Glia
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Spinal cord injury (SCI) involves the loss of neurons and glia due to initial mechanical and secondary biochemical mechanisms. Treatment with the sodium channel blocker tetrodotoxin (TTX) reduces acute white matter pathology and increases both axon density and hindlimb function chronically at 6 weeks after injury. We investigated the cellular composition of residual white matter chronically to determine whether TTX also has a significant effect on the numbers and types of cells present. ⋯ Our results support the hypothesis that the beneficial effect of TTX in SCI is related to its preservation of axons per se; no effect on chronic white matter cell composition was detected. They highlight the profound changes in cellular composition in preserved white matter chronically at 6 weeks after injury, including the accumulation of endogenous progenitor cells and the persistence of activated macrophages/microglia. The manipulation of these endogenous cells may be used in the future to enhance recovery after SCI.
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Glutamate transporter proteins are essential for the control of interstitial glutamate levels, with an impairment of their function or levels being a major potential contributor to excitotoxicity. We have investigated the effects of lateral fluid percussion on the levels of the glutamate transporter proteins GLT-1alpha, its splice variant GLT-1v, GLAST, and EAAC1 in the rat in order to evaluate their pathogenetic role in this model of traumatic brain injury (TBI). Immunoblot analysis revealed neuronal loss in the cerebral cortex was accompanied by a 54% decrease in GLT-1v 6 h following the insult which progressed to an 83% loss of the transporter after 24 h. ⋯ These alterations in transporter protein content were also confirmed using immunohistochemical methods. Our results show for the first time a pattern of early, dynamic changes in the levels of GLT-1 transporter splice variants in different brain regions in this trauma model. In addition, correlation of GLT-1v levels with both neuronal cell loss and alpha-internexin content in the injured cortex suggests that loss of this novel glutamate transporter may be a key factor in determining cerebral vulnerability following this type of brain injury.
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Immunosuppressant FK506 is neuroprotective in experimental models of cerebral ischemia, but the molecular mechanisms underlying this neuroprotection remain unknown. We have demonstrated that FK506 inhibits the signaling pathways that regulate hypertrophic/proliferative responses in cultured astrocytes. Ischemia/reperfusion injury is associated with the proliferation and hypertrophy of astrocytes and with inflammatory responses. ⋯ FK506 selectively decreased the levels of TNF-alpha, and IL-1beta mRNAs in astrocytes in vitro, with no effect on transforming growth factor-beta 1 (TGF-beta1) and IL-6 expression. Moreover, FK506 inhibits lipopolysaccharide (LPS)-induced activation and cytokine expression in microglia in vitro. Our findings suggest that astrocytes and microglia are targets for FK506, and that modulation of glial response and inflammation may be a mechanism of FK506-mediated neuroprotection in ischemia.
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Severe neurological symptoms, cerebral edema, and atrophy are common features of the inherited metabolic disorder maple syrup urine disease (MSUD). However, the pathomechanisms involved in the neuropathology of this disease are not well established. In this study, we investigated the effects of the branched-chain keto acids (BCKA) alpha-ketoisocaproic (KIC), alpha-ketoisovaleric (KIV), and alpha-keto-beta-methylvaleric (KMV), which accumulate in MSUD, on astrocyte morphology and cytoskeleton reorganization. ⋯ Furthermore, the effects of BCKA on astrocyte morphology were prevented by creatine. In addition, creatine kinase activity was inhibited by KIC and KIV; this inhibition was prevented by creatine, indicating that these keto acids compromise brain energy metabolism. Considering that astroglial cells are critical to brain development and functioning, it is conceivable that alterations of the actin network by BCKA may have important implications in astrocytic function and possibly in the pathogenesis of the neurological dysfunction and brain damage of MSUD patients.
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Accumulating evidence has demonstrated the existence of bidirectional communication between glial cells and neurons, indicating an important active role of glia in the physiology of the nervous system. Neurotransmitters released by presynaptic terminals during synaptic activity increase intracellular Ca(2+) concentration in adjacent glial cells. ⋯ As a consequence of this evidence, a new concept of the synaptic physiology, the tripartite synapse, has been proposed, in which glial cells play an active role as dynamic regulatory elements in neurotransmission. In the present article we review evidence showing the ability of astrocytes to modulate synaptic transmission directly, with the focus on studies performed on cell culture preparations, which have been proved extremely useful in the characterization of molecular and cellular processes involved in astrocyte-mediated neuromodulation.