Valproate is neuroprotective against malonate toxicity in rat striatum: an association with augmentation of high-affinity glutamate uptake.
The antiepileptic drug valproate (VPA) may be neuroprotective. We treated rats with VPA for 14 days (300 mg/kg twice daily) before intrastriatal injection of 1.5 micromol (1 M) of the succinate dehydrogenase inhibitor malonate. VPA-treated animals developed smaller lesions than control animals: 10 +/- 2 mm(3) versus 26 +/- 8 mm(3) (means +/- SD; P = 10(-4). Injection of NaCl that was equiosmolar with 1 M malonate caused lesions of only 1.2 +/- 0.4 mm(3) in control animals, whereas physiologic saline produced no lesion. VPA pretreatment reduced the malonate-induced extracellular accumulation of glutamate. This effect paralleled an increase in the striatal level of the glutamate transporter GLT, which augmented high-affinity glutamate uptake by 25%, as determined from the uptake of [(3)H] glutamate into striatal proteoliposomes. Malonate caused a 76% reduction in striatal adenosine triphosphate (ATP) content, but the glial, ATP-dependent formation of glutamine from radiolabeled glucose or glutamate was intact, indicating that glial ATP production supported uptake of glutamate. Striatal levels of HSP-70 and fos were reduced, and the levels of bcl-2 and phosphorylated extracellular signal-regulated kinase remained unaffected, but histone acetylation was increased by VPA treatment. The results suggest that augmentation of glutamate uptake may contribute importantly to VPA-mediated neuroprotection in striatum.
Morland
Cecilie
C
Norwegian Defense Research Establishment, Kjeller, Norway.
Boldingh
Karen Astrid
KA
Iversen
Evy Grini
EG
Hassel
Bjørnar
B
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002250:Carbon Radioisotopes; D016923:Cell Death / Q000187:drug effects; D003847:Deoxyglucose / Q000737:chemistry / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008297:Male; D008314:Malonates / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D017072:Neostriatum / Q000187:drug effects* / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014635:Valproic Acid / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
D002250:Carbon Radioisotopes; D018840:HSP70 Heat-Shock Proteins; D006657:Histones; D008314:Malonates; D018696:Neuroprotective Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D016760:Proto-Oncogene Proteins c-fos; D018698:Glutamic Acid; D014635:Valproic Acid; D000255:Adenosine Triphosphate; D003847:Deoxyglucose; C030290:malonic acid; D020928:Mitogen-Activated Protein Kinases; D004298:Dopamine