Age-related effects of NMDA-stimulated concomitant release of nitric oxide and glutamate in cortical slices prepared from DBA/2 mice

1995

1 In this study the effect of FPL 12495AA, the desglycinyl metabolite of remacemide hydrochloride and dizocilpine (MK-801), on potassium-and veratridine-stimulated release of neurotransmitter amino acids from mouse cortical slices was investigated.2 Veratridine (20 gM) and potassium (60 mM) produced a preferential release of glutamate and aspartate. Potassium-stimulated release was calcium-dependent, while veratridine-stimulated release was only partially affected by removal of calcium from the medium. 3 FPL 12495AA significantly inhibited veratridine-and potassium-stimulated release of glutamate and aspartate. Lower concentrations of FPL 12495AA were needed to inhibit veratridine-stimulated release of glutamate (12.5 gM) than potassium-stimulated release (100 gM).4 Dizocilpine significantly inhibited veratridine-and potassium-stimulated release of glutamate and aspartate at concentrations of 100 gM and above. 5 FPL 12495AA and dizocilpine both have an affinity for the ion channel subsite of the N-methyl-Daspartate (NMDA) receptor. The reduction of potassium-stimulated release of glutamate and aspartate by FPL 12495AA and dizocilpine is probably due to NMDA receptor blockade. 6 FPL 12495AA inhibited veratridine-stimulated release at a concentration of 12.5 uM while dizocilpine was effective only at a concentration of 100 gM. This difference in efficacy is probably due to the higher affinity of FPL 12495AA compared to dizocilpine at the veratridine-binding site on the sodium channel.

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The effect of the desglycinyl metabolite of remacemide hydrochloride (FPL 12495AA) and dizocilpine (MK‐801) on endogenous amino acid release from mouse cortex

Srinivasan

Richens

1995

“…The other postulated action of losigamone is through NMDA receptor antagonism as we have previously shown that losigamone inhibited NMDA‐induced depolarizations in cortical wedges, and was without effect on α‐amino‐3‐hydroxy‐5‐methyl‐4‐iosxazolapropionic acid (AMPA)‐induced depolarizations (Srinivasan et al ., 1997). NMDA has been shown to stimulate glutamate release from mouse cortical slices (Rowley et al ., 1993). The glutamate released from the slice probably comes from glutamatergic association or commisural fibres, and the dendrites of these neurones possess NMDA receptors (Huntley et al ., 1994).…”

Section: Discussionmentioning

confidence: 99%

The anticonvulsant effects of the enantiomers of losigamone

Jones

1999

1 Losigamone is a novel anticonvulsant undergoing phase III clinical trials in patients with partial and secondary generalized seizures. This study investigated the eects of the S(+)-and R(7)-enantiomers of losigamone on endogenous amino acid release from BALB/c mouse cortical slices, spontaneous depolarizations in the cortical wedge preparation of the DBA/2 mouse and audiogenic seizures in DBA/2 mice. 2 S(+)-losigamone (100 and 200 mM) signi®cantly reduced both potassium-and veratridine-elicited release of glutamate and aspartate from cortical slices. R(7)-losigamone had no eect on release at concentrations up to 400 mM. 3 Cortical wedges exhibit spontaneous depolarizations when perfused with magnesium-free arti®cial cerebrospinal¯uid. S(+)-losigamone signi®cantly reduced these depolarizations at 50 ± 200 mM whilst R(7)-losigamone had a signi®cant eect at 200 ± 800 mM. 4 DBA/2 mice are susceptible to audiogenic seizures and S(+)-losigamone dose-dependently (5, 10 and 20 mg kg 71 , i.p.) signi®cantly inhibited clonic/tonic convulsions with 91% of the mice protected at 20 mg kg 71 . There was no protection at 20 mg kg 71 with R(7)-losigamone. 5 These results, from both in vitro and in vivo experiments, con®rm that the pharmacological activity pro®les of the two losigamone enantiomers are not identical and suggest further that excitatory amino acid-mediated processes are involved in the mode of action of S(+)-losigamone whereas R(7)-losigamone does not possess such properties. For the treatment of neurological conditions involving exaggerated excitatory amino acid function the use of S(+)-losigamone might therefore be more eective clinically than losigamone or its R(7)-enantiomer.

“…Activation of the NMDA receptor by the endogenous ligand initiates a positive feedback loop occurring at the synaptic level, which acts on the presynaptic terminal to increase the release of transmitter. There are various modulators which have been shown to be involved in this positive feedback response, including nitric oxide (Rowley et al, 1993;Montague et al, 1994) and arachidonic acid (Dickie et al, 1994). Drugs which are NMDA receptor antagonists may prevent this positive feedback resulting in reduced neurotransmitter release and, conversely, NMDA has been shown to stimulate glutamate release from mouse cortical slices (Rowley et al, 1993).…”

Section: Min Losigamonementioning

confidence: 99%

“…There are various modulators which have been shown to be involved in this positive feedback response, including nitric oxide (Rowley et al, 1993;Montague et al, 1994) and arachidonic acid (Dickie et al, 1994). Drugs which are NMDA receptor antagonists may prevent this positive feedback resulting in reduced neurotransmitter release and, conversely, NMDA has been shown to stimulate glutamate release from mouse cortical slices (Rowley et al, 1993). The glutamate released from the cortical slice preparation probably comes from the glutamatergic neurones, which form association and commissural ®-bres, and the dendrites of these neurones possess NMDA receptors (Huntley et al, 1994).…”

Section: Min Losigamonementioning

confidence: 99%

The effect of losigamone (AO‐33) on electrical activity and excitatory amino acid release in mouse cortical slices

Srinivasan

Richens

1997

1 Losigamone is a novel anticonvulsant the mechanism of action of which is not known. This study investigated the e ect of losigamone on spontaneous, NMDA-and AMPA-induced depolarizations in the cortical wedge preparation of the DBA/2 mouse (which are susceptible to sound-induced seizures) and on endogenous amino acid release from BALB/c mouse cortical slices. 2 Cortical wedges exhibit spontaneous depolarizations in magnesium-free medium and losigamone was e ective in signi®cantly reducing these spontaneous depolarizations at concentrations of 100 mM and above. 3 NMDA-induced depolarizations were signi®cantly reduced by losigamone at concentrations of 25 mM and above. Losigamone had no e ect on AMPA-induced depolarizations. 4 Veratridine (20 mM) and potassium (60 mM) were used to stimulate the release of amino acids from mouse cortex. Veratridine-stimulated release of glutamate was signi®cantly reduced by losigamone at concentrations of 100 mM and above, while potassium-stimulated release was signi®cantly reduced by losigamone at 200 mM. 5 NMDA antagonism and inhibition of excitatory amino acid release may contribute to the anticonvulsant e ect of losigamone.