Blockade of lactate transport exacerbates delayed neuronal damage in a rat model of cerebral ischemia

Schurr, Avital; Payne, Ralphiel S.; Miller, James J.; Tseng, Michael T.; Rigor, Benjamin M.

doi:10.1016/s0006-8993(01)02082-0

Cited by 124 publications

(95 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Microscopical examination of Hematoxylin and Eosin, Perls and reticulin staining of kidney and liver and Gomori's Trichrome, NADH and cytochrome oxydase activity on skeletal muscle failed to observe any difference in mitochondrial functions and morphology between animals having received CIN and controls (Fig. 2) as suggested in previous reports (11,20) Disturbance of neuronal migration following CIN administration. Administration of CE induced to slight alteration in the cortical architecture of the parietal cortex observed in cresyl violet staining on P5 pups, including an increased apoptotic feature of the nucleus and a cytoarchitectonic disorganization in the parietal cortex (Fig.…”

Section: Resultssupporting

confidence: 68%

“…In vitro, using this transporter blocker, lactate has been reported to be a crucial energy substrate for neurons under activated conditions or during the reperfusion phase following hypoxic-ischemic insult (7,10). Similarly, blockade of monocarboxylate transport in vivo have been shown to exacerbate delayed ischemic neuronal damage in the adult (11). CIN could be diluted in DMSO (DMSO) but also in ethanol according to manufacturer's instructions (Sigma Chemical Co., St. Louis, MO).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cortical Consequences of In Vivo Blockade of Monocarboxylate Transport During Brain Development in Mice

et al. 2007

View full text Add to dashboard Cite

In addition to glucose, monocarboxylates including lactate represent a major source of energy for the developing brain and appears to be crucial in the pathogenesis and recovery after brain damage. We hypothesized a role of monocarboxylates transport in the energy supply of neurons of the immature cerebral cortex. The effects of the blockade of monocarboxylates transport in vivo on the cortical development was investigated in neonatal mice using alphacyano-4-hydroxycinnamate (CIN) diluted either in DMSO (CD) or in ethanol (CE) administered intraperitoneally over postnatal day (P) P1 to P3. Injection of CIN induced a cytoarchitectonic disorganization in the parietal cortex likely due to a combination of slight disturbance of cortical neuronal migration and an increased neuronal cell death observed in CE (p Ͻ 0.05) but not in CD group. An increased number of activated GFAP-positive astroglia was observed in the neocortex in groups treated with CIN (CD and CE) on P10. These data: 1) Provide first evidence of deleterious effects observed in vivo after blockade of monocarboxylates transport in the developing brain; 2) emphasize the role of lactate during neuronal migration as a major source of energy; and 3) suggest the synergistic effect of ethanolinduced hypoglycemia in cortical brain damage induced by CIN. C erebral activity requires delivery of an adequate amount of energy substrates to neurons. In addition to glucose, the main source of energy for the brain, monocarboxylates including lactate play a significant role as alternative energy suppliers (1). Delivery of energy substrates from the blood to the brain requires specific transporters across the endothelial cells involved in blood-brain barrier and cellular membranes of the neurons and glia (2). Therefore, monocarboxylate transporters (MCTs) were supposed to play a key role in astrocyte/ neuronal shuttle as lactate release by astrocytes is likely to be a major energy substrate coupled with neuronal activity as suggested in adults (3). Moreover, monocarboxylate including lactate play a significant role as alternative energy suppliers in developing brain (4) and under challenged conditions including excitotoxic insult or inadequate glucose supply (5-7).Little is known about the energy trafficking during CNS development (4). We previously emphasized the presence of monocarboxylate transporters (MCTs) in the different cell populations of the developing rat cerebral cortex and in the human visual cortex at midgestation including radial glia, mature astrocytes and ependimocytes (8,9). These studies demonstrate that lactate could be used as energy substrate in perinatal period, but physiologic relevance of its trafficking in developing brain have never been studied in vivo.Alpha-cyano-4-hydroxycinnamate (CIN) is a competitive inhibitor of monocarboxylate transporters which is blood brain barrier permeable and appears to block lactate utilization by cells that import monocarboxylates (10). In vitro, using this transporter blocker, lactate has been reporte...

show abstract

Section: Resultssupporting

confidence: 68%

mentioning

confidence: 99%

Cortical Consequences of In Vivo Blockade of Monocarboxylate Transport During Brain Development in Mice

et al. 2007

View full text Add to dashboard Cite

show abstract

“…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

J. Neurosci.

View full text Add to dashboard Cite

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.

show abstract

“…Time dependence of lactate C3 and alanine C3 enrichments in rat brain after blood circulation arrest. The rats treated with either pentobarbital (A), ␣-chloralose (B), or morphine (C) were infused with a solution of 750 mM [1][2][3][4][5][6][7][8][9][10][11][12][13] C]glucose plus 500 mM lactate. Time zero was defined as the instant when their cranium was split in two parts to remove brain hemispheres.…”

Section: Involvement Of Brain Lactate In the Neuronal Metabolism-mentioning

confidence: 99%

“…Using the specific enrichment of brain glucose C1 or C6 (equally labeled from liver gluconeogenesis) and that of brain and blood lactate, as shown in Equation 7, ␣{brain glucose C1 or C6} ϩ (100 Ϫ ␣){blood lactate C3} ϭ 100{brain lactate C3} (Eq. 7) this percent contribution (␣) may be estimated. Then, the contribution was 62% under pentobarbital and 83% under ␣-chloralose.…”

Section: Involvement Of Brain Lactate In the Neuronal Metabolism-mentioning

confidence: 99%

Ex Vivo Analysis of Lactate and Glucose Metabolism in the Rat Brain under Different States of Depressed Activity

Serres

Bezancon

Franconi

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

Brain metabolism of glucose and lactate was analyzed by ex vivo NMR spectroscopy in rats presenting different cerebral activities induced after the administration of pentobarbital, ␣-chloralose, or morphine. The animals were infused with a solution of either [1-13 C]glucose plus lactate or glucose plus [3-13 C]lactate for 20 min. Brain metabolite contents and enrichments were determined from analyses of brain tissue perchloric acid extracts according to their post-mortem evolution kinetics. When amino acid enrichments were compared, both the brain metabolic activity and the contribution of blood glucose relative to that of blood lactate to brain metabolism were linked with cerebral activity. The data also indicated the production in the brain of lactate from glycolysis in a compartment other than the neurons, presumably the astrocytes, and its subsequent oxidative metabolism in neurons. Therefore, a brain electrical activity-dependent increase in the relative contribution of blood glucose to brain metabolism occurred via the increase in the metabolism of lactate generated from brain glycolysis at the expense of that of blood lactate. This result strengthens the hypothesis that brain lactate is involved in the coupling between neuronal activation and metabolism.In the last decade, the idea of the involvement of lactate in the coupling between neuronal activation and energy metabolism has arisen from the results of various experimental investigations. Briefly, in vitro studies have evidenced lactate release from astrocytes after glycolysis stimulation by glutamate uptake (1, 2) and, in the particular case of the mammalian retina, the use of lactate from Mü ller cells as an energy substrate for photoreceptors (3). In vivo studies on brain have demonstrated the uncoupling of oxygen and glucose utilization (4) and the release of lactate into the extracellular fluid in response to neuronal activation (5, 6). On the other hand, brain lactate has been demonstrated to efficiently protect neurons against delayed ischemic damage (7). The metabolic fate of exogenous lactate in whole brain has been investigated by ex vivo NMR spectroscopy. In this way, it has been demonstrated that blood lactate enters the brain and is more specifically metabolized in neurons (8 -10). The proposed astrocyte-neuron lactate shuttle hypothesis (ANLSH) 1 (1) as the coupling model between neuronal activity and energy metabolism requires the involvement of different components, the occurrence and localization of which have been investigated analytically at the molecular level, i.e. glutamate transporter and Na ϩ ,K ϩ -ATPase (11), lactate dehydrogenase isoenzymes (12), and monocarboxylate transporters (13,14). Although brain lactate production and lactate use by neurons as an energy source are widely admitted, the relevance of the coupling model, particularly the neuronal utilization of glia-produced lactate, is a topical issue (15, 16).Brain lactate mostly derives from glycolysis. Therefore, the comparative analysis of the contribution of brain l...

show abstract

Blockade of lactate transport exacerbates delayed neuronal damage in a rat model of cerebral ischemia

Cited by 124 publications

References 24 publications

Cortical Consequences of In Vivo Blockade of Monocarboxylate Transport During Brain Development in Mice

Cortical Consequences of In Vivo Blockade of Monocarboxylate Transport During Brain Development in Mice

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

Ex Vivo Analysis of Lactate and Glucose Metabolism in the Rat Brain under Different States of Depressed Activity

Contact Info

Product

Resources

About