Thyrotropin-releasing hormone (protirelin) inhibits potassium-stimulated glutamate and aspartate release from hippocampal slices in vitro.
Excess excitatory amino acid release is involved in pathways associated with seizures and neurodegeneration. Thyrotropin-releasing hormone (TRH; protirelin), a brain-derived tripeptide, has shown efficacy in the treatment of such disorders, yet its mechanism of neuroprotection is poorly understood. Using superfused hippocampal slices, we tested the hypothesis that TRH could inhibit evoked glutamate/aspartate release in vitro. Rat hippocampal slices were first equilibrated in oxygenated Krebs buffer (KRB) (120 min) then superfused for 10 min with KRB (control), or KRB containing 0.1, 1, or 10 microM TRH respectively, prior to and during 5 min depolarization with high potassium KRB (50 mM [K(+)] +/- TRH). Fractions (1 min) were collected during the 5 min stimulation and for an additional 10 min thereafter and analyzed for glutamate and aspartate by HPLC. TRH had no effect on baseline glutamate/aspartate release, while all three TRH doses significantly (P < 0.05) inhibited peak 50 mM [K(+)]-stimulated glutamate/aspartate release, and glutamate remained below control (P < 0.05) at 15 min post stimulation. A 5 min pulse of TRH (10 microM) had no affect on basal glutamate/aspartate release, whereas the TRH pre-pulsed slices failed to release glutamate/aspartate by [K(+)]-stimulation given 15 min later. These results are the first to show a potent and prolonged inhibitory effect of TRH on evoked glutamate/aspartate release in vitro. These initial studies suggest that exogenous and/or endogenous TRH may function, in part, to modulate excess glutamate release in specific CNS loci. Additional studies are in progress to fully understand the mechanism of this potent effect of TRH and its implication in various CNS disorders.
Nie
Y
Y
Department of Anatomy and Cell Biology, MS 5035, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN 46202, USA.
Schoepp
D D
DD
Klaunig
J E
JE
Yard
M
M
Lahiri
D K
DK
Kubek
M J
MJ
D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D002118:Calcium / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004347:Drug Interactions; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D011188:Potassium / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology*; D013997:Time Factors
D001224:Aspartic Acid; D018698:Glutamic Acid; D013973:Thyrotropin-Releasing Hormone; D007770:L-Lactate Dehydrogenase; D011188:Potassium; D002118:Calcium