2018 |
Herrera-Marschitz, M; Perez-Lobos, R; Lespay-Rebolledo, C; Tapia-Bustos, A; Casanova-Ortiz, E; Morales, P; Valdes, J L; Bustamante, D; Cassels, B K Targeting Sentinel Proteins and Extrasynaptic Glutamate Receptors: A Therapeutic Strategy for Preventing the Effects Elicited by Perinatal Asphyxia? Artículo de revista Neurotoxicity Research, 33 (2), pp. 461-473, 2018, ISSN: 1029-8428. Resumen | Enlaces | BibTeX | Etiquetas: basal brain-damage, cell cell-death, cultures, death, delayed encephalopathy encephalopathy, factor-i, ganglia, gfap, hypoxia, hypoxic hypoxic-ischemic inducible ischaemic leukomalacia, map-2, memantine, n-acetylcysteine neonatal niacinamide, nitric-oxide nmda nnos, organotypic oxidative rat rat, receptors, stress, substantia-nigra, synthase, tunel @article{RN385, title = {Targeting Sentinel Proteins and Extrasynaptic Glutamate Receptors: A Therapeutic Strategy for Preventing the Effects Elicited by Perinatal Asphyxia?}, author = { M. Herrera-Marschitz and R. Perez-Lobos and C. Lespay-Rebolledo and A. Tapia-Bustos and E. Casanova-Ortiz and P. Morales and J.L. Valdes and D. Bustamante and B.K. Cassels}, url = {/brokenurl#<Go to ISI>://WOS:000422640700020}, doi = {10.1007/s12640-017-9795-9}, issn = {1029-8428}, year = {2018}, date = {2018-01-01}, journal = {Neurotoxicity Research}, volume = {33}, number = {2}, pages = {461-473}, abstract = {Perinatal asphyxia (PA) is a relevant cause of death at the time of labour, and when survival is stabilised, associated with short- and long-term developmental disabilities, requiring inordinate care by health systems and families. Its prevalence is high (1 to 10/1000 live births) worldwide. At present, there are few therapeutic options, apart from hypothermia, that regrettably provides only limited protection if applied shortly after the insult., PA implies a primary and a secondary insult. The primary insult relates to the lack of oxygen, and the secondary one to the oxidative stress triggered by re-oxygenation, formation of reactive oxygen (ROS) and reactive nitrogen (RNS) species, and overactivation of glutamate receptors and mitochondrial deficiencies. PA induces overactivation of a number of sentinel proteins, including hypoxia-induced factor-1 alpha (HIF-1 alpha) and the genome-protecting poly(ADP-ribose) polymerase-1 (PARP-1). Upon activation, PARP-1 consumes high amounts of ATP at a time when this metabolite is scarce, worsening in turn the energy crisis elicited by asphyxia. The energy crisis also impairs ATP-dependent transport, including glutamate re-uptake by astroglia. Nicotinamide, a PARP-1 inhibitor, protects against the metabolic cascade elicited by the primary stage, avoiding NAD(+) exhaustion and the energetic crisis. Upon re-oxygenation, however, oxidative stress leads to nuclear translocation of the NF-kappa B subunit p65, overexpression of the pro-inflammatory cytokines IL-1 beta and TNF-alpha, and glutamate-excitotoxicity, due to impairment of glial-glutamate transport, extracellular glutamate overflow, and overactivation of NMDA receptors, mainly of the extrasynaptic type. This leads to calcium influx, mitochondrial impairment, and inactivation of antioxidant enzymes, increasing further the activity of pro-oxidant enzymes, thereby making the surviving neonate vulnerable to recurrent metabolic insults whenever oxidative stress is involved. Here, we discuss evidence showing that (i) inhibition of PARP-1 overactivation by nicotinamide and (ii) inhibition of extrasynaptic NMDA receptor overactivation by memantine can prevent the short- and long-term consequences of PA. These hypotheses have been evaluated in a rat preclinical model of PA, aiming to identify the metabolic cascades responsible for the long-term consequences induced by the insult, also assessing postnatal vulnerability to recurrent oxidative insults. Thus, we present and discuss evidence demonstrating that PA induces long-term changes in metabolic pathways related to energy and oxidative stress, priming vulnerability of cells with both the neuronal and the glial phenotype. The effects induced by PA are region dependent, the substantia nigra being particularly prone to cell death. The issue of short- and long-term consequences of PA provides a framework for addressing a fundamental issue referred to plasticity of the CNS, since the perinatal insult triggers a domino-like sequence of events making the developing individual vulnerable to recurrent adverse conditions, decreasing his/her coping repertoire because of a relevant insult occurring at birth.}, keywords = {basal brain-damage, cell cell-death, cultures, death, delayed encephalopathy encephalopathy, factor-i, ganglia, gfap, hypoxia, hypoxic hypoxic-ischemic inducible ischaemic leukomalacia, map-2, memantine, n-acetylcysteine neonatal niacinamide, nitric-oxide nmda nnos, organotypic oxidative rat rat, receptors, stress, substantia-nigra, synthase, tunel}, pubstate = {published}, tppubtype = {article} } Perinatal asphyxia (PA) is a relevant cause of death at the time of labour, and when survival is stabilised, associated with short- and long-term developmental disabilities, requiring inordinate care by health systems and families. Its prevalence is high (1 to 10/1000 live births) worldwide. At present, there are few therapeutic options, apart from hypothermia, that regrettably provides only limited protection if applied shortly after the insult., PA implies a primary and a secondary insult. The primary insult relates to the lack of oxygen, and the secondary one to the oxidative stress triggered by re-oxygenation, formation of reactive oxygen (ROS) and reactive nitrogen (RNS) species, and overactivation of glutamate receptors and mitochondrial deficiencies. PA induces overactivation of a number of sentinel proteins, including hypoxia-induced factor-1 alpha (HIF-1 alpha) and the genome-protecting poly(ADP-ribose) polymerase-1 (PARP-1). Upon activation, PARP-1 consumes high amounts of ATP at a time when this metabolite is scarce, worsening in turn the energy crisis elicited by asphyxia. The energy crisis also impairs ATP-dependent transport, including glutamate re-uptake by astroglia. Nicotinamide, a PARP-1 inhibitor, protects against the metabolic cascade elicited by the primary stage, avoiding NAD(+) exhaustion and the energetic crisis. Upon re-oxygenation, however, oxidative stress leads to nuclear translocation of the NF-kappa B subunit p65, overexpression of the pro-inflammatory cytokines IL-1 beta and TNF-alpha, and glutamate-excitotoxicity, due to impairment of glial-glutamate transport, extracellular glutamate overflow, and overactivation of NMDA receptors, mainly of the extrasynaptic type. This leads to calcium influx, mitochondrial impairment, and inactivation of antioxidant enzymes, increasing further the activity of pro-oxidant enzymes, thereby making the surviving neonate vulnerable to recurrent metabolic insults whenever oxidative stress is involved. Here, we discuss evidence showing that (i) inhibition of PARP-1 overactivation by nicotinamide and (ii) inhibition of extrasynaptic NMDA receptor overactivation by memantine can prevent the short- and long-term consequences of PA. These hypotheses have been evaluated in a rat preclinical model of PA, aiming to identify the metabolic cascades responsible for the long-term consequences induced by the insult, also assessing postnatal vulnerability to recurrent oxidative insults. Thus, we present and discuss evidence demonstrating that PA induces long-term changes in metabolic pathways related to energy and oxidative stress, priming vulnerability of cells with both the neuronal and the glial phenotype. The effects induced by PA are region dependent, the substantia nigra being particularly prone to cell death. The issue of short- and long-term consequences of PA provides a framework for addressing a fundamental issue referred to plasticity of the CNS, since the perinatal insult triggers a domino-like sequence of events making the developing individual vulnerable to recurrent adverse conditions, decreasing his/her coping repertoire because of a relevant insult occurring at birth. |
2015 |
Mena, N P; Garcia-Beltran, O; Lourido, F; Urrutia, P J; Mena, R; Castro-Castillo, V; Cassels, B K; Nunez, M The Novel Mitochondrial Iron Chelator 5-((Methylamino)Methyl)-8-Hydroxyquinoline Protects against Mitochondrial-Induced Oxidative Damage and Neuronal Death Artículo de revista Biochemical and Biophysical Research Communications, 463 (4), pp. 787-792, 2015, ISSN: 0006-291x. Resumen | Enlaces | BibTeX | Etiquetas: brain chelation, contributes, degeneration, disease, diseases, homeostasis, hydroxyquinolines, in-vivo, inhibition iron iron, mitochondria, neurodegenerative parkinson's parkinsons-disease, substantia-nigra @article{RN243, title = {The Novel Mitochondrial Iron Chelator 5-((Methylamino)Methyl)-8-Hydroxyquinoline Protects against Mitochondrial-Induced Oxidative Damage and Neuronal Death}, author = { N.P. Mena and O. Garcia-Beltran and F. Lourido and P.J. Urrutia and R. Mena and V. Castro-Castillo and B.K. Cassels and M. Nunez}, url = {/brokenurl#<Go to ISI>://WOS:000358455300051}, doi = {10.1016/j.bbrc.2015.06.014}, issn = {0006-291x}, year = {2015}, date = {2015-01-01}, journal = {Biochemical and Biophysical Research Communications}, volume = {463}, number = {4}, pages = {787-792}, publisher = {2015 Elsevier Inc.}, abstract = {Abundant evidence indicates that iron accumulation, oxidative damage and mitochondrial dysfunction are common features of Huntington's disease, Parkinson's disease, Friedreich's ataxia and a group of disorders known as Neurodegeneration with Brain Iron Accumulation. In this study, we evaluated the effectiveness of two novel 8-OH-quinoline-based iron chelators, Q1 and Q4, to decrease mitochondrial iron accumulation and oxidative damage in cellular and animal models of PD. We found that at sub-micromolar concentrations, Q1 selectively decreased the mitochondrial iron pool and was extremely effective in protecting against rotenone-induced oxidative damage and death. Q4, in turn, preferentially chelated the cytoplasmic iron pool and presented a decreased capacity to protect against rotenone-induced oxidative damage and death. Oral administration of Q1 to mice protected substantia nigra pars compacta neurons against oxidative damage and MPTP-induced death. Taken together, our results support the concept that oral administration of Q1 is a promising therapeutic strategy for the treatment of NBIA.}, keywords = {brain chelation, contributes, degeneration, disease, diseases, homeostasis, hydroxyquinolines, in-vivo, inhibition iron iron, mitochondria, neurodegenerative parkinson's parkinsons-disease, substantia-nigra}, pubstate = {published}, tppubtype = {article} } Abundant evidence indicates that iron accumulation, oxidative damage and mitochondrial dysfunction are common features of Huntington's disease, Parkinson's disease, Friedreich's ataxia and a group of disorders known as Neurodegeneration with Brain Iron Accumulation. In this study, we evaluated the effectiveness of two novel 8-OH-quinoline-based iron chelators, Q1 and Q4, to decrease mitochondrial iron accumulation and oxidative damage in cellular and animal models of PD. We found that at sub-micromolar concentrations, Q1 selectively decreased the mitochondrial iron pool and was extremely effective in protecting against rotenone-induced oxidative damage and death. Q4, in turn, preferentially chelated the cytoplasmic iron pool and presented a decreased capacity to protect against rotenone-induced oxidative damage and death. Oral administration of Q1 to mice protected substantia nigra pars compacta neurons against oxidative damage and MPTP-induced death. Taken together, our results support the concept that oral administration of Q1 is a promising therapeutic strategy for the treatment of NBIA. |
2018 |
Targeting Sentinel Proteins and Extrasynaptic Glutamate Receptors: A Therapeutic Strategy for Preventing the Effects Elicited by Perinatal Asphyxia? Artículo de revista Neurotoxicity Research, 33 (2), pp. 461-473, 2018, ISSN: 1029-8428. |
2015 |
The Novel Mitochondrial Iron Chelator 5-((Methylamino)Methyl)-8-Hydroxyquinoline Protects against Mitochondrial-Induced Oxidative Damage and Neuronal Death Artículo de revista Biochemical and Biophysical Research Communications, 463 (4), pp. 787-792, 2015, ISSN: 0006-291x. |