Modulation of rat striatal glutamatergic response in search for new neuroprotective agents: evaluation of melatonin and some kynurenine derivatives.
Melatonin attenuates the excitatory response of striatal neurons to sensorimotor cortex (SMCx) stimulation, which may be the basis for its neuroprotective role. Searching for new compounds with melatonin-like properties, the effects of several kynurenine derivatives in the response of the rat striatum to SMCx stimulation were studied using electrophysiological and microiontophoretical techniques. Melatonin iontophoresis (-100 nA) significantly attenuated the striatal excitatory response in 89.4% of the recorded neurons, showing excitatory properties in the other 10.6%. Compound A [2-acetamide-4-(3-methoxyphenyl)-4-oxobutyric acid] (-100 nA) displayed similar attenuating effects (86.7% of neurons inhibited vs. 13.3% excited). Compound B [2-acetamide-4-(2-amine-5-methoxyphenyl)-4-oxobutyric acid] (-100 nA) was more potent than melatonin itself to attenuate the excitatory response in 100% of the recorded neurons. Compound C [2-butyramide-4-(3-methoxyphenyl)-4-oxobutyric acid] (-100 nA) significantly increased the excitatory response in 84.2% of the recorded neurons, showing attenuating effects on the other 15.8% of the neurons. Interestingly, compound C iontophoresis excited the neurons in which melatonin had attenuating properties, whereas it inhibited the neurons showing excitatory responses to melatonin. These data suggest melatonin inverse agonist properties for compound C. Also, the effects of compounds B and C appeared immediately after they were iontophoretized, whereas both melatonin and compound A onset latencies were longer (2-4 min). The lack of latency shown by these melatonin analogs points to the possibility that melatonin itself was metabolized before producing its effects on striatal neurons. The results show a family of structurally-related melatonin analogs that may open new perspectives in search for new neuroprotective agents, including its clinical potentiality.
León
J
J
Instituto de Biotecnología, Departamento de Fisiología, Universidad de Granada, Spain.
Vives
F
F
Gómez
I
I
Camacho
E
E
Gallo
M A
MA
Espinosa
A
A
Escames
G
G
Acuña-Castroviejo
D
D
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation; D004594:Electrophysiology / Q000379:methods; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000494:pharmacology*; D007478:Iontophoresis; D007736:Kynurenic Acid / Q000494:pharmacology; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time; D013329:Structure-Activity Relationship
D018696:Neuroprotective Agents; D007737:Kynurenine; D018698:Glutamic Acid; D007736:Kynurenic Acid; D008550:Melatonin