Serum 24S-hydroxycholesterol predicts long-term brain structural and functional outcomes after hypoxia-ischemia in neonatal mice

The major pathway of brain cholesterol turnover relies on its hydroxylation into 24S-hydroxycholesterol (24S-HC) using brain-specific cytochrome P450 46A1 (CYP46A1). 24S-HC produced exclusively in the brain normally traverses the blood-brain barrier to enter the circulation to the liver for excretion; therefore, the serum 24S-HC level is an indication of cholesterol metabolism in the brain. We recently reported an upregulation of CYP46A1 following hypoxia-ischemia (HI) in the neonatal mouse brain and a correlation between serum 24S-HC levels and acute brain damage. Here, we performed a longitudinal study to investigate whether the serum 24S-HC concentrations predict long-term brain structural and functional outcomes. In postnatal day 9 mice subjected to HI, the serum 24S-HC levels increased at 6 h and 24 h after HI and correlated with the infarct volumes measured histologically or by T2-weighted MRI. The 24 h levels were associated with white matter volume loss quantified by MBP immunostaining and luxol fast blue staining. The animals with higher serum 24S-HC at 6 h and 24 h corresponded to those with more severe motor and cognitive deficits at 35-40 days after HI. These data suggest that 24S-HC could be a novel and early blood biomarker for severity of neonatal HI brain damage and associated functional impairments.

Download Full-text

Hydrogen inhalation protects hypoxic–ischemic brain damage by attenuating inflammation and apoptosis in neonatal rats

Experimental Biology and Medicine ◽

10.1177/1535370219855399 ◽

2019 ◽

Vol 244 (12) ◽

pp. 1017-1027 ◽

Cited By ~ 2

Author(s):

Guojiao Wu ◽

Zhiheng Chen ◽

Peipei Wang ◽

Mingyi Zhao ◽

Masayuki Fujino ◽

...

Keyword(s):

Brain Injury ◽

Inflammatory Response ◽

Spatial Memory ◽

Brain Damage ◽

Morris Water Maze Test ◽

Ischemic Brain Damage ◽

Ischemic Brain ◽

Hypoxia Ischemia ◽

The Brain

Hypoxic–ischemic brain damage (HIBD) is one of the leading causes of brain injury in infant with high risk of mortality and disability; therefore, it is important to explore more feasible and effective treatment strategies. Here, we assessed the neuroprotective effects of different hydrogen inhalation times for the treatment of HIBD. We induced hypoxia–ischemia in Sprague–Dawley rats (postnatal day 7, both sexes), followed by treatment with hydrogen inhalation for 30, 60, or 90 min. Morphological brain injury was assessed by Nissl and TUNEL staining. Acute inflammation was evaluated by examining the expression of interleukin-1β (IL-1β) and NF-κB p65, as well as Iba-1 immunofluorescence in the brain. Neural apoptosis was evaluated by examining the expression of P-JNK and p53 as well as NeuN immunofluorescence. Neurobehavioral function of rats was evaluated by Morris water maze test at 36 days after surgery. The results showed that hypoxia–ischemia injury induced the inflammatory response of microglia; however, these changes were inhibited by hydrogen inhalation. The inhibitory effects became more apparent as the treatment duration increased ( P < 0.05). Furthermore, hypoxia–ischemia induced neuronal damage and increased the expression of the apoptotic factors, P-JNK, and p53, which were attenuated by hydrogen inhalation ( P < 0.05). Hypoxia–ischemia caused long-term spatial memory deficits during brain maturation, which were ameliorated by hydrogen inhalation ( P < 0.01). In conclusion, hypoxia–ischemia induced severe long-term damage to the brain, which could be alleviated by hydrogen inhalation in a time-dependent manner. Impact statement Oxidative stress is known to be involved in the main pathological progression of neonatal hypoxic–ischemic brain damage (HIBD). Hydrogen (H2) is an antioxidant that can be used to treat HIBD; however, the mechanism by which hydrogen may be used as a promising treatment for neonates with HIBD is not very clear. This study demonstrated that inhaled H2 is neuroprotective against HIBD in SpragueDawley rats by inhibiting the brain’s inflammatory response and neuronal apoptosis or damage and protecting against spatial memory decline. Further, this study showed that inhaled H2 has potential as a therapeutic approach for HIBD. This is relevant to clinical treatment protocols when hypoxia–ischemia is suspected in neonates.

Download Full-text

Neuroprotective Effect of Long-term MgSO4 Administration After Cerebral Hypoxia-Ischemia in Newborn Rats Is Related to the Severity of Brain Damage

Reproductive Sciences ◽

10.1177/1933719107305864 ◽

2007 ◽

Vol 14 (7) ◽

pp. 667-677 ◽

Cited By ~ 25

Author(s):

Evangelia Spandou ◽

Vassiliki Soubasi ◽

Stamatia Papoutsopoulou ◽

Persefoni Augoustides-Savvopoulou ◽

Theodoros Loizidis ◽

...

Keyword(s):

Brain Damage ◽

Neuroprotective Effect ◽

Cerebral Hypoxia ◽

Newborn Rats ◽

Hypoxia Ischemia

Download Full-text

Traumatic Injury to the Developing Brain: Emerging Relationship to Early Life Stress

Frontiers in Neurology ◽

10.3389/fneur.2021.708800 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kaila N. Parker ◽

Michael H. Donovan ◽

Kylee Smith ◽

Linda J. Noble-Haeusslein

Keyword(s):

Brain Injury ◽

Life Stress ◽

Early Life ◽

Brain Injuries ◽

Traumatic Injury ◽

Early Life Stress ◽

Early Age ◽

Functional Impairments ◽

The Brain

Despite the high incidence of brain injuries in children, we have yet to fully understand the unique vulnerability of a young brain to an injury and key determinants of long-term recovery. Here we consider how early life stress may influence recovery after an early age brain injury. Studies of early life stress alone reveal persistent structural and functional impairments at adulthood. We consider the interacting pathologies imposed by early life stress and subsequent brain injuries during early brain development as well as at adulthood. This review outlines how early life stress primes the immune cells of the brain and periphery to elicit a heightened response to injury. While the focus of this review is on early age traumatic brain injuries, there is also a consideration of preclinical models of neonatal hypoxia and stroke, as each further speaks to the vulnerability of the brain and reinforces those characteristics that are common across each of these injuries. Lastly, we identify a common mechanistic trend; namely, early life stress worsens outcomes independent of its temporal proximity to a brain injury.

Download Full-text

Isoflurane Preconditioning Improves Long-term Neurologic Outcome after Hypoxic–Ischemic Brain Injury in Neonatal Rats

Anesthesiology ◽

10.1097/01.anes.0000291447.21046.4d ◽

2007 ◽

Vol 107 (6) ◽

pp. 963-970 ◽

Cited By ~ 70

Author(s):

Ping Zhao ◽

Longyun Peng ◽

Liaoliao Li ◽

Xuebing Xu ◽

Zhiyi Zuo

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Brain Ischemia ◽

Neurologic Outcome ◽

Hypoxia Ischemia ◽

Oxide Synthase ◽

The Brain ◽

Inducible Nitric Oxide

Background Preconditioning the brain with relatively safe drugs seems to be a viable option to reduce ischemic brain injury. The authors and others have shown that the volatile anesthetic isoflurane can precondition the brain against ischemia. Here, the authors determine whether isoflurane preconditioning improves long-term neurologic outcome after brain ischemia. Methods Six-day-old rats were exposed to 1.5% isoflurane for 30 min at 24 h before the brain hypoxia-ischemia that was induced by left common carotid arterial ligation and then exposure to 8% oxygen for 2 h. The neuropathology, motor coordination, and learning and memory functions were assayed 1 month after the brain ischemia. Western analysis was performed to quantify the expression of the heat shock protein 70, Bcl-2, and survivin 24 h after isoflurane exposure. Results The mortality was 45% after brain hypoxia-ischemia. Isoflurane preconditioning did not affect this mortality. However, isoflurane preconditioning attenuated ischemia-induced loss of neurons and brain tissues, such as cerebral cortex and hippocampus in the survivors. Isoflurane also improved the motor coordination of rats at 1 month after ischemia. The learning and memory functions as measured by performance of Y-maze and social recognition tasks in the survivors were not affected by the brain hypoxia-ischemia or isoflurane preconditioning. The expression of Bcl-2, a well-known antiapoptotic protein, in the hippocampus is increased after isoflurane exposure. This increase was reduced by the inhibitors of inducible nitric oxide synthase. Inducible nitric oxide synthase inhibition also abolished isoflurane preconditioning-induced neuroprotection. Conclusions Isoflurane preconditioning improved the long-term neurologic outcome after brain ischemia. Inducible nitric oxide synthase may be involved in this neuroprotection.

Download Full-text

Benzodiazepine Receptors in the Periphery

The Benzodiazepines Crisis ◽

10.1093/med/9780197517277.003.0006 ◽

2020 ◽

pp. 81-96

Author(s):

Robert B. Raffa

Keyword(s):

Immune Function ◽

Cholesterol Metabolism ◽

Benzodiazepine Receptors ◽

Benzodiazepine Receptor ◽

Peripheral Benzodiazepine Receptor ◽

Pharmacologic Effect ◽

Ion Influx ◽

Transmembrane Potential Difference ◽

The Brain

The benzodiazepines are almost universally thought to produce one and only one pharmacologic effect: positive allosteric modulation of GABAA receptors located in the brain. This results in an increased Cl−ion influx, greater negative transmembrane potential difference, and neurons that are less likely to fire in response to anxiety-producing stimulation. Unfortunately, the simplicity and success of this mono-target belief has distracted researchers and clinicians from studying and appreciating their other pharmacology. A glaring example is the general lack of awareness of the peripheral benzodiazepine receptor. The peripheral benzodiazepine receptor alters mitochondrial function (energy supply), cholesterol transport, and immune function. A patient who is on long-term benzodiazepine therapy (or withdrawing from them) will have these sites affected, just as are the sites located in the brain. One can easily imagine that the adverse effects associated with the peripheral sites would be fundamental, varied, and potentially profound—involving lack of energy, altered cholesterol metabolism, and aberrant immune function.

Download Full-text

Brain Damage in Diabetes Mellitus

The British Journal of Psychiatry ◽

10.1192/bjp.122.3.337 ◽

1973 ◽

Vol 122 (568) ◽

pp. 337-341 ◽

Cited By ~ 76

Author(s):

R. N. Bale

Keyword(s):

Diabetes Mellitus ◽

Central Nervous System ◽

Brain Damage ◽

Cerebrovascular Accident ◽

Diabetic Encephalopathy ◽

Autopsy Study ◽

The Central Nervous System ◽

Permanent Brain Damage ◽

The Brain

Several previous studies have demonstrated involvement of the central nervous system in diabetes mellitus. Reske-Nielsen and Lundbaek (1963) gave a description of cerebral changes seen in an autopsy study of three cases of long term diabetes and considered these to contribute a diabetic encephalopathy. Lawrence et al. (1942) demonstrated lesions in the brain following fatal hypoglycaemia, and Fineberg and Altschul (1952) described cases in which permanent brain damage followed non-fatal hypoglycaemia. Grunnet (1963) found cerebral atherosclerosis to develop at an earlier age and more severely in the diabetic than the non-diabetic, and a higher incidence of cerebrovascular accident was found in diabetic than non-diabetic subjects by Alex et al. (1962).

Download Full-text

Measuring the Accentuation of the Brain Damage That Arises from Perinatal Cerebral Hypoxia-Ischemia

Neonatology ◽

10.1159/000244483 ◽

1997 ◽

Vol 72 (3) ◽

pp. 187-191 ◽

Cited By ~ 32

Author(s):

Robert C. Vannucci ◽

Anthony Rossini ◽

Javad Towfighi ◽

Susan J. Vannucci

Keyword(s):

Brain Damage ◽

Cerebral Hypoxia ◽

Hypoxia Ischemia ◽

The Brain

Download Full-text

Transcranial Ultrasound Stimulation Improves Long-Term Functional Outcomes and Protects Against Brain Damage in Traumatic Brain Injury

Molecular Neurobiology ◽

10.1007/s12035-018-0897-z ◽

2018 ◽

Vol 55 (8) ◽

pp. 7079-7089 ◽

Cited By ~ 6

Author(s):

Szu-Fu Chen ◽

Wei-Shen Su ◽

Chun-Hu Wu ◽

Tsuo-Hung Lan ◽

Feng-Yi Yang

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Damage ◽

Functional Outcomes ◽

Transcranial Ultrasound ◽

Ultrasound Stimulation

Download Full-text

Failure of Iron Chelators to Protect Against Cerebral Infarction in Hypoxia-Ischemia

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100047387 ◽

1993 ◽

Vol 20 (1) ◽

pp. 41-43 ◽

Cited By ~ 11

Author(s):

V. MacMillan ◽

I. Fridovich ◽

J. Davis

Keyword(s):

Carbon Monoxide ◽

Cerebral Infarction ◽

Brain Damage ◽

Histological Examination ◽

Iron Chelators ◽

Ischemic Brain ◽

Hypoxia Ischemia ◽

The Mean ◽

Preliminary Study ◽

The Brain

ABSTRACT:In this study the ability of iron chelators to attenuate hypoxic-ischemic brain damage was assessed in hyperglycemic rats that were exposed to 1% carbon monoxide and right carotid occlusion. The animals received deferoxamine (50 mg/kg), manganese-deferoxamine (50 mg/kg) or vehicle i.p. 0.5 h prior to hypoxemic-ischemic exposure and at 0.5, 3 and 24 h post-exposure; with subsequent histological examination of the brain at 7 days recovery. The area of cerebral infarction was measured at three levels using video imaging methods. The mean percentage of total hemisphere that was infarcted in the three groups was: vehicle — 28.5 ± 5.0; deferoxamine — 31.7 ± 12.1; and manganese deferoxamine — 30.6 ± 6.8 (p - n.s.). The results as obtained in this preliminary study indicate that aggressive pre- and post-treatment with iron chelators has no ability to attenuate cerebral infarction in this model.

Download Full-text