Publications (26) View all
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Article: Cyclophilin D as a potential target for antioxidants in neurodegeneration: the X-ALD case.
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ABSTRACT: Abstract X-linked adrenoleukodystrophy (X-ALD) is a severe inherited neurodegenerative disorder characterized by adrenal insufficiency and graded damage in the nervous system. Loss of function of the peroxisomal ABCD1 fatty-acid transporter, resulting in the accumulation in organs and plasma of very long-chain fatty acids, is the genetic cause. Treatment with a combination of antioxidants halts the axonal degeneration and locomotor impairment displayed by the animal model of X-ALD, as a proof of concept that oxidative stress, contributes to axonal damage. New evidence demonstrates that metabolic failure and the opening of the mitochondrial permeability transition pore orchestrated by cyclophilin D underlies oxidative stress-induced axonal degeneration. Thus, cyclophilin D could serve as a therapeutic target for the treatment of X-ALD and cyclophilin D-dependent neurodegenerative and non-neurodegenerative diseases.Biological Chemistry 03/2013; · 2.96 Impact Factor -
Article: ATP and noradrenaline activate CREB in astrocytes via noncanonical Ca(2+) and cyclic AMP independent pathways.
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ABSTRACT: In neurons, it is well established that CREB contributes to learning and memory by orchestrating the translation of experience into the activity-dependent (i.e., driven by neurotransmitters) transcription of plasticity-related genes. The activity-dependent CREB-triggered transcription requires the concerted action of cyclic AMP/protein kinase A and Ca(2+) /calcineurin via the CREB-regulated transcription co-activator (CRTC). It is not known, however, whether a comparable molecular sequence occurs in astrocytes, despite the unquestionable contribution of these cells to brain plasticity. Here we sought to determine whether and how ATP and noradrenaline cause CREB-dependent transcription in rat cortical astrocyte cultures. Both transmitters induced CREB phosphorylation (Western Blots), CREB-dependent transcription (CRE-luciferase reporter assays), and the transcription of Bdnf, a canonical regulator of synaptic plasticity (quantitative RT-PCR). We indentified a Ca(2+) and diacylglycerol-independent protein kinase C at the uppermost position of the cascade leading to CREB-dependent transcription. Notably, CREB-dependent transcription was partially dependent on ERK1/2 and CRTC, but independent of cyclic AMP/protein kinase A or Ca(2+) /calcineurin. We conclude that ATP and noradrenaline activate CREB-dependent transcription in cortical astrocytes via an atypical protein kinase C. It is of relevance that the signaling involved be starkly different to the one described in neurons since there is no convergence of Ca(2+) and cyclic AMP-dependent pathways on CRTC, which, moreover, exerts a modulatory rather than a central role. Our data thus point to the existence of an alternative, non-neuronal, glia-based role of CREB in plasticity.Glia 05/2012; 60(9):1330-44. · 4.82 Impact Factor -
Article: Increasing CNS Noradrenaline Reduces EAE Severity
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ABSTRACT: The endogenous neurotransmitter noradrenaline (NA) is known to exert potent anti-inflammatory effects in glial cells, as well as provide neuroprotection against excitatory and inflammatory stimuli. These properties raise the possibility that increasing levels of NA in the central nervous system (CNS) could provide benefit in neurological diseases and conditions containing an inflammatory component. In the current study, we tested this possibility by examining the consequences of selectively modulating CNS NA levels on the development of clinical signs in experimental autoimmune encephalomyelitis (EAE). In mice immunized with myelin oligodendrocyte glycoprotein peptide to develop a chronic disease, pretreatment to selectively deplete CNS NA levels exacerbated clinical scores. Elevation of NA levels using the selective NA reuptake inhibitor atomoxetine did not affect clinical scores, while treatment of immunized mice with the synthetic NA precursor l-threo-3,4-dihydroxyphenylserine (l-DOPS) prevented further worsening. In contrast, treatment of mice with a combination of atomoxetine and l-DOPS led to significant improvement in clinical scores as compared to the control group. The combined treatment reduced astrocyte activation in the molecular layer of the cerebellum as assessed by staining for glial fibrillary protein but did not affect Th1 or Th17 type cytokine production from splenic T cells. These data suggest that selective elevation of CNS NA levels could provide benefit in EAE and multiple sclerosis without influencing peripheral immune responses. Keywordsmultiple sclerosis-locus coeruleus-catecholamines-astrocyte-demyelination-antidepressantJournal of Neuroimmune Pharmacology 04/2012; 5(2):252-259. · 4.57 Impact Factor -
Article: Oxidative stress underlying axonal degeneration in adrenoleukodystrophy: A paradigm for multifactorial neurodegenerative diseases?
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ABSTRACT: X-linked adrenoleukodystrophy (X-ALD) is an inherited neurodegenerative disorder expressed as four disease variants characterized by adrenal insufficiency and graded damage in the nervous system. X-ALD is caused by a loss of function of the peroxisomal ABCD1 fatty-acid transporter, resulting in the accumulation of very long chain fatty acids (VLCFA) in the organs and plasma, which have potentially toxic effects in CNS and adrenal glands. We have recently shown that treatment with a combination of antioxidants containing α-tocopherol, N-acetyl-cysteine and α-lipoic acid reversed oxidative damage and energetic failure, together with the axonal degeneration and locomotor impairment displayed by Abcd1 null mice, the animal model of X-ALD. This is the first direct demonstration that oxidative stress, which is a hallmark not only of X-ALD, but also of other neurodegenerative processes, such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD), contributes to axonal damage. The purpose of this review is, first, to discuss the molecular and cellular underpinnings of VLCFA-induced oxidative stress, and how it interacts with energy metabolism and/or inflammation to generate a complex syndrome wherein multiple factors are contributing. Particular attention will be paid to the dysregulation of redox homeostasis by the interplay between peroxisomes and mitochondria. Second, we will extend this analysis to the aforementioned neurodegenerative diseases with the aim of defining differences as well as the existence of a core pathogenic mechanism that would justify the exchange of therapeutic opportunities among these pathologies. This article is part of a Special Issue entitled: Metabolic functions and biogenesis of peroxisomes in health and disease.Biochimica et Biophysica Acta 02/2012; 1822(9):1475-88. · 4.66 Impact Factor -
Article: JNK/ERK/FAK mediate promigratory actions of basic fibroblast growth factor in astrocytes via CCL2 and COX2.
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ABSTRACT: While the role of cytokines in causing pro- and anti-inflammatory cascades in the brain and that of chemokines in promoting chemotaxis is well recognized, the immunomodulatory actions of neurotrophins released during brain injury remains largely undetermined. This knowledge gap affects basic fibroblast growth factor (FGF2), which in the brain is mainly produced by astrocytes and characteristically upregulated in reactive astrocytes. The goal of this study was to characterize the inflammatory actions of FGF2 in astrocytes using primary cultures. We report that FGF2 induced the upregulation of monocyte chemoattractant protein (CCL2) and cyclo-oxygenase type 2 (COX2), and the inhibition of lipopolysaccharide-elicited ICAM1 upregulation. The effects of FGF2 were: (i) dependent on gene transcription as revealed by the concomitant regulation of CCL2 or ICAM1 mRNAs; (ii) mediated by the FGF2 receptor type 2; (iii) dependent on ERK, JNK and FAK, and (iv) NF-κB-independent. FGF2 also caused accelerated wound closure dependent on CCL2, COX2, ERK, JNK and FAK in a scratch assay. We conclude that the signaling network triggered by FGF2 in astrocytes converged into accelerating directed motion. It follows that astrocyte migration to injury sites may be a key factor in the repair mechanisms orchestrated by FGF2.Neurosignals 12/2011; 20(2):86-102. · 2.11 Impact Factor
