Lactate reduces glutamate‐induced neurotoxicity in rat cortex

Section: Discussionmentioning

confidence: 99%

Spontaneous Network Events Driven by Depolarizing GABA Action in Neonatal Hippocampal Slices are Not Attributable to Deficient Mitochondrial Energy Metabolism

Ruusuvuori

Kirilkin

Pandya³

et al. 2010

“…Lactate can be neuroprotective in vitro after glucose or oxygen deprivation (Izumi et al, 1997;Schurr et al, 1997a,b;Cater et al, 2001Cater et al, , 2003 or glutamate exposure (Schurr et al, 1999) and in vivo after ischemia (Schurr et al, 2001b) or glutamate exposure (Mendelowitsch et al, 2001;Ros et al, 2001). In agreement, we found that in the presence of increasing extracellular lactate, MCT2 overexpression enhanced neuronal survival after exposure to glutamate.…”

Section: Discussionmentioning

confidence: 99%

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

Bliss¹,

Ip²,

Cheng³

et al. 2004

Increasing evidence suggests that glutamate activates the generation of lactate from glucose in astrocytes; this lactate is shuttled to neurons that use it as a preferential energy source. We explore this multicellular "lactate shuttle" with a novel dual-cell, dual-gene therapy approach and determine the neuroprotective potential of enhancing this shuttle. Viral vector-driven overexpression of a glucose transporter in glia enhanced glucose uptake, lactate efflux, and the glial capacity to protect neurons from excitotoxicity. In parallel, overexpression of a lactate transporter in neurons enhanced lactate uptake and neuronal resistance to excitotoxicity. Finally, overexpression of both transgenes in the respective cell types provided more protection than either therapy alone, demonstrating that a dual-cell, dual-gene therapy approach gives greater neuroprotection than the conventional single-cell, single-gene strategy.

“…Considering the numerous interactions between neurons and astrocytes (Dringen, 2000;Bak et al, 2006;Magistretti, 2006;Barres, 2008), the profound changes in the astrocytic metabolic phenotype observed in response to amyloid peptides could potentially result either in neuroprotection (e.g., via GSH or lactate release) or neurotoxicity (e.g., ROS production) (Schurr et al, 1988(Schurr et al, , 2006Ben Yoseph et al, 1996;Izumi et al, 1997;Dringen et al, 1999;Dringen, 2000;Ros et al, 2001).…”

Section: Impact On Neuronal Viabilitymentioning

confidence: 99%

Amyloid-β Aggregates Cause Alterations of Astrocytic Metabolic Phenotype: Impact on Neuronal Viability

Allaman

Gavillet²,

Bélanger³

et al. 2010

252

209

Amyloid-␤(A␤)peptidesplayakeyroleinthepathogenesisofAlzheimer'sdiseaseandexertvarioustoxiceffectsonneurons;however,relatively littleisknownabouttheirinfluenceonglialcells.Astrocytesplayapivotalroleinbrainhomeostasis,contributingtotheregulationoflocalenergy metabolism and oxidative stress defense, two aspects of importance for neuronal viability and function. In the present study, we explored the effects of A␤ peptides on glucose metabolism in cultured astrocytes. Following A␤ 25-35 exposure, we observed an increase in glucose uptake and its various metabolic fates, i.e., glycolysis (coupled to lactate release), tricarboxylic acid cycle, pentose phosphate pathway, and incorporation into glycogen. A␤ increased hydrogen peroxide production as well as glutathione release into the extracellular space without affecting intracellular glutathione content. A causal link between the effects of A␤ on glucose metabolism and its aggregation and internalization into astrocytes through binding to members of the class A scavenger receptor family could be demonstrated. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by A␤ impair neuronal viability. The effects of the A␤ 25-35 fragment were reproduced by A␤ 1-42 but not by A␤ 1-40 . Finally, the phosphoinositide 3-kinase (PI3-kinase) pathway appears to be crucial in these events since both the changes in glucose utilization and the decrease in neuronal viability are prevented by LY294002, a PI3-kinase inhibitor. This set of observations indicates that A␤ aggregation and internalization into astrocytes profoundly alter their metabolic phenotype with deleterious consequences for neuronal viability.