Protection of malonate-induced GABA but not dopamine loss by GABA transporter blockade in rat striatum.
Previous work has shown that overstimulation of GABA(A) receptors can potentiate neuronal cell damage during excitotoxic or metabolic stress in vitro and that GABA(A) antagonists or GABA transport blockers are neuroprotective under these situations. Malonate, a reversible succinate dehydrogenase/mitochondrial complex II inhibitor, is frequently used in animals to model cell loss in neurodegenerative diseases such as Parkinson's and Huntington's diseases. To determine if GABA transporter blockade during mitochondrial impairment can protect neurons in vivo as compared with in vitro studies, rats received a stereotaxic infusion of malonate (2 micromol) into the left striatum to induce a metabolic stress. The nonsubstrate GABA transport blocker, NO711 (20 nmol) was infused in some rats 30 min before and 3 h following malonate infusion. After 1 week, dopamine and GABA levels in the striata were measured. Malonate caused a significant loss of striatal dopamine and GABA. Blockade of the GABA transporter significantly attenuated GABA, but not dopamine loss. In contrast with several in vitro reports, GABA(A) receptors were not a downstream mediator of protection by NO711. Intrastriatal infusion of malonate (2 micromol) plus or minus the GABA(A) receptor agonist muscimol (1 micromol), the GABA(A) Cl- binding site antagonist picrotoxin (50 nmol) or the GABA(B) receptor antagonist saclofen (33 nmol) did not modify loss of striatal dopamine or GABA when examined 1 week following infusion. These data show that GABA transporter blockade during mitochondrial impairment in the striatum provides protection to GABAergic neurons. GABA transporter blockade, which is currently a pharmacological strategy for the treatment of epilepsy, may thus also be beneficial in the treatment of acute and chronic conditions involving energy inhibition such as stroke/ischemia or Huntington's disease. These findings also point to fundamental differences between immature and adult neurons in the downstream involvement of GABA receptors during metabolic insult.
Zeevalk
Gail D
GD
Department of Neurology, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA.
Manzino
Lawrence
L
Sonsalla
Patricia K
PK
D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002404:Catheterization; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D004298:Dopamine / Q000032:analysis / Q000378:metabolism; D004333:Drug Administration Routes; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D050485:GABA Plasma Membrane Transport Proteins; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008297:Male; D008314:Malonates / Q000008:administration & dosage / Q000494:pharmacology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D026901:Membrane Transport Proteins; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D027361:Organic Anion Transporters; D010091:Oximes / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005680:gamma-Aminobutyric Acid / Q000032:analysis / Q000378:metabolism
D002352:Carrier Proteins; D018755:GABA Agonists; D018756:GABA Antagonists; D050485:GABA Plasma Membrane Transport Proteins; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008314:Malonates; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D018696:Neuroprotective Agents; D009557:Nipecotic Acids; D027361:Organic Anion Transporters; D010091:Oximes; C078793:NNC 711; D005680:gamma-Aminobutyric Acid; C030290:malonic acid; D004298:Dopamine