether constitutive Rap1 activation could reverse the increased astrocyte proliferation observed in transgenic mice expressing oncogenic RasG12V, we generated transgenic mice expressing both RasG12V and Rap1G12V in astrocytes. These double transgenic mice showed a striking reversion of the RasG12V astrocyte growth phenotype. Collectively, these results argue that the tumor suppressor properties of tuberin are unlikely to be related to Rap1 inactivation and that Rap1 inhibits mitogenic Ras pathway signaling in astrocytes. GLIA 42:225,234, 2003. © 2003 Wiley-Liss, Inc. [source]