Dual-Gene, Dual-Cell Type Therapy against an Excitotoxic Insult by Bolstering Neuroenergetics

Bliss, Tonya; Ip, Miranda; Cheng, Elise; Minami, Masabumi; Pellerin, Luc; Magistretti, Pierre J.; Sapolsky, Robert M.

doi:10.1523/jneurosci.0805-04.2004

Cited by 61 publications

(56 citation statements)

References 56 publications

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“…This implies that the decrease in glutamate-induced glucose uptake and lactate release might affect substrate delivery to neurons during neuronal activation. In this context, it is of interest to note that enhancing lactate ''shuttling'' by either increasing lactate utilization by neurons and/or lactate release by astrocytes increases neuronal resistance to excitotoxicity (Bliss et al, 2004). Stimulation of ROS and RNS production appears also to be potentially neurotoxic, since neurons, in contrast to astrocytes, are extremely sensitive to nitrosative stress and oxidative stress induced by H 2 O 2 in particular (Ben Yoseph et al, 1996;Bolanos et al, 2004;Dringen et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Modulation of astrocytic metabolic phenotype by proinflammatory cytokines

Gavillet

Allaman

Magistretti

2008

Glia

123

118

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Astrocytes play an important role in nervous system homeostasis. In particular, they contribute to the regulation of local energy metabolism and to oxidative stress defence. In previous experiments, we showed that long-term treatment with interleukin 1alpha (IL-1alpha) or tumor necrosis factor-alpha (TNFalpha) alone increases glucose utilization in primary culture of mouse astrocytes. In our study, we report that a combination of IL-1beta and TNFalpha exerts a synergistic effect on glucose utilization and markedly modifies the metabolic phenotype of astrocytes. Thus, IL-1beta+TNFalpha treated astrocytes show a marked decrease in glycogen levels, a slight but not significant decrease in lactate release as well as a massive increase in both the pentose phosphate pathway and TCA cycle activities. Glutamate-stimulated glucose utilization and lactate release, a typical feature of astrocyte energy metabolism, are altered after pretreatment with IL-1beta+TNFalpha. As far as mechanisms for oxidative stress defence are concerned, we observed that treatment with IL-1beta+TNFalpha decreases cellular glutathione content and increases glutathione release into the extracellular space while stimulating superoxide anion and nitric oxide production as well as H(2)O(2) release. Interestingly, stimulation of glucose utilization by IL-1beta+TNFalpha is not affected by the antioxidant N-acetyl-L-cysteine, suggesting that cellular stress does not account for this effect. Finally, the effects of cytokines on glucose utilization appear to involve multiple signaling cascades including the phosphoinositide 3-kinase and mitogen-activated protein kinases. Taken together these results establish that a proinflammatory environment such as observed in several neuropathological conditions including Alzheimer's disease, markedly modifies the metabolic phenotype of astrocytes.

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Section: Discussionmentioning

confidence: 99%

Modulation of astrocytic metabolic phenotype by proinflammatory cytokines

Gavillet

Allaman

Magistretti

2008

Glia

123

118

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“…It may also provide an alternative mechanism to supply mitochondrial NADH under oxidative stress conditions, where ␣-KGDH is selectively inhibited (65). Lactate, and not glucose, is the major neuronal energy substrate after an insult, and overexpression of a lactate transporter in neurons enhances neuronal resistance to excitotoxicity (66), suggesting that the aralar-MAS pathway might also enhance survival to glutamate excitotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Essential Role of Aralar in the Transduction of Small Ca+ Signals to Neuronal Mitochondria

Pardo

Contreras

Serrano

et al. 2006

Journal of Biological Chemistry

105

140

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Aralar, the neuronal Ca2؉ -binding mitochondrial aspartate-glutamate carrier, has Ca 2؉ binding domains facing the extramitochondrial space and functions in the malate-aspartate NADH shuttle (MAS). Here we showed that MAS activity in brain mitochondria is stimulated by extramitochondrial Ca 2؉ with an S 0.5 of 324 nM. By employing primary neuronal cultures from control and aralar-deficient mice and NAD(P)H imaging with two-photon excitation microscopy, we showed that lactate utilization involves a substantial transfer of NAD(P)H to mitochondria in control but not aralardeficient neurons, in agreement with the lack of MAS activity associated with aralar deficiency. The AGCs are one of the transporters responsible for the malateaspartate NADH shuttle (MAS). Because of the electrogenic nature of Asp/Glu exchange (20, 21), the AGC reaction is irreversible under physiological conditions and thus a potential site for regulation. The first aim of this work was to explore the potential of aralar as a brain AGC isoform to regulate MAS activity in brain at low Ca 2ϩ concentrations, below those required for the function of the mitochondrial Ca 2ϩ uniporter. MAS activity in brain mitochondria was found to have Ca 2ϩ -activation properties adequate for this purpose.The second aim of this work was to study the role of the aralar-MAS pathway in the supply of reducing equivalents to neuronal mitochondria. Aralar is expressed postnatally in rat and mouse brain, and it is located in neurons. Both MAS activity and aralar expression are acquired in parallel during neuronal maturation (22,23). Aralar is important for neuronal function as underscored by the finding that alterations in aralar gene and protein are associated with central nervous system diseases such as Mohr-Tranebjaerg syndrome, in which there is an impaired targeting of aralar to mitochondria (24), and autism (25). Aralar null mice also exhibit prominent motor coordination defects along with deficient myelination (26).We have employed primary neuronal cultures from control and aralar-deficient mice (26) and two-photon excitation microscopy imaging of NAD(P)H to monitor the transfer of reducing equivalents from cytosol to mitochondria. We show that MAS is the main pathway to transfer reducing equivalents to neuronal mitochondria. High [Ca 2ϩ ] i signals activate the Ca 2ϩ uniporter-mitochondrial dehydrogenases signaling pathway, whereas small [Ca 2ϩ ] i signals selectively activate MAS activity in neurons. We conclude that the aralar-MAS pathway plays an * This work was supported in part by Direcció n General de Investigació n del Ministerio de Ciencia y Tecnología Grant BMC2002-02072, Comunidad de Madrid Grant 08.5/ 0024/2003, Fondo de Investigaciones Sanitarias del Ministerio de Sanidad y Consumo 01/0395 (to J. S.), an institutional grant from the Fundació n Ramó n Areces to the Centro de Biología Molecular 'Severo Ochoa,' and by a Grant-in-aid for Scientific Research 16390100 from the Japan Society for the Promotion of Science (to K. K.). The costs of publicatio...

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“…As this case illustrates, astrocytes and their metabolic properties might represent an interesting therapeutic target in various neurological diseases. Some studies have already shown the putative neuroprotective impact of modifying the intrinsic metabolic characteristics of astrocytes, either by exposing them to specific trophic factors (Escartin et al, 2007) or by overexpression of intrinsic metabolic components (Bliss et al, 2004). …”

Section: The Indispensable Astrocyte – Implications In Various Brain mentioning

confidence: 99%

Unraveling the complex metabolic nature of astrocytes

Bouzier‐Sore

Pellerin

2013

Front. Cell. Neurosci.

113

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Since the initial description of astrocytes by neuroanatomists of the nineteenth century, a critical metabolic role for these cells has been suggested in the central nervous system. Nonetheless, it took several technological and conceptual advances over many years before we could start to understand how they fulfill such a role. One of the important and early recognized metabolic function of astrocytes concerns the reuptake and recycling of the neurotransmitter glutamate. But the description of this initial property will be followed by several others including an implication in the supply of energetic substrates to neurons. Indeed, despite the fact that like most eukaryotic non-proliferative cells, astrocytes rely on oxidative metabolism for energy production, they exhibit a prominent aerobic glycolysis capacity. Moreover, this unusual metabolic feature was found to be modulated by glutamatergic activity constituting the initial step of the neurometabolic coupling mechanism. Several approaches, including biochemical measurements in cultured cells, genetic screening, dynamic cell imaging, nuclear magnetic resonance spectroscopy and mathematical modeling, have provided further insights into the intrinsic characteristics giving rise to these key features of astrocytes. This review will provide an account of the different results obtained over several decades that contributed to unravel the complex metabolic nature of astrocytes that make this cell type unique.

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Dual-Gene, Dual-Cell Type Therapy against an Excitotoxic Insult by Bolstering Neuroenergetics

Cited by 61 publications

References 56 publications

Modulation of astrocytic metabolic phenotype by proinflammatory cytokines

Modulation of astrocytic metabolic phenotype by proinflammatory cytokines

Essential Role of Aralar in the Transduction of Small Ca+ Signals to Neuronal Mitochondria

Unraveling the complex metabolic nature of astrocytes

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