No abstract

The aim of this work was to investigate the potential neuroprotective effects of the metabotropic glutamate receptor 5 (mGlu5R) antagonist 2-Methyl-6-(phenylethynyl)-pyridine (MPEP) towards quinolinic acid (QA)-induced striatal excitoxicity. Intrastriatal MPEP (5 nmol/0.5 lL) significantly attenuated the body weight loss, the electroencephalographic alterations, the impairment in spatial memory and the striatal damage induced by bilateral striatal injection of QA (210 nmol/ 0.7 lL). In a second set of experiments, we aimed to elucidate the mechanisms underlying the neuroprotective effects of MPEP. In microdialysis studies in naive rats MPEP (80-250 lM through the dialysis probe) significantly reduced the increase in glutamate levels induced by 5 mM QA. In primary cultures of striatal neurons MPEP (50 lM) reduced the toxicity induced by direct application of glutamate [measured as release of lactate dehydrogenase [LDH]). Finally, we found that 50 lM MPEP was unable to directly block NMDA-induced effects (namely field potential reduction in corticostriatal slices, as well as LDH release and intracellular calcium increase in striatal neurons). We conclude that: (i) MPEP has neuroprotective effects towards QA-induced striatal excitotoxicity; (ii) both pre-and post-synaptic mechanisms are involved; (iii) the neuroprotective effects of MPEP do not appear to involve a direct blockade of NMDA receptors.

Perinatal asphyxia is a major cause of immediate and postponed brain damage in the newborn. It may be responsible for several delayed neurologic disorders and, in this respect, early markers of brain injury would be relevant for therapeutic intervention as well as for identification of infants at high risk for developmental disabilities. Biochemical measurements (brain F 2 -isoprostane levels) and behavioral tests (ultrasonic vocalization pattern on postnatal days (pnd) 5, 8, and 11, spontaneous motor behaviors on pnd 7 and 12, and homing response on pnd 10) were performed in a rat model of global perinatal asphyxia in the immature neonate. Caesarean section was performed in rats and the pups, still in uterus horns, were placed into a water bath at 37°C for either 10 or 20 min. Caesarean delivered pups were used as controls. Pups experiencing severe (20 min), in contrast to those undergoing the 10 min, asphyctic insult presented with detectable abnormalities including early (two hours after the insult) increase in brain F 2 -isoprostane (a direct marker of oxidative injury) without detectable changes in PGE 2 , COX-2 and iNOS levels, and delayed physical (reduced weight gain on pnd 5 and thereafter) and behavioral disturbances (alterations in ultrasound emission on pnd 11 and spontaneous motricity levels mainly). These findings suggest that increased brain F 2 -isoprostane levels shortly after the asphyctic insult are predictive of delayed behavioral disturbances in the newborn rat. The present 20-min asphyxia model might serve for the assessment of preventive and curative strategies to treat neurologic/behavioral disturbances associated with perinatal asphyxia. Perinatal asphyxia is a major cause of neonatal mortality and irreversible damage to the brain. Severe asphyxia may induce major deficits (cerebral palsy, dystonia, epilepsy) shortly after birth (1), while mild/moderate asphyxia episodes may result in cognitive/attentional disorders later on in development. A critical concept emerging from recent research is that of a "therapeutic window." namely a narrow period of time between the insult and the occurrence of CNS injury, during which adoption of neuroprotective strategies could be effective (2, 3). A primary aim for clinical research is to identify as early as possible reliable indexes of brain injury in the asphyctic newborns to apply potential therapeutic interventions at the optimal time and to identify those infants at high risk for developmental delays and disabilities (4).To date the major advances in the early prediction of hypoxic-ischemic insult have been attained by means of EEG and

In vitro cultured cerebellar granule cells (cgc) undergo apoptotic death when the depolarising concentration of KCl 25 mM is adjusted to 5 mM. We investigated whether the apoptotic message can be transferred from a group of neurons to neighbouring but separated sister cultures by resorting to two different culture systems, one based on the use of concentric dishes, the other employing the transwells. The extent of transferred death was 38.6% in the two dishes system and 31.3% in the transwell system. The transfer of such death-inducing signal(s), accompanied by chromatin condensation, was inhibited by actinomicin D. Preliminary experiments aimed at identifying such apoptosis-inducing signal(s) suggest the involvement of beta-amyloid fragment(s).