Folic Acid Prevents Behavioral Impairment and Na+,K+-ATPase Inhibition Caused by Neonatal Hypoxia–Ischemia

Carletti, Jaqueline Vieira; Deniz, Bruna Ferrary; Miguel, Patrícia Maidana; Rojas, Joseane Jiménez; Kolling, Janaína; Scherer, Emilene B. S.; Wyse, Ângela T. S.; Netto, Carlos Alexandre; Pereira, Lenir Orlandi

doi:10.1007/s11064-012-0757-6

Cited by 23 publications

(20 citation statements)

References 36 publications

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“…After the HI procedure, the animals returned immediately to maternal care. Control animals were sub mitted to sham surgery, receiving only anesthesia and neck inci sion (Carletti et al, 2012;Pereira et al, 2008;Rojas et al, 2013).…”

Section: Hi Proceduresmentioning

confidence: 99%

Neonatal hypoxia-ischemia induces attention-deficit hyperactivity disorder-like behavior in rats.

Miguel

Schuch

Rojas

et al. 2015

Behavioral Neuroscience

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Attention-deficit hyperactivity disorder (ADHD) may be caused by genetic or environmental factors. Among environmental factors, perinatal complications are related, such as neonatal hypoxia-ischemia (HI). Thus, the aim of this study was to investigate whether HI contributes to the development of characteristics related to ADHD in adult rats, and to correlate the behavioral results with brain damage volume. Male Wistar rats were divided into 2 groups: HI and control. The HI procedure consisted of a permanent occlusion of the right common carotid artery followed by a period of hypoxia (90 min; 8% O₂ and 92% N₂) on the 7th postnatal day. Two months later, animals were evaluated in the open field test during a single 5-min session, and in the 5-choice serial reaction time task (5-CSRTT), over 25 weeks. Our results demonstrated that animals submitted to HI manifest cognitive impairments in task acquisition, deficits in sustained attention, and increases in impulsivity and compulsivity in response to task manipulation in the 5-CSRTT. Locomotor activity observed in open field did not differ between groups. Moreover, brain volume loss in the total hemisphere, cerebral cortex, white matter, hippocampus, and striatum were observed in HI animals, especially on the side ipsilateral to the lesion. From these results, we can infer that neonatal HI is an environmental factor that could contribute to the development of behavioral characteristics observed in ADHD that are associated with general brain atrophy.

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Section: Hi Proceduresmentioning

confidence: 99%

Neonatal hypoxia-ischemia induces attention-deficit hyperactivity disorder-like behavior in rats.

Miguel

Schuch

Rojas

et al. 2015

Behavioral Neuroscience

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“…39) Previous finding also indicated the important role of Na + , K + -ATPase activity to in cellular neuroprotection. 40) Under hypoxic conditions, increased release of ROS from the inner mitochondrial membrane to the intermembrane space leads to internalization of the membrane Na + , K + -ATPase from the basolateral membrane of alveolar epithelial cells. 41) So the mitochondrial Na + , K + -ATPase activity could be an indication of mitochondrial disfunction.…”

Section: )mentioning

confidence: 99%

The Antioxidative Effect of a Novel Free Radical Scavenger 4′-Hydroxyl-2-substituted Phenylnitronyl Nitroxide in Acute High-Altitude Hypoxia Mice

Fan

Jing

et al. 2013

Biological & Pharmaceutical Bulletin

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Acute mountain sickness is caused by sub-acute hypoxia in healthy individuals going rapidly to altitude. Both tissue hypoxia in vitro and whole-body hypoxia in vivo have been found to promote the release of reactive oxygen species. Nitronyl nitroxide can trap free radicals such as ·NO or ·OH, and may therefore be efficient protective agents. This study assessed the ability of nitronyl nitroxide to against acute mountain sickness as a free radical scavenger in acute high-altitude hypoxia mice model. Normobaric hypoxia and hypobaric hypoxia model were used to estimate the protect effects of nitronyl nitroxide against acute mountain sickness. Low pressure oxygen compartment system was used to stimulate high-altitude hypobaric hypoxia environment. Mice in nitronyl nitroxide groups survived longer than acetazolamide group in normobaric hypoxia test. Hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) increased in both cerebrum and myocardium in vehicle group. The results indicated more radicals were generated during high-altitude hypobaric hypoxia environment. In therapeutic groups H 2 O 2 and MDA were significantly reduced while the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were similar to normal group. These results demonstrated that nitronyl nitroxide was an efficient tissue radical scavenger and a potential protective agent for acute mountain sickness.Key words nitronyl nitroxide; antioxidant; free radical scavenger; acute high-altitude hypoxia More than 140 million people worldwide live >2500 m above sea level. Eighty million live in Asia, and 35 million live in the Andean mountains. The latter region has its major population density living above 3500 m.1) Barometric pressure falls with increasing altitude and consequently in the partial pressure of oxygen reduced. This leads to a hypoxic challenge to any individual ascending to altitude. A spectrum of highaltitude illnesses can occur when the hypoxic stress outstrips the subject's ability to acclimatize.2) Acute mountain sickness (AMS) is a condition affecting otherwise healthy individuals going rapidly to altitude. It is caused by sub-acute hypoxia in susceptible subjects.3) Acute hypoxia induces pulmonary vascular permeability and contributes to forms of noncardiogenic pulmonary edema such as high-altitude pulmonary edema and acute respiratory distress syndrome.4,5) AMS can sharply limit people's recreation and working at high altitude, especially in the first few days following arrival at a new, higher altitude. 6)More and more studies were concerned on the prophylaxis and therapy of AMS. 7-9)In vitro hypoxia and in vivo whole-body hypoxia can cause tissue release reactive oxygen species (ROS) which are potentially damaging to the cardiovascular system. 10) Hypoxia rapidly increases the levels of free radicals in organism, which is thought to overwhelm the reserves of scavengers. The radicals then damage cell walls, reduce the flexibility of blood vessels, destroy enzymes, and cause other molecular damage...

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“…Few studies have evaluated the effects of FA supplementation in the mother and this was the first to analyze the Na + , K + ‐ ATPase activity in the hippocampus of the dams. Our previous studies with FA administration (Carletti et al, 2012, 2016) in young rats also did not find changes in this enzyme activity in the hippocampus, striatum and cortex. As mentioned, Sittig et al, (2012) correlated the memory deficits after FA supplementation in young rats with decreased thyroid hormones function in the hippocampus.…”

Section: Discussionmentioning

confidence: 63%

“…Our previous studies have already shown that neonatal HI impaired the Na + , K + ‐ ATPase activity in different brain structures in adult rats (Carletti et al, 2012, 2016). Considering the importance of this enzyme (McLean and Ferriero, 2004; Rumajogee et al, 2016; Rocha‐Ferreira and Hristova, 2016) and that the hippocampus is primarily affect by the HI injury we decide to assess the Na + , K + ‐ ATPase activity in the hippocampus of HI rats.…”

Section: Discussionmentioning

confidence: 93%

“…We can to propose that these rudimentary responses are preserved due the importance of sensorimotor responses to neonates’ survival, probably involved in a spontaneous recovery after the HI injury (Farkas et al, 2009; Trollmann and Gassmann, 2009). Other point to be considered is that the Levine‐Vannucci HI model is well‐recognized by the cognitive deficits observed, especially, in adult rats (Carletti et al, 2012, 2016; Deniz et al, 2018; Miguel et al, 2015, 2017; Pereira et al, 2007; Rojas et al, 2013, 2015) but there is no consensus about motor deficits in this model (Lubics et al, 2005; Sanches et al, 2012; Van der Kooij et al, 2010) Taken that neonatal reflexes are almost all correlated to sensorimotor function it is possible that this HI model is not the best one to evaluate motor function. This limitation should be considered in this study that has its main focus on early development; future studies with adult rats can give further support for the impact of gestational FA supplementation on pup's development.…”

Section: Discussionmentioning

confidence: 99%

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Gestational folic acid supplementation does not affects the maternal behavior and the early development of rats submitted to neonatal hypoxia‐ischemia but the high supplementation impairs the dam's memory and the Na⁺, K⁺ ‐ ATPase activity in the pup's hippocampus

Deniz

Confortim

Deckmann

et al. 2018

Intl J of Devlp Neuroscience

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Folic acid (FA) is a B‐complex vitamin important to the development of the fetus, being supplemented during pregnancy. Our recent findings showed that gestation supplementation (normal and excess doses) prevented the cognitive deficits and BDNF imbalance in adult rats that were submitted to neonatal hypoxia‐ischemia (HI). To better understand this protective effect, the present study aimed to evaluate whether FA supplementation could be related to (1) maternal behavior, memory and Na+, K+ ‐ ATPase activity in the hippocampus of the dams; (2) on somatic growth, early neurobehavioral development and Na+, K+ ‐ ATPase activity in the hippocampus of the offspring; and (3) the effects of this supplementation in pups submitted to neonatal HI. Pregnant Wistar rats were divided into three groups, according to the diet they received during gestation: standard diet (SD), supplemented with 2 mg/kg of FA (FA2 – normal dose) and supplemented with 20 mg/kg of FA (FA20 –excessive dose). At the 7th PND pups were submitted to the Levine‐Vannucci model of HI. During weaning the maternal behavior, the somatic growth and the neurobehavior development of pups were assessed. After weaning, the memory of the dams (by the Ox‐maze task) and the Na+, K+ ‐ ATPase activity in the hippocampus of both dams and offspring were evaluated. Considering the dams (1), both doses of FA did not alter the maternal behavior or the Na+, K+ ‐ ATPase activity in the hippocampus, but a memory deficit was observed in the high FA‐supplemented mothers. Considering the offspring (2), both FA doses did not affect the somatic growth or the neurobehavior development, but the FA20 pups had a decreased Na+, K+ ‐ ATPase activity in the hippocampus. The FA supplementation did not change the parameters evaluated in the HI rats (3) and did not prevent the decreased Na+, K+ ‐ ATPase activity in the hippocampus of the HI pups. These results indicate that normal FA supplementation dose does not influence the maternal behavior and memory and does not impact on the offspring early development in rats. Further studies are needed to confirm the effects of the high FA supplementation dose in the dams’ memory and in the Na+, K+ ‐ ATPase activity in the hippocampus of the offspring.

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Folic Acid Prevents Behavioral Impairment and Na+,K+-ATPase Inhibition Caused by Neonatal Hypoxia–Ischemia

Cited by 23 publications

References 36 publications

Neonatal hypoxia-ischemia induces attention-deficit hyperactivity disorder-like behavior in rats.

Neonatal hypoxia-ischemia induces attention-deficit hyperactivity disorder-like behavior in rats.

The Antioxidative Effect of a Novel Free Radical Scavenger 4′-Hydroxyl-2-substituted Phenylnitronyl Nitroxide in Acute High-Altitude Hypoxia Mice

Gestational folic acid supplementation does not affects the maternal behavior and the early development of rats submitted to neonatal hypoxia‐ischemia but the high supplementation impairs the dam's memory and the Na⁺, K⁺ ‐ ATPase activity in the pup's hippocampus

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Folic Acid Prevents Behavioral Impairment and Na+,K+-ATPase Inhibition Caused by Neonatal Hypoxia–Ischemia

Cited by 23 publications

References 36 publications

Neonatal hypoxia-ischemia induces attention-deficit hyperactivity disorder-like behavior in rats.

Neonatal hypoxia-ischemia induces attention-deficit hyperactivity disorder-like behavior in rats.

The Antioxidative Effect of a Novel Free Radical Scavenger 4′-Hydroxyl-2-substituted Phenylnitronyl Nitroxide in Acute High-Altitude Hypoxia Mice

Gestational folic acid supplementation does not affects the maternal behavior and the early development of rats submitted to neonatal hypoxia‐ischemia but the high supplementation impairs the dam's memory and the Na+, K+ ‐ ATPase activity in the pup's hippocampus

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Gestational folic acid supplementation does not affects the maternal behavior and the early development of rats submitted to neonatal hypoxia‐ischemia but the high supplementation impairs the dam's memory and the Na⁺, K⁺ ‐ ATPase activity in the pup's hippocampus