Electrophysiological studies on oxindole, a neurodepressant tryptophan metabolite

Abstract

1 The aim of the present work was to investigate the electrophysiological e ects 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 e ects on the neurotransmission of the CA1 region following orthodromic stimulation of the Scha er 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 a ect the resting membrane potential or the neuronal input resistance, but reduced the probability of ®ring 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 ®ring action potentials elicited by depolarizing steps without changing the duration or the peak amplitude of the spikes. It also signi®cantly 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, signi®cantly decrease neuronal excitability by modifying the threshold of action potential generation.

Design, synthesis, and biological evaluation of oxindole derivatives as antidepressive agents

“…All the compounds were obtained in excellent yield (>81%) and their synthesis was confirmed by UV, IR, 1 H NMR, and mass spectroscopic techniques. The UV spectra of final compounds (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) showed two typical chalcone bands between 312.60-368.40 nm (band-I) and 240.80-258.20 nm (band-II). The IR spectra of compounds (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) exhibited peaks at 3138.26-3186.51, 1690.14-1712.85, and 1587.47-1622.19 cm À1 characteristic to the NAH, C@O, and C@C groups of compounds, respectively.…”

“…The estimated free energy of binding of all the docked eighteen molecules ranged between À4.95 and À3.69 kcal/mol and is presented in Table 4. The docked complexes of ligands (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) within the active site of MAO-A revealed that the secondary amine (ANHA) and carbonyl (C@O) groups of synthesized derivatives were involved in hydrogen bonding with the Asn-181, Tyr-407, and Tyr-444 residues of the MAO-A. The most active compound (12) of in vivo study showed lowest estimated free energy of binding (À4.95 kcal/mol).…”

“…The title compounds (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) were synthesized by Claisen-Schmidt condensation reaction of a ketone with various aldehydes. The commercially available oxindole (indolin-2-one) (1) was stirred with appropriate aldehydes (2) in the presence of alcoholic NaOH to afford 3-substituted oxindole derivatives (3-20) (Scheme 1).…”

“…An obvious advantage of this test is its ability to detect a broad spectrum of antidepressants irrespective of their mechanisms and it is inexpensive, methodologically unsophisticated, and easily amenable to automation. 29 All the synthesized 3-substituted oxindole derivatives (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) were tested in vivo for antidepressant activity employing FST and TST models. Imipramine was used as the standard drug.…”

“…3 Oxindole is a neurodepressant tryptophan metabolite physiologically present in mammalian brain and blood, and affects brain functions. [19][20][21] Like indole, several oxindole derivatives have also been reported to possess antidepressant activity. 3 Relying on the notion that some of the indole and oxindole derivatives share structural similarity with neurotransmitters and endogenous amines, 3 such as MAO substrates serotonin and tryptamine; 22 we thought to synthesize oxindole derivatives as possible antidepressants.…”