Glia
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Conventional studies of brain changes in normal aging have concentrated on gray matter as the locus for cognitive dysfunction. However, there is accumulating evidence from studies of normal aging in the rhesus monkey that changes in white matter may be a more critical factor in cognitive decline. Such changes include ultrastructural and biochemical evidence of myelin breakdown with age, as well as more recent magnetic resonance imaging of global loss of forebrain white matter volume and magnetic resonance diffusion tension imaging evidence of increased diffusivity in white matter. ⋯ Of particular interest was the identification of Klotho, a multifunctional protein that regulates phosphate and calcium metabolism, as well as insulin resistance, and is known to defend against oxidative stress and apoptosis. Combining the findings from the microarray study enabled us to formulate a model of white matter aging where specific genes are suggested as primary factors in disrupting white matter function. In conclusion, the overall changes described in this study could provide an explanation for aging changes in white matter that might be initiated or enhanced by an altered expression of life span associated genes such as Klotho.
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Neuropathic pain, a debilitating chronic pain following nerve damage, is a reflection of the aberrant functioning of a pathologically altered nervous system. One hallmark is abnormal pain hypersensitivity to innocuous stimuli (tactile allodynia), for which effective therapy is lacking, and the underlying mechanisms of which remain to be determined. Here we show that Lyn, a member of the Src family kinases (SFKs), plays an important role in the pathogenesis of neuropathic pain. ⋯ Importantly, lyn(-/-) mice displayed impaired upregulation of the ionotropic ATP receptor subtype P2X(4) receptors (P2X(4)R) in the spinal cord after nerve injury, which is crucial for tactile allodynia. Microglial cells from lyn(-/-) mice showed a deficit in their ability to increase P2X(4)R expression in response to fibronectin, a factor implicated as a microglial P2X(4)R upregulator in allodynia. Together, our findings suggest that Lyn may be a critical kinase mediating nerve injury-induced P2X(4)R upregulation and neuropathic pain.
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Astrogliosis and microglial activation are a common feature during prion diseases, causing the release of chemoattractant and proinflammatory factors as well as reactive free radicals, involved in neuronal degeneration. The recombinant protease-resistant domain of the prion protein (PrP90-231) displays in vitro neurotoxic properties when refolded in a beta-sheet-rich conformer. Here, we report that PrP90-231 induces the secretion of several cytokines, chemokines, and nitric oxide (NO) release, in both type I astrocytes and microglial cells. ⋯ In summary, we demonstrate that glial cells are activated by extracellular misfolded PrP90-231 resulting in a proliferative/secretive response of astrocytes and functional activation of microglia, both dependent on MAP kinase activation. In particular, in microglia, PrP90-231 activated a complex signalling cascade involved in the regulation of NO and chemokine release. These data argue in favor of a causal role for misfolded prion protein in sustaining glial activation and, possibly, glia-mediated neuronal death.
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Nitric oxide induces apoptosis-like cell death in cultured astrocytes, but the exact mechanism is not known. This study further characterized the mechanism of nitric oxide-induced cytotoxicity, and examined the effect of edaravone, a radical scavenger, on cytotoxicity. Treatment of cultured rat astrocytes with sodium nitroprusside (SNP), a nitric oxide donor, for 72 h, decreased cell viability by causing apoptosis-like cell death. ⋯ Edaravone (10 microM) protected astrocytes against SNP-induced cell injury and it inhibited SNP-induced phosphorylation of p38 MAP kinase, JNK, and ERK, and the production of reactive oxygen species. Edaravone also attenuated SNP-induced increase in nuclear apoptosis-inducing factor levels. These results suggest that MAP kinase pathways play a key role in nitric oxide-induced apoptosis and that edaravone protects against nitric oxide-induced cytotoxicity by inhibiting nitric oxide-induced MAP kinase activation in astrocytes.
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Astrocytes play a critical role in the regulation of brain metabolic responses to activity. One detailed mechanism proposed to describe the role of astrocytes in some of these responses has come to be known as the astrocyte-neuron lactate shuttle hypothesis (ANLSH). Although controversial, the original concept of a coupling mechanism between neuronal activity and glucose utilization that involves an activation of aerobic glycolysis in astrocytes and lactate consumption by neurons provides a heuristically valid framework for experimental studies. ⋯ Aspects revisited include the existence of glutamate-induced glycolysis in astrocytes in vitro, ex vivo, and in vivo, lactate as a preferential oxidative substrate for neurons, and the notion of net lactate transfer between astrocytes and neurons in vivo. Inclusion of a role for glycogen in the ANLSH is discussed in the light of a possible extension of the astrocyte-neuron lactate shuttle (ANLS) concept rather than as a competing hypothesis. New perspectives offered by the application of this concept include a better understanding of the basis of signals used in functional brain imaging, a role for neuron-glia metabolic interactions in glucose sensing and diabetes, as well as novel strategies to develop therapies against neurodegenerative diseases based upon improving astrocyte-neuron coupled energetics.