Glutamate modulators as novel interventions for mood disorders

Recentes evidências sugerem que as moléculas críticas nas cascatas de sinalizacão neurotrófica são alvos de longo prazo dos antidepressivos monoaminérgicos disponíveis atualmente. Na medida em que transtornos graves e crônicos são caracterizados por deficiências na resiliência neuronal, estratégias farmacológicas que sejam úteis para uma funcão neuroprotetora talvez possam alterar a fisiopatologia e modificar a progressão da doenca. Vários enfoques promissores envolvem a modulacão do sistema neurotransmissor do glutamato, via bloqueio ou potencializacão do receptor pós-sináptico e inibicão da liberacão vesicular pré-sináptica. Foi realizada uma revisão focada da literatura científica existente, com a discussão de três compostos ou classes de drogas que estão atualmente sob investigacão clínica: a ketamina, o riluzol e os potencializadores de receptores de AMPA. DISCUSSAO: Estudos recentes com pacientes com transtornos de humor sugerem que a ketamina, um antagonista do receptor NMDA, poderia ter demonstrado propriedades antidepressivas rápidas. O riluzol demonstrou reverter deficiências mediadas pelo glutamato na plasticidade neuronal e estimular a síntese de fatores neurotróficos derivados do cérebro. Ensaios abertos com depressão resistente ao tratamento produziram resultados promissores. Da mesma forma, os potencializadores de receptores de AMPA impactam favoravelmente os fatores neurotróficos, assim como melhoram a cognicão. CONCLUSÕES: Enfoques farmacológicos que modulam os componentes do sistema de glutamato oferecem novos alvos para transtornos de humor recorrentes e graves. São necessários estudos controlados.

Estresse, depressäo e hipocampo / Stress, depression and the hippocampus

A exposiçäo a fatores estressantes tem papel importante no desenvolvimento de transtornos depressivos. Os mecanismos envolvidos nesta relaçäo, no entanto, ainda säo pouco conhecidos, mas algumas evidências sugerem a participaçäo da formaçäo hipocampal: 1. o estresse pode causar alteraçöes plásticas no hipocampo, que incluem remodelaçäo dendrítica e inibiçäo de neurogênese. Drogas antidepressivas impendem estes efeitos, possivelmente por aumentarem a expressäo de fatores neurotróficos; 2. a facilitaçäo da neurotransmissäo serotoninérgica no hipocampo atenua conseqüências comportamentais do estresse e produz efeitos antidepressivos em modelos animais; 3. o antagonismo do principal neurotransmissor excitatório no hipocampo, o glutamato, produz efeitos semelhantes; 4. o hipocampo parece estar "hiperativo" em animais mais sensíveis em modelos de depressäo e em humanos resistentes à antidepressivos; 5. o hipocampo, em conjunto com o complexo amigdalar, parece ter papel fundamental na consolidaçäo e evocaçäo de memórias aversivas. Näo obstante estas evidências, o desafio futuro será o de tentar integrar os resultados destes diferentes campos (farmacológico, molecular, eletrofisiológico, clínico) em uma teoria unificadora sobre o papel do hipocampo na regulaçäo do humor e seus transtornos bem como nos efeitos de tratamentos antidepressivos

Neuroprotective agents in acute ischemic stroke.

The concept of neuroprotection relies on the principle that delayed neuronal injury occurs after ischemia. The phenomenon of the "ischemic cascade" has been described, and each step along this cascade provides a target for therapeutic intervention. A wide variety of drugs have been studied in humans. Ten classes of neuroprotective agents have reached phase III efficacy trials but have shown mixed results. They included calcium channel antagonists, NMDA receptor antagonists, lubeluzole, CDP-choline, the free radical scavenger tirilazad and ebselen, enlimomab, GABA agonist clomethiazole, the sodium channel antagonist fosphenytoin, magnesium, glycine site antagonist GV150526 and piracetam. Furthermore, the mechanisms that underlie the development of focal ischemic injury continue to be discovered, opening new therapeutic perspective for neuroprotection that might clinically be applicable in the future.

Neuroprotective effect of memantine in a rabbit model of optic nerve ischemia

The purpose of this study was to evaluate the neuroprotective effect of memantine, a N-methyl-D-aspartate antagonist, in an experimental optic nerve ischemia. Endothelin-1 (ET-1) in a dosage of 0.1 microg/day was delivered to the perineural region of the anterior optic nerve by osmotically driven minipumps for 8 weeks in 10 rabbits. In 5 rabbits, 1 mg/kg memantine was administered concurrently by intramuscular injection once a daily. Morphologic optic nerve head changes were monitored with a confocal scanning laser ophthalmoscope. Multivariate statistical analysis showed a significant change in topometric parameters (cup area, cup depth and rim volume), indicating an increase in optic nerve head cupping and a decrease of neural rim volume in the ET-1 administered eyes (P < 0.0001). In rabbits where memantine was given concurrently with ET-1, no significant change in topometric parameters was observed after ET-1 administration (P = 0.78). The current results suggest that memantine has a neuroprotective effect in optic nerve ischemia. Memantine may potentially be useful in the management of various ischemic disorders of the optic nerve, including glaucoma.

Effect of fluvoxamine and N-methyl-D-aspartate receptor antagonists on shock-induced depression in mice.

We have earlier demonstrated that NMDA receptor antagonists possess antidepressant effect and also they show a synergism with imipramine. The present study attempts to investigate whether NMDA receptor antagonists also interact with selective serotonin reuptake inhibitors. The study was conducted in albino mice using shock-induced depression model. The mice were placed on a grid floor and shock delivered were of 2 sec duration with a 9 sec interval for 1 h. Twenty four hours later depression was measured by an open field test followed by a forced swimming test. Presentation of inescapable foot shock significantly reduced ambulation (from 159.50 +/- 5.42 to 80.50 +/- 4.61) and rearing (from 22.10 +/- 2.15 to 11.30 +/- 1.32) in the open field arena and increased immobility duration in the forced swimming test (from 82.20 +/- 3.51 to 158.90 +/- 4.61). Pretreatment with fluvoxamine, MK-801, ketamine and the combination of fluvoxamine with either of the NMDA antagonists antagonised shock-induced depression. Haloperidol and ketanserin pretreatment modified the effect of these agents. These findings suggest an interaction of NMDA receptor antagonists with fluvoxamine, and an involvement of brain dopaminergic and tryptaminergic mechanisms in the behavioural suppression observed after inescapable foot shock.