alpha-Difluoromethylornithine decreases inhibitory transmission in hippocampal slices independently of its inhibitory effect on ornithine decarboxylase.
We tested the effect of DL-alpha-(difluoromethyl)ornithine (DFMO), a specific inhibitor of ornithine decarboxylase (ODC), on recordings in area CA1 of rat hippocampal slices. In the concentration range in which it is used as an ODC inhibitor, DFMO increased neuronal excitability and blocked paired-pulse inhibition. The effect of DFMO was reversed by perfusing the slice with normal bathing solution. These effects were not attenuated by the simultaneous addition of putrescine; thus the activity of DFMO was not related to a decrease in putrescine caused by the inhibition of ODC. Mediation by the N-methyl-D-aspartate (NMDA) receptor was ruled out because DL-2-amino-5-phosphonovalerate (APV), an NMDA antagonist, did not block the effect of DFMO. Intracellular and extracellular recordings of pharmacologically isolated IPSPs supported the notion that DFMO depressed GABAergic transmission. DFMO has frequently been used as a tool to study the role of the ODC-polyamine system in neural preparations. This report suggests that the results from such studies must be interpreted with caution. In addition, our findings raise questions about the proposed use of DFMO as a neuroprotective agent against excitotoxicity.
Ferchmin
P A
PA
Department of Biochemistry, School of Medicine, Universidad Central del Caribe, Bayamón, PR 00960.
DiScenna
P
P
Borroni
A M
AM
Morales Velez
M
M
Rivera
E M
EM
Teyler
T J
TJ
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D003864:Depression, Chemical; D000518:Eflornithine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology; D066298:In Vitro Techniques; D065108:Ornithine Decarboxylase Inhibitors; D011700:Putrescine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D009435:Synaptic Transmission / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D065108:Ornithine Decarboxylase Inhibitors; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; D015763:2-Amino-5-phosphonovalerate; D011700:Putrescine; D000518:Eflornithine