carlos matute - Academia.edu (original) (raw)

Papers by carlos matute

Journal of Neuroscience, 2007

Oligodendrocyte death and demyelination are hallmarks of multiple sclerosis (MS). Here we show th... more Oligodendrocyte death and demyelination are hallmarks of multiple sclerosis (MS). Here we show that ATP signaling can trigger oligodendrocyte excitotoxicity via activation of calcium-permeable P2X 7 purinergic receptors expressed by these cells. Sustained activation of P2X 7 receptors in vivo causes lesions that are reminiscent of the major features of MS plaques, i.e., demyelination, oligodendrocyte death, and axonal damage. In addition, treatment with P2X 7 antagonists of chronic experimental autoimmune encephalomyelitis (EAE), a model of MS, reduces demyelination and ameliorates the associated neurological symptoms. Together, these results indicate that ATP can kill oligodendrocytes via P2X 7 activation and that this cell death process contributes to EAE. Importantly, P2X 7 expression is elevated in normal-appearing axon tracts in MS patients, suggesting that signaling through this receptor in oligodendrocytes may be enhanced in this disease. Thus, P2X 7 receptor antagonists may be beneficial for the treatment of MS.

Neurobiology of Disease, 2006

Brain ischemia induces neuronal loss which is caused in part by excitotoxicity and free radical f... more Brain ischemia induces neuronal loss which is caused in part by excitotoxicity and free radical formation. Here, we report that mangiferin and morin, two antioxidant polyphenols, are neuroprotective in both in vitro and in vivo models of ischemia. Cell death caused by glutamate in neuronal cultures was decreased in the presence of submicromolar concentrations of mangiferin or morin which in turn attenuated receptor-mediated calcium influx, oxidative stress as well as apoptosis. In addition, both antioxidants diminished the generation of free radicals and neuronal loss in the hippocampal CA1 region due to transient forebrain ischemia in rats when administered after the insult. Importantly, neuroprotection by these antioxidants was functionally relevant since treated-ischemic rats performed significantly better in three hippocampal-dependent behavioral tests. Together, these results indicate that mangiferin and morin have potent neuroprotectant activity which may be of therapeutic value for the treatment of acute neuronal damage and disability. D

Trends in Pharmacological Sciences, 2004

Glia, 2005

Glutamate uptake is crucial to terminate glutamate signaling and to prevent excitotoxicity. The p... more Glutamate uptake is crucial to terminate glutamate signaling and to prevent excitotoxicity. The present study describes the expression of functional glutamate transporters GLAST and GLT-1 in oligodendrocytes by means of electrophysiology, uptake assays, and immunocytochemistry. Inhibition of glutamate uptake, both in oligodendrocyte cultures and in isolated optic nerves, increases glutamate levels and causes oligodendrocyte excitotoxicity, which is prevented by alpha-amino-3-hydroxy-5-methylisoxazole-4propionic acid (AMPA) and kainate receptor antagonists. Furthermore, glutamate transporter inhibitors or antisense oligonucleotides applied onto the optic nerve in vivo lead to oligodendroglial loss, massive demyelination, and severe axonal damage. Overall, these results demonstrate that the integrity of oligodendrocytes and white matter depends on proper glutamate transporter function. Deregulated transporter activity may contribute to acute and chronic white matter damage.

Trends in Neurosciences, 2001

Proceedings of The National Academy of Sciences, 1993

The presence of mRNAs encoding neurotransmitter receptors and voltage-gated channels in the adult... more The presence of mRNAs encoding neurotransmitter receptors and voltage-gated channels in the adult human and bovine corpus caflosum was investigated using Xenopus oocytes. Oocytes injected with mRNA extracted from the corpus callosum expressed functional receptors to glutamate, acetylcholine, and serotonin, and also voltage-operated Ca2+ channels, all with similar properties in the two species studied. Acetylcholine and serotonin elicited oscillatory Cl1 currents due to activation of the inositol phosphate-Ca2+ receptor-channel coupling system. Glutamate and its analogs N-methyl-D-aspartate (NMDA), kainate, quisqualate, and a-amino-3 -hydroxy-5 -methyl-4-isoxazolepropionic acid (AMPA) induced smooth currents. The non-NMDA responses showed a strong inward rectification at positive potentials and were potently blocked by 6,7-dinitroquinoxaline-2,3-dione, as observed for the AMPA/kainate glutamate receptors GLUR1 and GLUR3. Furthermore, in situ hybridization experiments showed that GLUR1 and GLUR3 mRNAs are present in corpus

Neurobiology of Disease, 2002

Oligodendrocytes are vulnerable to excitotoxic insults mediated by AMPA receptors and by low and ... more Oligodendrocytes are vulnerable to excitotoxic insults mediated by AMPA receptors and by low and high affinity kainate receptors, a feature that is dependent on Ca 2؉ influx. In the current study, we have analyzed the intracellular concentration of calcium [Ca 2؉ ] i as well as the entry routes of this cation, upon activation of these receptors. Selective activation of either receptor type resulted in a substantial increase (up to fivefold) of [Ca 2؉ ] i , an effect which was totally abolished by the non-NMDA receptor antagonist CNQX or by removing Ca 2؉ from the culture medium. Blockade of voltage-gated Ca 2؉ channels with La 3؉ or nifedipine, reduced the amplitude of the Ca 2؉ current triggered by AMPA receptor activation by ϳ65%, but not that initiated by low and high affinity kainate receptors. In contrast, KB-R7943, an inhibitor of the plasma membrane Na ؉ -Ca 2؉ exchanger, solely attenuated the rise in [Ca 2؉ ] i by ϳ25% due to activation of low affinity kainate receptors. However, oligodendroglial death by glutamate receptor overactivation was largely unaffected in the presence of La 3؉ or KB-R7943. These findings indicate that Ca 2؉ influx via AMPA and kainate receptors alone is sufficient to initiate cell death in oligodendrocytes, which does not require the entry of calcium via other routes such as voltage-activated calcium channels or the plasma membrane Na ؉ -Ca 2؉ exchanger.

Proceedings of The National Academy of Sciences, 1997

In cultured oligodendrocytes isolated from perinatal rat optic nerves, we have analyzed the expre... more In cultured oligodendrocytes isolated from perinatal rat optic nerves, we have analyzed the expression of ionotropic glutamate receptor subunits as well as the effect of the activation of these receptors on oligodendrocyte viability. Reverse transcription-PCR, in combination with immunocytochemistry, demonstrated that most oligodendrocytes differentiated in vitro express the ␣-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptor subunits GluR3 and GluR4 and the kainate receptor subunits GluR6, GluR7, KA1 and KA2. Acute and chronic exposure to kainate caused extensive oligodendrocyte death in culture. This effect was partially prevented by the AMPA receptor antagonist GYKI 52466 and was completely abolished by the non-N-methyl-Daspartate receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), suggesting that both AMPA and kainate receptors mediate the observed kainate toxicity. Furthermore, chronic application of kainate to optic nerves in vivo resulted in massive oligodendrocyte death which, as in vitro, could be prevented by coinfusion of the toxin with CNQX. These findings suggest that excessive activation of the ionotropic glutamate receptors expressed by oligodendrocytes may act as a negative regulator of the size of this cell population.

Proceedings of The National Academy of Sciences, 1990

Blood sera from many vertebrate species elicit large oscillatory chloride currents in oocytes fro... more Blood sera from many vertebrate species elicit large oscillatory chloride currents in oocytes from the frog Xenopus laevis. Rabbit serum was active at dilutions as great as one part in 10 million. Intracellularly applied serum was ineffective, and externally applied serum failed to trigger oscillatory currents when the intracellular level of ionized calcium was prevented from rising by loading the oocyte with EGTA. The serum also caused an increase of inositol 1,4,5trisphosphate in the oocyte. We conclude that serum contains a factor which activates a membrane receptor that is coupled to the phosphatidylinositol second messenger system. The active factor is a protein with an apparent molecular mass of 60-70 kDa in gel permeation chromatography. Although the normal function of the serum factor is still unknown, it may have far-reaching implications, because it acts on the multifunctional phosphatidylinositol phosphate signaling system.