Unilateral neonatal hypoxia–ischemia causes important damage to the hippocampus of the hemisphere ipsilateral to carotid artery occlusion; two forms of neonatal handling, tactile stimulation and ...maternal separation for a short period, have been shown to produce functional/behavioral protection in distinct models of CNS challenge. In this paper we investigated whether neonatal handling could alter the hippocampal damage caused by neonatal hypoxia–ischemia (HI) in the Wistar rat. Pups at postnatal day 7, P7, received HI (8% O
2–92% N
2) for 90 min and were submitted to neonatal handling, tactile stimulation of maternal separation daily, from P8 to P21, for 10 min. On adulthood, hippocampal volume was analyzed by stereological techniques, along with measures of cortical thickness and hemispheric area at the level −3.30 mm from bregma. HI caused a reduction of volume of whole hippocampus, of Amon's horn and of dentate gyrus, with no effect on cortical and hemispheric measures; neonatal handling prevented such effect. This is the first report showing that both tactile stimulation and neonatal handling exert a morphological neuroprotective action for HI-induced damage to the hippocampus.
Agmatine is a new putative neurotransmitter; however, the physiological role(s) of this endogenous released polyamine is still to be determined. We investigated its cognitive effect in an inhibitory ...avoidance task in adult rats. Agmatine (0.1, 1, 10, and 20 mg/kg) or saline was administered ip immediately after training or 1 h before testing. Posttraining injection of agmatine facilitated (
p < 0.05) memory consolidation in this task; however pretest treatment showed no effect on retrieval (
p > 0.05). We suggest that the facilitatory effect of agmatine on memory consolidation in inhibitory avoidance task might be mediated through the activation of the locus coeruleus.
Early life events lead to behavioral and neurochemical changes in adulthood. The aim of this study is to verify the effects of neonatal handling on spatial memory, nitric oxide (NO) production, ...antioxidant enzymatic activities and DNA breaks in the hippocampus of male and female adult rats. Litters of rats were non-handled or handled (10 min/day, days 1–10 after birth). In adulthood they were subjected to a Morris water maze or used for biochemical evaluations. Female handled rats showed impairment in spatial learning. They also showed decreased NO production, while no effects were observed in these parameters in male rats. No effects were observed on the number of hippocampal NADPH diaphorase positive cells. In the Comet Assay, male handled rats showed increased DNA breaks index when compared to non-handled ones. We conclude that neonatal handling impairs learning performance in a sex-specific manner, what may be related to NO decreased levels.
Hypoxia–ischemia is a common cause of neonatal brain damage producing serious impact on cerebral maturation. This report demonstrates that rats submitted to hypoxia–ischemia present a marked decrease ...in hippocampal gangliosides, phospholipids and cholesterol contents as from 7 days after the injury. Although chromatographic profiles of the different ganglioside species (GM1, GD1a, GD1b, and GT1b) from the hippocampus of hypoxic-ischemic hippocampi groups (HI) were apparently unaffected, as compared with controls, there were quantitative absolute reductions in HI. The phospholipid patterns were altered in HI as from the 14th to the 30th day after the injury, where phosphatidylcholine (PC) quantities were higher than phosphatidylethanolamine (PE); additionally, the cardiolipin band was detected only in hippocampi of control adult rats. In general, the absolute quantities of phospholipids were lower in HI than in correspondent controls since 7th day after the injury. Considering that reported effects were maintained, we suggest they express a late biochemical response triggered by the neonatal hypoxic-ischemic episode; the consequences would be cell death and a delay on brain development, expressed by a reduction on synaptogenesis and myelinogenesis processes.
Changes in the thiol/disulphide status in the neonatal rat brain were evaluated after an episode of neonatal hypoxia-ischemia (HI) in 7-day-old rats. The glutathione level decreased in the post-HI ...period. The lowest values (43–68%) were obtained 24 h post-HI. A statistically significant difference first appeared in hippocampus, immediately after the HI event, and only 12 h later in striatum and cortex. On the 7th day post-HI the glutathione content was completely recovered in the hippocampus and the striatum, and partially in the cortex. The glutathione loss could not be explained through its conversion to glutathione disulphide or to protein mixed disulphide (S-thiolation), whose values remained constant. Furthermore, we found a consistent decrease (20–30%) in protein thiols, which were not recovered after 7 days post-HI. Perturbations in protein thiols, along with the glutathione loss, may represent a valuable marker of immature rat brain damage.
Environmental enrichment (EE) results in improved learning and spatial memory, as well as attenuates morphological changes resulting from cerebral ischemia in adult animals. This study examined the ...effects of daily EE on memory deficits in the water maze and cerebral damage, assessed in the hippocampus and cerebral cortex, caused by neonatal hypoxia-ischemia. Male Wistar rats in the 7th postnatal day were submitted to the Levine-Rice model of neonatal hypoxia-ischemia (HI), comprising permanent occlusion of the right common carotid artery and a period of hypoxia (90
min, 8%O
2–92%N
2). Starting two weeks after the HI event, animals were stimulated by the enriched environment (1
h/day for 9 weeks); subsequent to the stimulation, performance of animals in the water maze was assessed. HI resulted in spatial reference and working memory impairments that were completely reversed by EE. Following the behavioral study, animals were killed and the hippocampal volume and cortical area were estimated. There was a significant reduction of both hippocampal volume and cortical area, ipsilateral to arterial occlusion, in HI animals; environmental stimulation had no effect on these morphological measurements. Presented data indicate that stimulation by the daily environmental enrichment recovers spatial memory deficits caused by neonatal hypoxia-ischemia without affecting tissue atrophy in either hippocampus or cortex.
Neonatal hypoxia–ischemia (HI) has been extensively studied in a rat model characterized by unilateral brain damage (Rice–Vannucci Model). However, as well as in humans, each rat brain hemisphere is ...distinctly involved in cognitive functions, as for example retrieval of emotionally based memory, and neurochemical asymmetries have been described. In this paper we investigated whether hypoxia–ischemia could cause distinct cognitive deficits depending on which hemisphere is damaged. Seven-day-old male Wistar rats were submitted to permanent occlusion of left or right common carotid artery and were exposed to a mixture of 8% oxygen–92% nitrogen for 2.5 h. On adulthood, these rats were trained in step-down inhibitory avoidance and in two tasks in the Morris water maze. Both experimental groups (right and left lesioned) showed a deficit of retrieval in the inhibitory avoidance task compared to controls, although rats with right hemisphere lesion showed a significantly greater deficit than the left damaged group (
P<0.05). In the Morris maze, both damaged groups presented cognitive deficits in the reference memory task (
P<0.05), however only the right damaged group had an impairment in the working memory task. Brain coronal areas, at levels +1.20 and −3.30 mm from bregma of both HI groups were smaller than those of control, with no differences between the right and left damaged groups (
P<0.05). These results show that cerebral hypoxia–ischemia in neonatal rats causes asymmetric behavioral outcomes depending on which of the hemispheres is lesioned and support the hypothesis of lateralization of cognitive functions in the rodent brain.
Agmatine is an endogenous released polyamine recently proposed to be a putative neurotransmitter, however its physiological role is still to be determined. We investigated the hypothesis that ...agmatine, systemically administered to adult Wistar rats, might exert anxiolytic-like behavior in the elevated plus maze (EPM) and the open field. Agmatine (1, 10, 20, 40 and 100 mg/kg) and saline were administered i.p. 30 min before the EPM and the open field. Administration of agmatine (20 and 40 mg/kg) increased the time spent in the open arms of the EPM, as compared to the saline group, with no effect on locomotion activity in the open field. However, 100 mg/kg of agmatine significantly reduced the number of entries into enclosed arms of the EPM and the total number of crossings in the open field. We suggest that agmatine, in doses of 20 and 40 mg/kg, causes a mild anxiolytic-like behavior and discuss the possibility that this first reported effect could be caused either by the inhibition of nitric oxide synthase, the blockage of NMDA receptors or by the activation of alpha-2-adrenoceptors.
Abstract Neonatal hypoxic–ischemic encephalopathy (HI) is a major cause of nervous system damage and neurological morbidity. Perinatal malnutrition affects morphological, biochemical and behavioral ...aspects of neural development, including pathophysiological cascades of cell death triggered by ischemic events, so modifying resulting brain damage. Female Wistar rats were subjected to protein restriction during pregnancy and lactation (control group: 25% soybean protein; malnourished group: 7%). Seven days after delivery (PND7), their offspring were submitted to unilateral cerebral HI; rats were then tested for sensorimotor (PND7 and PND60) and memory (PND60) functions. Offspring of malnourished mothers showed marked reduction in body weight starting in lactation and persisting during the entire period of observation. There was a greater sensorimotor deficit after HI in malnourished (M) animals, in righting reflex and in home bedding task, indicating an interaction between diet and hypoxia–ischemia. At PND60, HI rats showed impaired performance when compared to controls in training and test sessions of rota-rod task, however there was no effect of malnutrition per se. In the open field, nourished HI (HI-N) presented an increase in crossings number; this effect was not present in HI-M group. Surprisingly, HI-M rats presented a better performance in inhibitory avoidance task and a smaller hemispheric brain damage as compared to HI-N animals. Our data points to a possible metabolic adaptation in hypoxic–ischemic animals receiving protein malnutrition during pregnancy and lactation; apparently we observed a neuroprotective effect of diet, possibly decreasing the brain energy demand, under a hypoxic–ischemic situation.
Synapsins are phosphoproteins related to the anchorage of synaptic vesicles to the actin skeleton. Hypoxia-ischemia causes an increased calcium influx into neurons through ionic channels gated by ...activation of glutamate receptors. In this work seven-day-old Wistar rats were submitted to hypoxia-ischemia and sacrificed after 21 hours, 7, 30, or 90 days. Synaptosomal fractions were obtained by Percoll gradients and incubated with 32P (10 microCi/g). Proteins were analysed by SDS-PAGE and radioactivity incorporated into synapsin 1 was counted by liquid scintillation. Twenty-one hours after hypoxia-ischemia we observed a reduction on the in vitro phosphorylation of synapsin 1, mainly due to hypoxia, rather than to ischemia; this effect was reversed at day 7 after the insult. There was another decrease in phosphorylation 30 days after the event interpreted as a late effect of hypoxia-ischemia. No changes were observed at day 90. Our results suggest that decreased phosphorylation of synapsin 1 could be related to neuronal death that follows hypoxia-ischemia.
PDF