Glia
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ATP acts as a growth factor as well as a toxic agent by stimulating P2 receptors. The P2 receptor-activated signaling cascades mediating cellular growth and cell survival after injury are only incompletely understood. Therefore, the aim of the present study was to identify the role of the phosphoinositide 3 kinase (PI3-K/Akt) and the mitogen-activated protein kinase/extracellular signal regulated protein kinase (MAPK/ERK) pathways in P2Y receptor-mediated astrogliosis after traumatic injury and after microinfusion of ADP beta S (P2Y(1,12,13) receptor agonist) into the rat nucleus accumbens (NAc). ⋯ The ADP beta S-enhanced expression of the early apoptosis marker active caspase 3 was reduced by PPADS and PD98059, but not by wortmannin. Multiple immunofluorescence labeling indicated a time-dependent expression of pAkt and pMAPK on astrocytes and neurons and additionally the colocalization of pAkt, pMAPK, and active caspase 3 with the P2Y(1) receptor especially at astrocytes. In conclusion, the data show for the first time the involvement of PI3-K/Akt-pathway in processes of injury-induced astroglial proliferation and anti-apoptosis via activation of P2Y(1) receptors in vivo, suggesting specific roles of P2 receptors in glial cell pathophysiology in neurodegenerative diseases.
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Progesterone is emerging as a myelinizing factor for central nervous system injury. Successful remyelination requires proliferation and differentiation of oligodendrocyte precursor cells (OPC) into myelinating oligodendrocytes, but this process is incomplete following injury. To study progesterone actions on remyelination, we administered progesterone (16 mg/kg/day) to rats with complete spinal cord injury. ⋯ These results suggest that early progesterone treatment enhanced the density of OPC and induced their differentiation into mature oligodendrocytes by increasing the expression of Olig2 and Nkx2.2. Twenty-one days after injury, progesterone favors remyelination by increasing Olig1 (involved in repair of demyelinated lesions), PLP expression, and enhancing oligodendrocytes maturation. Thus, progesterone effects on oligodendrogenesis and myelin proteins may constitute fundamental steps for repairing traumatic injury inflicted to the spinal cord.
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Many studies have shown that adenosine triphosphate (ATP), as a neurotransmitter, is involved in plastic changes of synaptic transmission in central nervous system. In the present study, we tested whether extracellular ATP can induce long-term potentiation (LTP) of C-fiber-evoked field potentials in spinal dorsal horn. The results showed the following: (1) ATP at a concentration of 0.3 mM induced spinal LTP of C-fiber-evoked field potentials, lasting for at least 5 h; (2) spinal application of 2',3'-O-(2,4,6-trinitrophenyl)adenosine-5-triphosphate (TNP-ATP; an antagonist of P2X(1-4) receptors), but not pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; an antagonist of P2X(1,2,3,5,7) receptors), 30 min before ATP blocked ATP-induced LTP, indicating that ATP may induce spinal LTP by activation of P2X(4) receptors; (3) at 60 min after LTP induction the level of phospho-p38 mitogen-activated protein kinase (p-p38 MAPK) was significantly elevated and at 180 min after LTP the number of P2X(4) receptors increased significantly; both p-p38 and P2X(4) receptors were exclusively co-located with the microglia marker, but not with neuronal or astrocyte marker; (4) spinal application of TNP-ATP but not PPADS prevented p38 activation; (5) spinal application of SB203580, a p38 MAPK inhibitor, prevented both spinal LTP and the upregulation of P2X(4) receptors. The results suggested that ATP may activate p38 MAPK by binding to intrinsic P2X(4) receptors in microglia, and subsequently enhance the expression of P2X(4) receptors, contributing to spinal LTP.
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The Group I metabotropic glutamate receptor 5 (mGluR5) can modulate addiction, pain, and neuronal cell death. Expression of some mGluRs, such as Group II and III mGluRs, has been reported in microglia and may affect their activation. However, the expression and role of mGluR5 in microglia is unclear. ⋯ The anti-inflammatory effects of CHPG are not observed in microglial cultures from mGluR5 knockout mice and are blocked by selective mGluR5 antagonists, suggesting that these actions are mediated by the mGluR5 receptor. Anti-inflammatory actions of mGluR5 activation are attenuated by phospholipase C and protein kinase C inhibitors, as well as by calcium chelators, suggesting that the mGluR5 activation in microglia involves the G(alphaq)-protein signal transduction pathway. These data indicate that microglial mGluR5 may represent a novel target for modulating neuroinflammation, an important component of both acute and chronic neurodegenerative disorders.
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Microglial phagocytosis contributes to the maintenance of brain homeostasis. Mechanisms involved, however, remain unclear. Using Abeta(42) solely as a stimulant, we provide novel insight into regulation of microglial phagocytosis by rafts. ⋯ This resulted in aberrant receptor recruitment to rafts and impaired receptor-mediated phagocytosis by microglial cells. Specifically, recruitment of the scavenger receptor CD36 to rafts during active phagocytosis was affected. Thus, we propose that maintaining raft integrity is crucial for determining microglial phagocytic outcomes and disease progression.