Behavioral sequelae in young rats of acute intermittent antenatal hypoxia

Hermans, R; Hunter, David E.; McGivern, Robert F.; Cain, Christopher D.; Longo, Lawrence D.

doi:10.1016/0892-0362(92)90060-n

Cited by 84 publications

(96 citation statements)

References 40 publications

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“…These functional deficits were associated with decreased staining for neurofilament immunoreactivity, astrocytes (GFAP), and oligodendrocytes (RIP) in the hippocampus and somatosensory and motor cortices in the younger animals and only minimal changes in these regions upon reaching adulthood (30). Similar findings have been reported using other hypoxic paradigms during early postnatal life (31)(32)(33). For example, Nyakas and colleagues (34) have conclusively demonstrated that application of hypoxia or hypoxic-like treatments leads to substantial effects in the architectural development of specific neural regions (e.g.…”

Section: Discussionsupporting

confidence: 73%

Intermittent Hypoxia during Development Induces Long-Term Alterations in Spatial Working Memory, Monoamines, and Dendritic Branching in Rat Frontal Cortex

et al. 2005

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Exposure to intermittent hypoxia (IH), such as occurs in sleep-disordered breathing, is associated with increased apoptosis in vulnerable brain regions as well as with spatial reference memory deficits in adult and developing rats. The latter are more susceptible to IH, suggesting that early exposure to IH may have long-term consequences. Rats were exposed to 14 d of room air (RA) or IH starting at postnatal d 10. Working memory was then assessed in the water maze at 4 mo of age using a delayed matching to place task in which the rats were required to locate a submerged platform hidden in a novel location on the first trial (T1 or acquisition trial), and then remember that position after a delay (T2 or test trial). Mean escape latencies and swim distances were derived and the savings (T1-T2) were used as a measure of working memory. Male but not female rats exposed to IH showed working memory deficits at both a 10-and 120-min delay (for both latency and pathlength). Additionally, Sholl analysis of Golgi-stained neurons revealed decreased dendritic branching in the frontal cortex, but not the hippocampus, of male rats exposed to IH. Norepinephrine concentrations, dopamine turnover, and tyrosine hydroxylase activity were increased similarly in males and females. However, increased dopamine concentrations were present only in the frontal cortex of female rats. In conclusion, exposure to IH during a critical developmental period is associated with long-term alterations in frontal cortical dopaminergic pathways that may underlie gender differences in neurobehavioral deficits. OSA is a highly prevalent condition that affects 2-3% of all children (1-3). It is characterized by the repetitive development of either complete or partial upper airway occlusion that leads to periodic hypoxemia and hypercapnia and to recurring arousals. In recent years, it has become apparent that OSA imposes substantial neurobehavioral morbidity (4 -6), particularly of functions pertaining to the PFC (7), and that such alterations in attention, executive, and intellectual function may not be completely reversible (8). The recent development of a rodent model, whereby IH is applied during sleep, has allowed for improved delineation of some of the potential mechanisms underlying the morbid consequences of OSA (8 -17). Furthermore, a unique period of neuronal susceptibility emerged, such that developing rats exposed to IH displayed reduced apoptosis during the immediate postnatal period but markedly enhanced neuronal cell loss between 10 and 25 d of age, compared with adult animals (18). Furthermore, exposure to IH during this period was associated with marked reductions in the ability to acquire a spatial task in the water maze and with locomotor hyperactivity in males but not in females (9). The potential irreversibility of the IH-induced effects was further suggested by Decker and colleagues (19), who reported altered dopaminergic transmission in rats exposed perinatally

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Section: Discussionsupporting

confidence: 73%

Intermittent Hypoxia during Development Induces Long-Term Alterations in Spatial Working Memory, Monoamines, and Dendritic Branching in Rat Frontal Cortex

et al. 2005

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“…The step-through avoidance test is a passive avoidance response which can be used to evaluate the learning and memory capabilities as well as maturation of the inhibitory process (Hermans et al, 1992). In the present study, scopolamine significantly shortened the TLT in the retention trial, demonstrating that the central cholinergic neuronal system plays an important role in learning acquisition.…”

Section: Discussionmentioning

confidence: 48%

Combretum mucronatumandCapparis thonningiiprevent scopolamine-induced memory deficit in mice

Ishola

Adeyemi

Agbaje

et al. 2012

Pharmaceutical Biology

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“…Previous studies have reported that neonatal HI injury retards the development of several neurological reflexes like ear twitch, grasping, gait, negative geotaxis and also results in delayed performance in righting, geotaxis and gait reflexes (22). We measured short-term functional neurological outcomes by cliff aversion and negative geotaxis, which tests labyrinthine and cerebellar integration (26). Both functional outcomes at day 7 were significantly better in the HYP ϩ NAC group compared with vehicle treated, NAC or hypothermia treatment alone.…”

Section: Discussionmentioning

confidence: 99%

Combination of Systemic Hypothermia and N-acetylcysteine Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

et al. 2006

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Hypoxic ischemic (HI) injury in neonates may have devastating, long-term consequences. Recently completed clinical trials in HI neonates indicate that hypothermia within 6 h of birth results in modest improvement in the combined outcome of death or severe disability. The aim of this study was to investigate the effects of combining hypothermia and N-acetylcysteine (NAC) on brain injury, neonatal reflexes and myelination after neonatal HI. Sevenday-old rats were subjected to right common carotid artery ligation and hypoxia (8% oxygen) for 2 h. Systemic hypothermia (30 ϩ 0.5°C) was induced immediately after the period of HI and was maintained for 2 h. NAC (50 mg/kg) was administered by intraperitoneal injection daily until sacrifice. Brain infarct volumes were significantly reduced at 48 h post-HI in the hypothermia plus NAC group (21.5 Ϯ 3.84 mm3) compared with vehicle (240.85 Ϯ 4.08 mm 3 ). Neonatal reflexes were also significantly improved by combination therapy at days 1 and 7. There was a significant loss of right hemispheric brain volume in the untreated group at 2 and 4 wk after HI insult. Brain volumes were preserved in hypothermia plus NAC group and were not significantly different when compared with the sham group. Similarly, increased myelin expression was seen in brain sections from hypothermia plus NAC group, when stained for Luxol Fast Blue (LFB), Myelin Basic Protein (MBP) and Proteolipid protein (PLP). These results indicate that hypothermia plus NAC combination therapy improves infarct volume, myelin expression and functional outcomes after focal HI injury. H ypoxic ischemic (HI) injury in neonates occurs in termneonates at a frequency of 1-4 per 1,000 live births (1) and may result in reduced potential for motor and cognitive development (2,3). Hypothermia improves survival and neurologic outcomes in neonatal animal models of severe HI injury (4 -7), and in recently completed clinical trials of HI neonates when instituted within 6 h of birth (8 -11). Animal data shows that initiation of hypothermia between 6 and 12 h after HI reduces cerebral injury (12,13), perhaps moderating secondary injury cascades during a time when cellular recovery is still possible. However, some inflammatory mediators are merely delayed by hypothermia treatment (14), indicating that hypothermia may be most helpful in extending the therapeutic window after HI injury.Therefore, the combination of hypothermia with other pharmacologic interventions may allow for significant improvements in outcome, which are not possible when the therapies are used separately. There have been limited reports of hypothermia treatment with other pharmacologic interventions. Systemic hypothermia and a pan-caspase inhibitor, bocaspartyl-(OMe)-fluoromethyl-ketone (BAF), produced a strong protective effect against neuronal cell damage in the ipsilateral hippocampal CA1 region of the developing rat brain, along with a reduction in caspase-3 activity (15). The combination of MK-801 and hypothermia also protected animals against HI injury ...

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Behavioral sequelae in young rats of acute intermittent antenatal hypoxia

Cited by 84 publications

References 40 publications

Intermittent Hypoxia during Development Induces Long-Term Alterations in Spatial Working Memory, Monoamines, and Dendritic Branching in Rat Frontal Cortex

Intermittent Hypoxia during Development Induces Long-Term Alterations in Spatial Working Memory, Monoamines, and Dendritic Branching in Rat Frontal Cortex

Combretum mucronatumandCapparis thonningiiprevent scopolamine-induced memory deficit in mice

Combination of Systemic Hypothermia and N-acetylcysteine Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

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