“…Indeed, it has been suggested that PCr levels constitute a dynamic metabolic pool that can facilitate transfer of high energy phosphate equivalents from sites of ATP production at mitochondria to remotes sites of ATP utilization, functioning as a ‘phosphocreatine shuttle’ (Friedman and Roberts 1994). It is unlikely that changes in PCr levels observed in the studies discussed reflect a pH-dependent shift in the creatine kinase equilibrium, as suggested by Marini and Nowak (2000), since significant changes in pH were already observed after 6 min of asphyxia, decreasing in parallel in peripheral and brain tissue (Engidawork et al 2001). Fig.…”
Section: Short-term Effects Produced By Perinatal Asphyxiamentioning
Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD+ tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care.
“…Indeed, it has been suggested that PCr levels constitute a dynamic metabolic pool that can facilitate transfer of high energy phosphate equivalents from sites of ATP production at mitochondria to remotes sites of ATP utilization, functioning as a ‘phosphocreatine shuttle’ (Friedman and Roberts 1994). It is unlikely that changes in PCr levels observed in the studies discussed reflect a pH-dependent shift in the creatine kinase equilibrium, as suggested by Marini and Nowak (2000), since significant changes in pH were already observed after 6 min of asphyxia, decreasing in parallel in peripheral and brain tissue (Engidawork et al 2001). Fig.…”
Section: Short-term Effects Produced By Perinatal Asphyxiamentioning
Delivery is a stressful and risky event menacing the newborn. The mother-dependent respiration has to be replaced by autonomous pulmonary breathing immediately after delivery. If delayed, it may lead to deficient oxygen supply compromising survival and development of the central nervous system. Lack of oxygen availability gives rise to depletion of NAD+ tissue stores, decrease of ATP formation, weakening of the electron transport pump and anaerobic metabolism and acidosis, leading necessarily to death if oxygenation is not promptly re-established. Re-oxygenation triggers a cascade of compensatory biochemical events to restore function, which may be accompanied by improper homeostasis and oxidative stress. Consequences may be incomplete recovery, or excess reactions that worsen the biological outcome by disturbed metabolism and/or imbalance produced by over-expression of alternative metabolic pathways. Perinatal asphyxia has been associated with severe neurological and psychiatric sequelae with delayed clinical onset. No specific treatments have yet been established. In the clinical setting, after resuscitation of an infant with birth asphyxia, the emphasis is on supportive therapy. Several interventions have been proposed to attenuate secondary neuronal injuries elicited by asphyxia, including hypothermia. Although promising, the clinical efficacy of hypothermia has not been fully demonstrated. It is evident that new approaches are warranted. The purpose of this review is to discuss the concept of sentinel proteins as targets for neuroprotection. Several sentinel proteins have been described to protect the integrity of the genome (e.g. PARP-1; XRCC1; DNA ligase IIIα; DNA polymerase β, ERCC2, DNA-dependent protein kinases). They act by eliciting metabolic cascades leading to (i) activation of cell survival and neurotrophic pathways; (ii) early and delayed programmed cell death, and (iii) promotion of cell proliferation, differentiation, neuritogenesis and synaptogenesis. It is proposed that sentinel proteins can be used as markers for characterising long-term effects of perinatal asphyxia, and as targets for novel therapeutic development and innovative strategies for neonatal care.
“…Mechanisms proposed for cytosolic acidification include: dysregulation of ion transport [42]; proton leakage from acidic organelles [43]; and hydrolysis of high energy nucleotides [44]. Notably, the PD toxin 1-methyl-4-phenylpyridinium (MPP + ) impairs cellular energy metabolism and leads to a decrease in pHi [45].…”
Section: Oxidative and Metabolic Stresses Induce Cytosolic Acidificationmentioning
Mitochondrial dysfunction plays a central role in the selective vulnerability of dopaminergic neurons in Parkinson's disease (PD) and is influenced by both environmental and genetic factors. Expression of the PD protein α-synuclein or its familial mutants often sensitizes neurons to oxidative stress and to damage by mitochondrial toxins. This effect is thought to be indirect, since little evidence physically linking α-synuclein to mitochondria has been reported. Here, we show that the distribution of α-synuclein within neuronal and non-neuronal cells is dependent on intracellular pH. Cytosolic acidification induces translocation of α-synuclein from the cytosol onto the surface of mitochondria. Translocation occurs rapidly under artificially-induced low pH conditions and as a result of pH changes during oxidative or metabolic stress. Binding is likely facilitated by low pH-induced exposure of the mitochondria-specific lipid cardiolipin. These results imply a direct role for α-synuclein in mitochondrial physiology, especially under pathological conditions, and in principle, link α-synuclein to other PD genes in regulating mitochondrial homeostasis.
“…It has previously been observed that MPP+ induced cell death in vitro results from low pH due to lactic acid production and rapid depletion of glucose in the media due to increased dependence on anaerobic respiration to compensate for Complex I inhibition in the mitochondria. 57,58 ROS production and inability to maintain ATP levels were determined to be unlikely causes for immediate cell death in both primary neurons and astrocytes. 57,58 Thus, it is reasonable to expect higher cell seeding density to correspond to increased LUHMES cell death in the presence of MPP+.…”
Section: Discussionmentioning
confidence: 99%
“…57,58 ROS production and inability to maintain ATP levels were determined to be unlikely causes for immediate cell death in both primary neurons and astrocytes. 57,58 Thus, it is reasonable to expect higher cell seeding density to correspond to increased LUHMES cell death in the presence of MPP+. Increased numbers of MPP+ treated cells would result in more rapid depletion of resources and acidification of the media.…”
SH‐SY5Y and LUHMES cell lines are widely used as model systems for studying neurotoxicity. Most of the existing data regarding the sensitivity of these cell lines to neurotoxicants have been recorded from cells growing as two‐dimensional (2D) cultures on the surface of glass or plastic. With the emergence of 3D culture platforms designed to better represent native tissue, there is a growing need to compare the toxicology of neurons grown in 3D environments to those grown in 2D to better understand the impact that culture environment has on toxicant sensitivity. Here, a simple 3D culture method was used to assess the impact of growth environment on the sensitivity of SH‐SY5Y cells and LUHMES cells to MPP+, tunicamycin, and epoxomicin, three neurotoxicants that have been previously used to generate experimental models for studying Parkinson's disease pathogenesis. SH‐SY5Y cell viability following treatment with these three toxicants was significantly lower in 2D cultures as compared to 3D cultures. On the contrary, LUHMES cells did not show significant differences between growth conditions for any of the toxicants examined. However, LUHMES cells were more sensitive to MPP+, tunicamycin, and epoxomicin than SH‐SY5Y cells. Thus, both the choice of cell line and the choice of growth environment must be considered when interpreting in vitro neurotoxicity data.
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