Dual-gene, dual-cell type therapy against an excitotoxic insult by bolstering neuroenergetics.
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.
Bliss
Tonya M
TM
Department of Biological Sciences, Stanford University, Stanford, California 94305-5020, USA.
Ip
Miranda
M
Cheng
Elise
E
Minami
Masabumi
M
Pellerin
Luc
L
Magistretti
Pierre
P
Sapolsky
Robert M
RM
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D004357:Drug Synergism; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics*; D005240:Feasibility Studies; D015316:Genetic Therapy / Q000379:methods*; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D051272:Glucose Transporter Type 1; D019344:Lactic Acid / Q000378:metabolism / Q000493:pharmacokinetics; D027501:Monocarboxylic Acid Transporters / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity*; D010957:Plasmids / Q000235:genetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection / Q000379:methods; D019076:Transgenes
D051272:Glucose Transporter Type 1; D027501:Monocarboxylic Acid Transporters; D009004:Monosaccharide Transport Proteins; D009498:Neurotoxins; C091633:Slc16a7 protein, rat; D019344:Lactic Acid; D005947:Glucose