Electrophysiological studies on oxindole, a neurodepressant tryptophan metabolite.
1. The aim of the present work was to investigate the electrophysiological effects of oxindole, a tryptophan metabolite present in rat blood and brain, and recently proposed as a contributing factor in the pathogenesis of hepatic encephalopathy. 2. Using rat hippocampal slices in vitro and extra- or intracellular recordings, we evaluated oxindole effects on the neurotransmission of the CA1 region following orthodromic stimulation of the Schaffer collaterals. 3. Oxindole (0.3-3 mM) decreased the amplitude of population spikes extracellularly recorded at the somatic level and of the fEPSPs recorded at the dendritic level. In intracellular recordings, oxindole (0.1-3 mM) did not affect the resting membrane potential or the neuronal input resistance, but reduced the probability of firing action potentials upon either synaptic or direct activation of the pyramidal cells. 4. Oxindole (0.3-3 mM) increased the threshold and the latency of firing action potentials elicited by depolarizing steps without changing the duration or the peak amplitude of the spikes. It also significantly increased the spike frequency adaptation induced by long lasting (400 ms) depolarizing stimuli. 5. In separate experiments, performed by measuring AMPA or NMDA-induced responses in cortical slices, oxindole (1-3 mM) did not modify glutamate receptor agonist responses. 6. Our results show that concentrations of oxindole which may be reached in pathological conditions, significantly decrease neuronal excitability by modifying the threshold of action potential generation.
Mannaioni
G
G
Department of Pharmacology, University of Florence, Firenze, Italy.
Carpenedo
R
R
Pugliese
A M
AM
Corradetti
R
R
Moroni
F
F
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D000078183:Oxindoles; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects; D014364:Tryptophan / Q000378:metabolism*
D002492:Central Nervous System Depressants; D007211:Indoles; D000078183:Oxindoles; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; D014364:Tryptophan; C022960:2-oxindole