RESUMO
Kainic acid receptor (KA-R) subunits are differentially expressed during brain development, and they modulate both neural growth and survival. High concentrations of glutamate in the brain can induce neuronal injury through these receptors, altering normal development. However, it is unclear whether KAR subunit expression itself is also modified by neonatal exposure to high glutamate. To analyze this, monosodium glutamate (4mg/g of body weight) was subcutaneously administered on postnatal days 1, 3, 5 and 7, and the expression of GluR5, GluR6, KA1 and KA2, as well as [(3)H]-kainic acid (KA-R) binding, was evaluated on postnatal days 14, 21, 30 and 60 in different regions of rat brain. As a result, high levels of GluR5 expression associated with strong [(3)H]-kainic acid binding were observed on postnatal days 30 and 60 in the cerebral cortex of rats exposed to glutamate. Similarly, the changes induced by glutamate administration in the expression of the KA1 and KA2 subunits were paralleled by those of [(3)H]-kainic acid binding in the striatum at postnatal days 21 and 30. In contrast, while KAR subunits were over expressed in the hippocampus, no changes were observed in [(3)H]-kainic acid binding in adult rats that had been exposed to glutamate. Therefore, glutamate modifies both the expression of kainic acid receptor subunits and kainic acid binding in a determined spatial and temporal manner, which may be indicative of a regional susceptibility to glutamate neurotoxicity.
Assuntos
Encéfalo , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Ácido Glutâmico/toxicidade , Receptores de Ácido Caínico/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Encéfalo/anatomia & histologia , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Ácido Caínico/genética , Trítio/farmacocinéticaRESUMO
Monosodium l-glutamate (MSG) was administered subcutaneously to male neonatal rats, and the effect on developmental profile of tyrosine hydroxylase (TH), D1, D2 receptors, and dopamine (DA) transporter expression in the striatum was examined using Western blot. In addition, TH-immunopositive neurons at substantia nigra (SN) were also examined. MSG treatment (4mg/g of body weight, administered on postnatal days 1, 3, 5, and 7) resulted in a reduction of D1 and D2 receptor expression from 30 days of age and persisted to adulthood (120 days of age), while DA transporter expression was significantly reduced from 14 days of age to adulthood. TH immunopositive neurons at SN showed a significant reduction, as well as TH expression on postnatal days 10, 30, 60, and 120 at striatum was reduced. No changes of TH were observed at 14 days of age. Results indicate that an over-stimulation of the glutamatergic system by neonatal exposure to a high glutamate concentration induces a partial loss in TH-positive neurons in the SN and an important reduction in dopaminergic markers expression in the striatum, suggesting that early excitotoxicity could contribute to developmental alterations in the nigrostriatal pathway, which may be associated with various disorders of the basal ganglia.
Assuntos
Envelhecimento/metabolismo , Corpo Estriado/metabolismo , Ácido Glutâmico/administração & dosagem , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Biomarcadores/metabolismo , Corpo Estriado/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Injeções Subcutâneas , Masculino , Ratos , Ratos Wistar , Distribuição Tecidual/efeitos dos fármacosRESUMO
Monosodium L-glutamate (MSG) causes neuronal lesions in certain brain regions when systemically given to young animals. Also, when glutamate (Glu) builds up in the intersynaptic space, it induces neuroexcitatory and neurocytotoxic effects, events mediated by several Glu receptors. Some of these receptors such as NMDA and AMPA receptors are present in the very earliest developmental stages of the central nervous system and play a major role in neuronal plasticity during synaptogenesis. In this paper, the GABAergic system vulnerability was determined in terms of [3H]-GABA release during postnatal development. [3H]-GABA release on days 14, 21, 30, and 60 days after birth was assessed for the cerebral cortex (CC), hippocampus (Hp) and striatum (S) in rats perinatally treated at days 1, 3, 5, and 7 after birth with MSG. The results show a major decrease in baseline [3H]-GABA release in the CC (30 and 60 days after birth) and the Hp (beginning day 21 after birth) vs the control groups [intact rats and rats given a NaCl solution equimolar to that of MSG (eqNaCl)] while in the S baseline release remained unchanged. Stimulated [3H]-GABA release was decreased in the CC on days 14 and 21 after birth and significantly increased on day 60 after birth vs the controls. In the Hp, a decrease was seen on days 14, 21, and 60 after birth vs the controls while stimulated [3H]-GABA release was decreased in the S vs the controls at all ages studied. No significant differences in stimulated [3H]-GABA release were found between the intact group and the group treated with eqNaCl on days 30 and 60 after birth. Results show that CC, Hp and S GABAergic neurones are a major target for the effect of perinatally given MSG and suggest a possible decrease in the number of Hp GABAergic neurones while these results in CC and S suggest a modified neuronal plasticity. NMDA receptor and calcium involvement are discussed as significant mediators of these events.
Assuntos
Envelhecimento , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/crescimento & desenvolvimento , Glutamato de Sódio/farmacologia , Ácido gama-Aminobutírico/metabolismo , Animais , Córtex Cerebral/metabolismo , Corpo Estriado/metabolismo , Hipocampo/metabolismo , Ratos , Ratos Wistar , Cloreto de Sódio/farmacologia , TrítioRESUMO
The effects of NMDA receptor antagonists on the convulsant action of the administration of 4-aminopyridine in the rat lateral cerebral ventricle (i.c.v. injection) and motor cerebral cortex (i.cx. injection) were studied. 4-Aminopyridine administration in both regions induced various preconvulsive symptoms, such as salivation, tremors, chewing and rearing, followed by continuous clonic convulsions and, only after i.c.v. injection, running fits and generalized tonic convulsions. This behavioral pattern appeared 5-9 min after administration of 4-aminopyridine and persisted for 100-150 min. 4-Aminopyridine also generated epileptiform electroencephalographic (EEG) discharges characterized by isolated spikes, poly-spikes and spike-wave complexes, which began some seconds after administration of the drug and were present for more than 2 h. The NMDA receptor antagonists (+/-)-3-(2-carboxy-piperazin-4-yl)-propyl-1-phosphonic acid (CPP), (+/-)-2-amino-7-phosphono-heptanoic acid (AP7) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801) clearly protected against some of the behavioral alterations induced by i.c.v. 4-aminopyridine, particularly the tonic convulsions, but were less effective against those produced by i.cx. 4-aminopyridine. These antagonists also delayed the appearance of EEG epileptiform discharges, reduced its amplitude, frequency and duration, and blocked their propagation to other cortical regions after i.cx. 4-aminopyridine. These results, together with previous data showing that 4-aminopyridine stimulates the release of glutamate in vivo, suggest that an excessive glutamatergic neurotransmission involving NMDA receptors is implicated in 4-amino-pyridine-induced seizures.