Neuroprotective effects of electroacupuncture on hypoxic-ischemic encephalopathy in newborn rats are associated with increased expression of GDNF-RET and protein kinase B

Hypoxic–ischemic encephalopathy (HIE) is a devastating neonatal brain condition caused by lack of oxygen and limited blood flow. Environmental enrichment (EE) is a classic paradigm with a complex stimulation of physical, cognitive, and social components. EE can exert neuroplasticity and neuroprotective effects in immature brains. However, the exact mechanism of EE on the chronic condition of HIE remains unclear. HIE was induced by a permanent ligation of the right carotid artery, followed by an 8% O2 hypoxic condition for 1 h. At 6 weeks of age, HIE mice were randomly assigned to either standard cages or EE cages. In the behavioral assessments, EE mice showed significantly improved motor performances in rotarod tests, ladder walking tests, and hanging wire tests, compared with HIE control mice. EE mice also significantly enhanced cognitive performances in Y-maze tests. Particularly, EE mice showed a significant increase in Cav 2.1 (P/Q type) and presynaptic proteins by molecular assessments, and a significant increase of Cav 2.1 in histological assessments of the cerebral cortex and hippocampus. These results indicate that EE can upregulate the expression of the Cav 2.1 channel and presynaptic proteins related to the synaptic vesicle cycle and neurotransmitter release, which may be responsible for motor and cognitive improvements in HIE.

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Neuroprotective effects of hypothermia in inflammatory‐sensitized hypoxic‐ischemic encephalopathy

International Journal of Developmental Neuroscience ◽

10.1016/j.ijdevneu.2016.09.002 ◽

2016 ◽

Vol 55 (1) ◽

pp. 1-8 ◽

Cited By ~ 13

Author(s):

Mathilde Chevin ◽

Clémence Guiraut ◽

Caroline Maurice‐Gelinas ◽

Jessica Deslauriers ◽

Sylvain Grignon ◽

...

Keyword(s):

Hypoxic Ischemic Encephalopathy ◽

Neuroprotective Effects ◽

Ischemic Encephalopathy

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Sestrin2, as a negative feedback regulator of mTOR, provides neuroprotection by activation AMPK phosphorylation in neonatal hypoxic-ischemic encephalopathy in rat pups

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16656201 ◽

2016 ◽

Vol 37 (4) ◽

pp. 1447-1460 ◽

Cited By ~ 36

Author(s):

Xudan Shi ◽

Liang Xu ◽

Desislava Met Doycheva ◽

Jiping Tang ◽

Min Yan ◽

...

Keyword(s):

Protein Kinase ◽

Mammalian Target Of Rapamycin ◽

Adenosine Monophosphate ◽

Neurological Function ◽

Hypoxic Ischemic Encephalopathy ◽

Brain Infarct ◽

Rat Pups ◽

Infarct Area ◽

Ischemic Encephalopathy ◽

Feedback Regulator

Hypoxic-ischemic encephalopathy is a condition caused by reduced oxygen and cerebral blood flow to the brain resulting in neurological impairments. Effective therapeutic treatments to ameliorate these disabilities are still lacking. We sought to investigate the role of sestrin2, a highly conserved stress-inducible protein, in a neonatal rat hypoxic-ischemic encephalopathy model. Ten-day-old rat pups underwent right common carotid artery ligation followed by 2.5 h hypoxia. At 1 h post hypoxic-ischemic encephalopathy, rats were intranasally administered with recombinant human sestrin2 and sacrificed for brain infarct area measurement, Fluoro-Jade C, immunofluorescence staining, Western blot, and neurological function testing. rh-sestrin2 reduced brain infarct area, brain atrophy, apoptosis, ventricular area enlargement, and improved neurological function. Western blot showed that sestrin2 expression levels were increased after treatment with rh-sestrin2, and sestrin2 exerts neuroprotective effects via activation of the adenosine monophosphate-activated protein kinase pathway which in turn inhibits mammalian target of rapamycin signaling resulting in the attenuation of apoptosis. In conclusions: Sestrin2 plays an important neuroprotective role after hypoxic-ischemic encephalopathy via adenosine monophosphate-activated protein kinase signaling pathway and serves as a negative feedback regulator of mammalian target of rapamycin. Administration of rh-sestrin2 not only reduced infarct area and brain atrophy, but also significantly improved neurological function.

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Neuronal apoptosis can be prevented by the combined therapy with melatonin and hypothermia in a neonatal rat model of hypoxic-ischemic encephalopathy

Medicine and Pharmacy Reports ◽

10.15386/mpr-1903 ◽

2021 ◽

Author(s):

Alina Mihaela Toader ◽

Oana Hoteiuc ◽

Cristina Bidian ◽

Dan-Daniel Oltean ◽

Flaviu Tabaran ◽

...

Keyword(s):

Cell Death ◽

Neuroprotective Effect ◽

Ischemic Injury ◽

Brain Regions ◽

Hypoxic Ischemic Encephalopathy ◽

Newborn Rats ◽

Neonatal Hypoxia ◽

Hypoxia Ischemia ◽

The Brain ◽

Ischemic Encephalopathy

Introduction. Birth hypoxia is a leading cause of perinatal mortality and neurological morbidity, resulting in central nervous system injury. Cerebral hypoxia and ischemia can produce a severe brain damage following a typical pattern, defined by selective vulnerability of the brain regions. The neonates are most prone to hypoxic-ischemic injuries due to the lack of efficient antioxidant defense. Neonatal hypoxia–ischemia (HI) in a 7-day-old rat HI model can produce cell death by apoptotic or necrotic mechanisms. The degree of apoptotic or necrotic mechanisms responsible for cell death in neonatal hypoxia–ischemia are not very clear as yet. The form of neuronal death may also depend on the severity of ischemic injury. Necrosis predominates in more severe cases, whereas apoptosis occurs in areas with milder ischemic injury. A human study demonstrated apoptotic and necrotic forms of cell death after hypoxic injury, whereas in some brains from stillbirths, only apoptotic figures were observed. The expression of activated caspase-3 reflects the role of apoptosis in neonatal hypoxic ischemic brain injury. Objectives. The aim of this study was to evaluate the possible neuroprotective effect of melatonin and hypothermia in hypoxic-ischemic encephalopathy in newborn rats. Local damages induced by hypoxia and ischemia were assessed by evaluating the changes in terms of histology and apoptosis. Methods. The experiment was conducted on 20 newborn Wistar rats premedicated for seven days with melatonin in a dose of 20 mg/kg/day. On the 7th postnatal day (P7), the newborn rats were exposed to ischemia (by clamping the right carotid artery) and hypobaric hypoxia (8% O2 for 90 minutes) and some groups to hypothermia. Results. In this experimental model of neonatal encephalopathy, melatonin, in a dose of 20 mg/kg/day has neuroprotective effect by reducing the number of cells expressing apoptosis in Cornu Ammonis (CA) (Ammon’s Horn) CA1, CA2, CA3 and dentate gyrus of the hippocampus when combined with hypothermia. Conclusion. The results of this study prove that melatonin is protective in ischemic-hypoxic brain injuries, but the protection is conditioned in most of the brain regions (excepting cerebral cortex) by conjugation with post-injury hypothermia treatment.

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Efficacy of different treatment times of mild cerebral hypothermia on oxidative factors and neuroprotective effects in neonatal patients with moderate/severe hypoxic–ischemic encephalopathy

Journal of International Medical Research ◽

10.1177/0300060520943770 ◽

2020 ◽

Vol 48 (9) ◽

pp. 030006052094377

Author(s):

Tingting Yang ◽

Shan Li

Keyword(s):

Mild Hypothermia ◽

Neuron Specific Enolase ◽

The Other ◽

Hypoxic Ischemic Encephalopathy ◽

Psychomotor Development ◽

Controlled Study ◽

Neurological Assessment ◽

Neuroprotective Effects ◽

Assessment Scores ◽

Ischemic Encephalopathy

Objective To investigate the efficacy of different treatment times of mild cerebral hypothermia for treating moderate/severe hypoxic–ischemic encephalopathy (HIE) in neonatal patients and its effects on oxidative factors. Methods This prospective, randomized, controlled study included 92 neonatal patients with moderate/severe HIE and 30 controls. The patients with HIE received routine treatment, 48 hours of hypothermia, or 72 hours of hypothermia. Results Superoxide dismutase (SOD) values were significantly lower and malondialdehyde (MDA) and neuron-specific enolase (NSE) values were higher in patients with HIE than in controls before the study. After 24, 48, and 72 hours of treatment, SOD values in all patients with HIE gradually increased and MDA and NSE values gradually decreased. At 3, 7, and 10 days, the Neonatal Behavioral Neurological Assessment scores were highest in the mild hypothermia for 72 hours group than in the other groups. The Mental and Psychomotor Development Indices scores of the Bayley Scales were significantly higher in the mild hypothermia for 72 hours group than in the other groups. Conclusion Hypothermia treatment of 72 hours is better than 48 hours for improving oxidative conditions, reducing NSE values, and improving neurological behavior and development for neonates with moderate/severe HIE.

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Effects of Nogo-A receptor antagonist on the regulation of the Wnt signaling pathway and neural cell proliferation in newborn rats with hypoxic ischemic encephalopathy

Molecular Medicine Reports ◽

10.3892/mmr.2013.1579 ◽

2013 ◽

Vol 8 (3) ◽

pp. 883-886 ◽

Cited By ~ 5

Author(s):

YONGXIANG WANG ◽

JIAXIANG GU ◽

XINMIN FENG ◽

HUA WANG ◽

YUPING TAO ◽

...

Keyword(s):

Cell Proliferation ◽

Wnt Signaling ◽

Receptor Antagonist ◽

Signaling Pathway ◽

Wnt Signaling Pathway ◽

Neural Cell ◽

Hypoxic Ischemic Encephalopathy ◽

Newborn Rats ◽

Ischemic Encephalopathy

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Combination treatment with ethyl pyruvate and IGF-I exerts neuroprotective effects against brain injury in a rat model of neonatal hypoxic-ischemic encephalopathy

International Journal of Molecular Medicine ◽

10.3892/ijmm.2015.2219 ◽

2015 ◽

Vol 36 (1) ◽

pp. 195-203 ◽

Cited By ~ 8

Author(s):

ZHIHUI RONG ◽

RUI PAN ◽

LIWEN CHANG ◽

WEIHUA LEE

Keyword(s):

Brain Injury ◽

Rat Model ◽

Combination Treatment ◽

Ethyl Pyruvate ◽

Hypoxic Ischemic Encephalopathy ◽

Neuroprotective Effects ◽

Igf I ◽

Ischemic Encephalopathy

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The role of G-CSF neuroprotective effects in neonatal hypoxic-ischemic encephalopathy (HIE): current status

Journal of Neuroinflammation ◽

10.1186/s12974-021-02084-4 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

John Sieh Dumbuya ◽

Lu Chen ◽

Jang-Yen Wu ◽

Bin Wang

Keyword(s):

Ex Vivo ◽

Neuroprotective Effect ◽

Hypoxic Ischemic Encephalopathy ◽

Cell Swelling ◽

Current Status ◽

Clinical Practices ◽

Neonatal Brain ◽

Neuroprotective Effects ◽

Ischemic Encephalopathy ◽

Stimulation Of

AbstractHypoxic-ischemic encephalopathy (HIE) is an important cause of permanent damage to central nervous system (CNS) that may result in neonatal death or manifest later as mental retardation, epilepsy, cerebral palsy, or developmental delay. The primary cause of this condition is systemic hypoxemia and/or reduced cerebral blood flow with long-lasting neurological disabilities and neurodevelopmental impairment in neonates. About 20 to 25% of infants with HIE die in the neonatal period, and 25-30% of survivors are left with permanent neurodevelopmental abnormalities. The mechanisms of hypoxia-ischemia (HI) include activation and/or stimulation of myriad of cascades such as increased excitotoxicity, oxidative stress, N-methyl-d-aspartic acid (NMDA) receptor hyperexcitability, mitochondrial collapse, inflammation, cell swelling, impaired maturation, and loss of trophic support. Different therapeutic modalities have been implicated in managing neonatal HIE, though translation of most of these regimens into clinical practices is still limited. Therapeutic hypothermia, for instance, is the most widely used standard treatment in neonates with HIE as studies have shown that it can inhibit many steps in the excito-oxidative cascade including secondary energy failure, increases in brain lactic acid, glutamate, and nitric oxide concentration. Granulocyte-colony stimulating factor (G-CSF) is a glycoprotein that has been implicated in stimulation of cell survival, proliferation, and function of neutrophil precursors and mature neutrophils. Extensive studies both in vivo and ex vivo have shown the neuroprotective effect of G-CSF in neurodegenerative diseases and neonatal brain damage via inhibition of apoptosis and inflammation. Yet, there are still few experimentation models of neonatal HIE and G-CSF’s effectiveness, and extrapolation of adult stroke models is challenging because of the evolving brain. Here, we review current studies and/or researches of G-CSF’s crucial role in regulating these cytokines and apoptotic mediators triggered following neonatal brain injury, as well as driving neurogenesis and angiogenesis post-HI insults.

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