Effects of some synthetic kynurenines on brain amino acids and nitric oxide after pentylenetetrazole administration to rats

Abstract

We have previously proven that some synthetic kynurenines behave as antagonists of the N-methyl-d-aspartate receptor inhibiting neuronal subtype of nitric oxide synthase activity. We now investigate the anticonvulsant activity of four of these kynurenines in pentylenetetrazole (PTZ)-treated rats. The rats were treated with each kynurenine (10-160 mg/kg, s.c.) 30 min before PTZ administration (100 mg/kg, s.c.). Then, latency, duration and intensity of the first seizure and the percent animal survival were noted. PTZ-induced death was counteracted by high doses of kynurenines. Latency of the first seizure was significantly increased and its intensity reduced at the same doses, whereas the duration of the first seizure significantly decreased with doses of 20 mg/kg in most of the kynurenines tested. Three hours after PTZ administration, the surviving animals were sacrificed and the levels of brain amino acids and nitrite were measured. PTZ administration increased glutamate, glutamine, serine and taurine levels in different brain areas. High doses of kynurenines generally counteracted the effects of PTZ on excitatory amino acids, but they also reduced inhibitory aminoacids. However, the most consistent effect of kynurenines was the dose-dependent reduction of brain nitrite levels induced by PTZ. These results reveal a new family of anticonvulsant drugs that affect mainly to nitric oxide production in the brain.

Melatonin role in the mitochondrial function

“…The anticonvulsant activity of melatonin was initially related to its effects on both brain GABA-benzodiazepine receptor complex and Na + , K + -ATPase (27-29). Reduced melatonin levels were related to increased brain damage after stroke or excitotoxic seizures in rats (177), whereas anticonvulsant activity of melatonin against seizures induced by a series of drugs in mice was reported (99,100). However, due to the inhibitory effect of melatonin on the NO/NOS system, an effect of the indoleamine on glutamate-induced excitotoxicity was soon proposed.…”

“…The effects of melatonin were related to increased GABA and reduced glutamate activity, and to a reduction of brain NO levels in a dose-dependent manner (103). Some of synthetic kynurenines, structurally related to melatonin, were also effective to counteract pentylenetetrazole-induced seizures in vivo (100). The effects of melatonin against brain excitotoxicity were the basis for the clinical use of melatonin in infantile seizures.…”

Role of Kynurenines in the Central and Peripherial Nervous Systems

“…The most consistent effect of such KYN compounds is the dose-dependent reduction of brain nitrite levels induced by PTZ. This is a promising possibility for the use of a new family of anticonvulsant drugs that mainly affect NO production in the brain (Bikjdaouene et al, 2004). Another way to ward off the harmful effects of PTZ is the administration of high doses of L-KYN together with probenecid PROB .…”

Combined blockade of AMPA and NMDA receptors in the brain of rats prevents pentylenetetrazole-induced clonic and tonic-clonic seizures without ataxia

“…Intramuscular injection of IEM-1913 (combined blockade of NMDA and AMPA receptors in the brain) decreased the incidence of pentylenetetrazole-induced clonic and tonic-clonic seizures in rats by 4-8 times. The therapeutic index of IEM-1913 surpassed that of memantine and arcaine by 200-600 times.Pentylenetetrazole in toxic doses induces massive release of endogenous glutamate in various structures of the brain [4,5]. Pentylenetetrazole-induced seizures in rats are associated with glutamate activation of AMPA and NMDA receptors in the brain [5,6,14].…”

“…Pentylenetetrazole in toxic doses induces massive release of endogenous glutamate in various structures of the brain [4,5]. Pentylenetetrazole-induced seizures in rats are associated with glutamate activation of AMPA and NMDA receptors in the brain [5,6,14].…”