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The Journal of Neuroscience, July 7, 2004, 24(27):6202-6208; doi:10.1523/JNEUROSCI.0805-04.2004

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

Tonya M. Bliss,^1,2 Miranda Ip,¹ Elise Cheng,¹ Masabumi Minami,³ Luc Pellerin,⁴ Pierre Magistretti,⁴ and Robert M. Sapolsky¹

Departments of ¹Biological Sciences and ²Neurosurgery, Stanford University, Stanford, California 94305, ³Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan, and ⁴Institut de Physiologie, 1005 Lausanne, Switzerland

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.

Key words: lactate; glucose; gene therapy; neuron death; energy; neurotoxicity

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Received March 5, 2004; revised May 20, 2004; accepted May 25, 2004.

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