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Abstract: Hippocampal vulnerability to excitotoxicity has been widely studied along with its implication to learning and memory. Neonatal glutamate excitotoxicity induces loss of CA1 pyramidal neurons in adult rats concomitantly with some plastic changes in the dendritic spines of surviving neurons. At least in part, these may underlie the place learning impairments seen in previous studies based on a similar excitotoxicity-inducing model. In the present study, cytoarchitecture of dentate gyrus, CA3 and CA1 fields were evaluated in 120-day-old rats, after they had been neonatally treated with glutamate as monosodium salt. Dentate granule cells and CA1 pyramidal neurons were less than those counted in NaCl-treated control animals. In addition, dentate granule cells had more dendrites as well as more branched spines. Spine density in CA1 pyramidal neurons was greater than in the controls. Additionally, thin and mushroom spines were proportionally more abundant in monosodium glutamate-treated animals. No effects were seen in the hippocampal CA3 field. Our results strongly suggest a long-term induction of plastic changes in the cytoarchitecture of the hippocampal trisynaptic circuit neurons after cell death provoked by the monosodium glutamate-induced excitotoxicity. These plastic events as well as the aberrant expression of the glutamate NMDA receptors resulting from monosodium glutamate neonatal treatment could be strongly associated with the place learning impairments previously reported. [Copyright &y& Elsevier]

Abstract: Overactivation of NMDA-Rs may mediate excitotoxic cell death associated with epileptic seizures, and hypoxic–ischemic conditions. We assessed whether repeated subcutaneous administration of l-glutamate to neonatal rats affects the subunit composition of NMDA-Rs. Accordingly, cortical and hippocampal tissue from 14-day-old rats was analyzed by Western blotting and RT-PCR to quantify the protein and mRNA expression of different NMDA-R subunits. In addition, tissue sections were Nissl stained to assess the cell damage in this tissue. Early exposure of neonatal rats to l-glutamate differentially affects the expression of mRNA transcripts for NMDA-R subunits in the cerebral cortex and hippocampus. In the cerebral cortex, a decrease in NR2B subunit mRNA expression was observed, as well as a loss of NR1 and NR2A protein. By contrast, neonatal l-glutamate administration augmented the transcripts encoding the NR1, NR2B, and NR2C subunits in the hippocampal formation. The expression of mRNA encoding the NR2A subunit was not affected by neonatal l-glutamate administration in either of the brain regions examined. This differential expression of NMDA-R subunits following neonatal exposure to l-glutamate may represent an adaptive response of the glutamate receptors to overactivation in order to reduce the effect of high l-glutamate during the early period of life when the animal is more vulnerable to excitotoxicity. [Copyright &y& Elsevier]

Abstract: Pro-inflammatory cytokines TNF-α, IL-1β and IL-6 rises significantly during neuronal damage and activate the signaling p38 MAPK pathway, which is involved in the apoptotic (AP) neuronal death. Systemic administration of glutamate as monosodium salt (MSG) to newborn animals induces neuronal death, however whether neurons die by AP or necrosis through MAPK p38 pathway activation it is unknown. In this study, TNF-α, IL-1β and IL-6 expression levels, AP neuronal death and cellular type that produces TNF-α was also identified in the cerebral cortex (CC) and striatum (St) of rats at 8, 10, and 14 days of age after neonatal exposure to MSG. TNF-α production and AP neuronal death was significantly increased in the CC at PD8–10, and in the St in all ages studied by excitotoxicity effect induced with MSG. This effect was completely inhibited by SB203580 (p38 inhibitor) in both regions studied. TNF-α, IL-1β and IL-6 RNAm increased after MSG administration, whereas SB203580 did not modify their expression. These data indicates that neuronal death induced by excitotoxicity appears to be mediated through p38 signaling pathway activated by TNF-α and their inhibition may have an important neuroprotective role as part of anti-inflammatory therapeutic strategy. [Copyright &y& Elsevier]

Abstract: 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 [3H]-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 [3H]-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 [3H]-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 [3H]-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. [Copyright &y& Elsevier]

Abstract: Sparteine is a quinolizidine alkaloid (QA) produced by Lupine species that has generated much interest due to its anti-hypertensive, anti-pyretic, and anti-inflammatory properties. In the nervous system, sparteine has been shown to display anti-cholinergic and depressive activity, although how sparteine exerts its toxic effects in the brain remains unclear. We have addressed this issue by administering subcutaneous injections of sparteine (25mg/kg of body weight) to rats on postnatal days 1 and 3, and then examining the expression of the muscarinic acetylcholine receptor (mAChR) subunits m1–m4 in the brains of the neonatal rats 14–60 days later. Administration of sparteine to neonatal rats caused neuronal damage in the cerebral motor cortex accompanied by transient changes in the expression of m1–m4 mAChR subunits as revealed by both RT-PCR and Western blotting. This effect could be prevented by pre-treatment with atropine (10mg/kg) 1h prior to the injection of sparteine, suggesting that the cytotoxic activity of sparteine is mediated through mAChRs. [Copyright &y& Elsevier]

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Abstract: 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. [Copyright &y& Elsevier]

Monosodium glutamate (MSG) was administered subcutaneously to male neonate rats, and the effects on N-methyl-d-asparatate (NMDA) subunit receptor types NR2C and NR2D from different brain regions were studied. A semi-quantitative reverse transcription-polymerase chain reaction was used to measure NR2C and NR2D expression levels in the cerebral cortex, hippocampus and striatum. MSG treatment (4 mg/g body weight, on postnatal days 1, 3, 5, and 7) produced an important increase of NR2C and NR2D subunit gene expression levels in the hippocampus and striatum of adults rats. No change was observed in the cerebral cortex. We propose that an early excessive activation of glutamate receptors could modify NMDA subunit expression and its structural composition on postnatal development. This, as part of a compensatory response by an altered neuronal circuitry, mainly in the hippocampus and striatum, suggests that the NMDA receptor could be a determinant factor to modulate the dendritic arrangement and the synaptogenesis. [Copyright &y& Elsevier]

To evaluate the effects on the GABAergic system, Wistar rats were raised on a chronically protein- and tryptophan-restricted diet with 8% protein, based on either Purina chow or corn. There was a significant decrease in both body and cerebral weight in the restricted animals compared with the control group fed with a 23% protein diet. In animals fed mainly corn, glutamic acid decarboxylase (GAD) activity increased significantly at the ages studied (14, 30, and 60 days) in the cerebral cortex and hippocampus. In the same way, γ-aminobutyric acid (GABA) release decreased significantly in early life in both brain regions, then increased in 30–60-day-old animals corn-fed predominantly in the cerebral cortex.The reduction in GABA release may be attributable to a decrease in GABAergic cell density, which could induce an over-activation of 5-hydroxytryptamine (5-HTergic) receptors, leading in turn to the observed enhancement of GAD activity. Taken together, these results may represent a plastic response by GABAergic neurons to (5-HTergic under-stimulation in mainly corn-fed animals. [Copyright &y& Elsevier]

Dendritic spines are the main postsynaptic neuronal targets of excitatory inputs in cortical neurons, and both spine density and shape possess a well known adaptive synaptic-stimulation-dependent plastic capacity. Eighteen Sprague–Dawley adult male rats were used. Monosodium glutamate-treated rats (4 g/kg of body weight, i.p.) showed tonic and clonic epileptic seizures, as well as less dendritic spines in the apical arborization of their hippocampal CA1 pyramidal cells, compared to both control groups. No changes were seen in the proportional density of thin, stubby, mushroom-shaped, wide, or ramified spines between groups. Excessive glutamate-mediated excitatory activity on receptors could have led dendritic spines to shrink until they disappeared, while the spine-type proportion may be kept balanced as an adaptive response. [Copyright &y& Elsevier]

Abstract: Excitotoxic neuronal death occurs through the activation of NMDA and non-NMDA glutamatergic receptors in the CNS. Glutamate also induces strong activation of p38 and indeed, cell death can be prevented by inhibitors of the p38 pathway. Furthermore, intracellular signals generated by AMPA receptors activate the stress sensitive MAP kinases implicated in apoptotic neuronal death, such as JNK and p38. To investigate the relationship between these elements, we have used immunohistochemistry to analyze the expression of GluR2 in the cerebral cortex of postnatal rats (postnatal Day [PD] 8 and 14) after administering them with monosodium glutamate (MSG; 4mg/g body weight on PD1, 3, 5, and 7). Similarly, the expression of REST, Fas-L and Bcl-2 mRNA transcripts in animals exposed to a p38 inhibitor, SB203580 (0.42μg/g body weight, administered subcutaneously) was determined by reverse transcriptase-PCR. The enhanced GluR2-expression in the cerebral cortex at PD8 and the down regulation of this receptor at PD14 was correlated with neuronal damage induced by excitotoxicity. In addition, the enhanced expression of REST at PD8 and PD14 suggests that the induction of REST transcription contributes to glutamate-induced excitotoxic neurodegeneration, possibly by modulating GluR2 expression. Fas-L and Bcl-2 over expression at PD8 and their subsequent down regulation at PD14 also suggests that Fas-L could be the direct effector of apoptosis in the cerebral cortex. On the other hand, the presence of Bcl-2 at PD8 could attenuate certain survival signals in neurons under these neurotoxic conditions. Thus, a change in glutamate receptor composition, and enhanced Fas-L and Bcl-2 expression, coupled with activation of the p38/SAPK pathway appear to be events involved in the neuronal apoptosis induced under neurotoxic conditions. [Copyright &y& Elsevier]

Neuronal death and lactate dehydrogenase (LDH) activity were evaluated in the cerebral cortices of neonatal rats after exposure to monosodium L-glutamate (MSG) to induce neuroexcitotoxicity. A time–response profile for tumor necrosis factor-alpha (TNF-α) expression was drawn, with measurements taken every 6 h after the first dose of MSG during the first 8 postnatal days, and at days 10 and 14 after birth. An increase in neuronal loss accompanied by high LDH activity and high TNF-α levels was observed at 8 and 10 days. These results indicate that neuronal loss may occur via an apoptosis-like mechanism directed selectively against neurons that express glutamate receptors, mainly the N-methyl-d-aspartate, which it may be strengthen by high TNF-α levels through a feedback mechanism to induce cell death via apoptosis. [Copyright &y& Elsevier]