Partial Neural Protection with Prophylactic Low-Dose Melatonin after Asphyxia in Preterm Fetal Sheep

Melatonin is a naturally occurring indolamine with mild antioxidant properties that is neuroprotective in perinatal animals. There is limited information on its effects on preterm brain injury. In this study, 23 chronically instrumented fetal sheep received 25 minutes of complete umbilical cord occlusion at 101 to 104 days gestation (term is 147 days). Melatonin was administered to the ewe 15 minutes before occlusion (0.1 mg/kg bolus followed by 0.1 mg/kg per hour for 6 hours, n=8), or the equivalent volume of vehicle (2% ethanol, n=7), or saline ( n=8), or maternal saline plus sham occlusion ( n=8). Sheep were killed after 7 days recovery in utero. Fetal blood pressure, heart rate, nuchal activity, and temperature were similar between groups. Vehicle infusion was associated with improved neuronal survival in the caudate nucleus, but greater neuronal loss in the regions of the hippocampus, with reduced proliferation and increased ameboid microglia in the white matter ( P<0.05). Maternal melatonin infusion was associated with faster recovery of fetal EEG, prolonged reduction in carotid blood flow, similar neuronal survival to vehicle, improved numbers of mature oligodendrocytes, and reduced microglial activation in the white matter ( P<0.05). Prophylactic maternal melatonin treatment is partially protective but its effects may be partly confounded by ethanol used to dissolve melatonin.

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The Effect of Antenatal Betamethasone on White Matter Inflammation and Injury in Fetal Sheep and Ventilated Preterm Lambs

Developmental Neuroscience ◽

10.1159/000496466 ◽

2018 ◽

Vol 40 (5-6) ◽

pp. 497-507 ◽

Cited By ~ 2

Author(s):

Vanesa Stojanovska ◽

Samantha K. Barton ◽

Mary Tolcos ◽

Andrew W. Gill ◽

Martin Kluckow ◽

...

Keyword(s):

Oxidative Stress ◽

White Matter ◽

Oxygen Delivery ◽

Late Preterm ◽

Limited Information ◽

Fetal Sheep ◽

Activated Microglia ◽

Protein Extravasation ◽

To Receive ◽

And Oxidative Stress

Antenatal administration of betamethasone (BM) is a common antecedent of preterm birth, but there is limited information about its impact on the acute evolution of preterm neonatal brain injury. We aimed to compare the effects of maternal BM in combination with mechanical ventilation on the white matter (WM) of late preterm sheep. At 0.85 of gestation, pregnant ewes were randomly assigned to receive intra-muscular (i.m.) saline (n = 9) or i.m. BM (n = 13). Lambs were delivered and unventilated controls (UVCSal, n = 4; UVCBM, n = 6) were humanely killed without intervention; ventilated lambs (VentSal, n = 5; VentBM, n = 7) were injuriously ventilated for 15 min, followed by conventional ventilation for 75 min. Cardiovascular and cerebral haemodynamics and oxygenation were measured continuously. The cerebral WM underwent assessment of inflammation and injury, and oxidative stress was measured in the cerebrospinal fluid (CSF). In the periventricular and subcortical WM tracts, the proportion of amoeboid (activated) microglia, the density of astrocytes, and the number of blood vessels with protein extravasation were higher in UVCBM than in UVCSal (p < 0.05 for all). During ventilation, tidal volume, mean arterial pressure, carotid blood flow, and oxygen delivery were higher in VentBM lambs (p < 0.05 vs. VentSal). In the subcortical WM, microglial infiltration was increased in the VentSal group compared to UVCSal. The proportion of activated microglia and protein extravasation was higher in the VentBM group compared to VentSal within the periventricular and subcortical WM tracts (p < 0.05). CSF oxidative stress was increased in the VentBM group compared to UVCSal, UVCBM, and VentSal groups (p < 0.05). Antenatal BM was associated with inflammation and vascular permeability in the WM of late preterm fetal sheep. During the immediate neonatal period, the increased carotid perfusion and oxygen delivery in BM-treated lambs was associated with increased oxidative stress, microglial activation and microvascular injury.

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Magnesium sulfate reduces EEG activity but is not neuroprotective after asphyxia in preterm fetal sheep

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16655548 ◽

2016 ◽

Vol 37 (4) ◽

pp. 1362-1373 ◽

Cited By ~ 19

Author(s):

Robert Galinsky ◽

Vittoria Draghi ◽

Guido Wassink ◽

Joanne O Davidson ◽

Paul P Drury ◽

...

Keyword(s):

White Matter ◽

Magnesium Sulfate ◽

Marked Reduction ◽

Neuronal Loss ◽

Periventricular White Matter ◽

Fetal Sheep ◽

Eeg Activity ◽

Fetal Movements ◽

To Receive ◽

Anticonvulsant Effects

Magnesium sulfate is now widely recommended for neuroprotection for preterm birth; however, this has been controversial because there is little evidence that magnesium sulfate is neuroprotective. Preterm fetal sheep (104 days gestation; term is 147 days) were randomly assigned to receive sham occlusion (n = 7), i.v. magnesium sulfate (n = 10) or saline (n = 8) starting 24 h before asphyxia until 24 h after asphyxia. Sheep were killed 72 h after asphyxia. Magnesium sulfate infusion reduced electroencephalograph power and fetal movements before asphyxia. Magnesium sulfate infusion did not affect electroencephalograph power during recovery, but was associated with marked reduction of the post-asphyxial seizure burden (mean ± SD: 34 ± 18 min vs. 107 ± 74 min, P < 0.05). Magnesium sulfate infusion did not affect subcortical neuronal loss. In the intragyral and periventricular white matter, magnesium sulfate was associated with reduced numbers of all (Olig−2+ve) oligodendrocytes in the intragyral (125 ± 23 vs. 163 ± 38 cells/field) and periventricular white matter (162 ± 39 vs. 209 ± 44 cells/field) compared to saline-treated controls ( P < 0.05), but no effect on microglial induction or astrogliosis. In conclusion, a clinically comparable dose of magnesium sulfate showed significant anticonvulsant effects after asphyxia in preterm fetal sheep, but did not reduce asphyxia-induced brain injury and exacerbated loss of oligodendrocytes.

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Subclinical exposure to low-dose endotoxin impairs EEG maturation in preterm fetal sheep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00216.2012 ◽

2012 ◽

Vol 303 (3) ◽

pp. R270-R278 ◽

Cited By ~ 29

Author(s):

Michael J. Keogh ◽

Laura Bennet ◽

Paul P. Drury ◽

Lindsea C. Booth ◽

Sam Mathai ◽

...

Keyword(s):

White Matter ◽

Plasma Cortisol ◽

Low Dose ◽

Blood Gases ◽

Power Spectral Analysis ◽

Periventricular White Matter ◽

Fetal Sheep ◽

Beta Power ◽

Dose Infusion ◽

Arterial Plasma

Exposure to chorioamnionitis is strongly associated with neurodevelopmental disability after premature birth; however, it remains unclear whether subclinical infection affects functional EEG maturation. Chronically instrumented 103–104-day-old (0.7 gestational age: term 147 days) fetal sheep in utero were randomized to receive either gram-negative LPS by continuous low-dose infusion (100 ng iv over 24 h, followed by 250 ng/24 h for 4 days; n = 6) or the same volume of normal saline ( n = 9). Arterial plasma cortisol, ACTH, and IL-6 were measured. The delta (0–3.9 Hz), theta (4–7.9 Hz), alpha (8–12.9 Hz), and beta (13–22 Hz) components of the EEG were determined by power spectral analysis. Brains were taken after 10 days for histopathology. There were no changes in blood gases, cardiovascular variables, or EEG power during LPS infusion, but a transient rise in plasma cortisol and IL-6 ( P < 0.05). LPS infusion was associated with loss of the maturational increase to higher frequency activity, with reduced alpha and beta power, and greater delta power than saline controls from 6 to 10 days ( P < 0.05). Histologically, LPS was associated with increased numbers of microglia and TNF-α-positive cells in the periventricular white matter and frontoparietal cortex, increased caspase-3-positive cells in white matter, but no loss of CNPase-positive oligodendrocytes, Nurr-1 subplate cells, or gyral complexity. These data suggest that low-dose endotoxin exposure can impair EEG maturation in preterm fetal sheep in association with neural inflammation but without hemodynamic disturbances or cortical injury.

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Ambroxol Improves Neuronal Survival and Reduces White Matter Damage through Suppressing Endoplasmic Reticulum Stress in Microglia after Intracerebral Hemorrhage

BioMed Research International ◽

10.1155/2020/8131286 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Xuheng Jiang ◽

Ji Zhang ◽

Bojin Kou ◽

Chao Zhang ◽

Jun Zhong ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

White Matter ◽

Endoplasmic Reticulum Stress ◽

Intracerebral Hemorrhage ◽

Microglial Activation ◽

Neuronal Survival ◽

Public Health Problem ◽

Additional Treatment ◽

White Matter Damage ◽

Overall Mortality

Intracerebral hemorrhage (ICH) has been becoming a serious public health problem. Pneumonia, occurring in 43% of all ICH patients, is a common complication heavily influencing outcome and accounting for more than 1/3 of the overall mortality in patients with ICH. Ambroxol may be an effective additional treatment for ICH patients with pneumonia. But its effect and potential mechanism on functional recovery post-ICH still remain elusive. In the present study, the results indicated that 35 mg/kg and 70 mg/kg ambroxol facilitated neuronal survival and reduced white matter fiber bundle damage due to mitigating microglial activation and reducing proinflammatory cytokine accumulation in mice with ICH. The possible mechanism might be due to suppressing endoplasmic reticulum stress involving the IRE1α/TRAF2 signaling pathway, which paves a new path for the treatment of ICH and opens a new window for the use of ambroxol in clinical practice.

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Lipopolysaccharide-Induced Preconditioning Attenuates Apoptosis and Differentially Regulates TLR4 and TLR7 Gene Expression after Ischemia in the Preterm Ovine Fetal Brain

Developmental Neuroscience ◽

10.1159/000433422 ◽

2015 ◽

Vol 37 (6) ◽

pp. 497-514 ◽

Cited By ~ 13

Author(s):

Simerdeep K. Dhillon ◽

Alistair J. Gunn ◽

Yewon Jung ◽

Sam Mathai ◽

Laura Bennet ◽

...

Keyword(s):

Microglial Activation ◽

Low Dose ◽

Fetal Brain ◽

Acute Ischemia ◽

Dependent Manner ◽

Fetal Sheep ◽

Fetal Plasma ◽

Important Mediator ◽

Cellular Apoptosis ◽

Ovine Fetal

Acute exposure to subclinical infection modulates subsequent hypoxia-ischemia (HI) injury in a time-dependent manner, likely by cross-talk through Toll-like receptors (TLRs), but the specific pathways are unclear in the preterm-equivalent brain. In the present study, we tested the hypothesis that repeated low-dose exposure to lipopolysaccharide (LPS) before acute ischemia would be associated with induction of specific TLRs that are potentially neuroprotective. Fetal sheep at 0.65 gestation (term is ∼145 days) received intravenous boluses of low-dose LPS for 5 days (day 1, 50 ng/kg; days 2-5, 100 ng/kg) or the same volume of saline. Either 4 or 24 h after the last bolus of LPS, complete carotid occlusion was induced for 22 min. Five days after LPS, brains were collected. Pretreatment with LPS for 5 days decreased cellular apoptosis, microglial activation and reactive astrogliosis in response to HI injury induced 24 but not 4 h after the last dose of LPS. This was associated with upregulation of TLR4, TLR7 and IFN-β mRNA, and increased fetal plasma IFN-β concentrations. The association of reduced white matter apoptosis and astrogliosis after repeated low-dose LPS finishing 24 h but not 4 h before cerebral ischemia, with central and peripheral induction of IFN-β, suggests the possibility that IFN-β may be an important mediator of endogenous neuroprotection in the developing brain.

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Acute on chronic exposure to endotoxin in preterm fetal sheep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00388.2012 ◽

2013 ◽

Vol 304 (3) ◽

pp. R189-R197 ◽

Cited By ~ 14

Author(s):

Sam Mathai ◽

Lindsea C. Booth ◽

Joanne O. Davidson ◽

Paul P. Drury ◽

Mhoyra Fraser ◽

...

Keyword(s):

White Matter ◽

Low Dose ◽

White Matter Lesions ◽

White Matter Injury ◽

Fetal Mortality ◽

High Dose ◽

Periventricular White Matter ◽

Fetal Sheep ◽

Severe Hypotension ◽

Dose Infusion

Acute, high-dose exposure to endotoxin lipopolysaccharide (LPS) in preterm fetal sheep can trigger periventricular white matter lesions (PVL), in association with severe hypotension/hypoxemia and significant mortality. Intriguingly, however, chronic or repeated exposure to LPS can induce tachyphylaxis. We therefore tested the hypothesis that progressive, acute on chronic fetal infection would be associated with white matter injury with little fetal mortality. Chronically instrumented preterm (0.7 gestational age) fetal sheep were exposed to a continuous low-dose LPS infusion (100 ng over 24 h, followed by 250 ng/24 h for 96 h) or saline. Boluses of 1 μg LPS or saline were given at 48, 72, and 96 h; sheep were killed at day 10. Six of 11 fetal sheep exposed to saline infusion + LPS boluses died 4–7 h after the first bolus. In contrast, there was no fetal mortality after saline infusions alone ( n = 9), low-dose LPS infusion + saline boluses ( n = 5), or low-dose LPS + LPS boluses ( n = 9). Low-dose LPS infusion + LPS boluses was associated with greater microglial induction than low-dose LPS + saline boluses but a similar area of periventricular white matter inflammation. One fetus developed severe focal white matter necrosis after LPS infusion + boluses. The acute cardiovascular compromise associated with high-dose, acute exposure to LPS is markedly attenuated by previous low-dose infusions, with limited apparent exacerbation of periventricular white matter injury compared with low-dose infusion alone.

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Flavonoids as Potential Therapeutic Agents for the Management of Diabetic Neuropathy

Current Pharmaceutical Design ◽

10.2174/1381612826666200826164322 ◽

2020 ◽

Vol 26 (42) ◽

pp. 5468-5487 ◽

Cited By ~ 1

Author(s):

Ankita Sood ◽

Bimlesh Kumar ◽

Sachin Kumar Singh ◽

Pankaj Prashar ◽

Anamika Gautam ◽

...

Keyword(s):

Neuropathic Pain ◽

Diabetic Neuropathy ◽

Glucose Utilization ◽

Antioxidant Properties ◽

Therapeutic Agents ◽

Secondary Complications ◽

Naturally Occurring ◽

Glycation End Products ◽

Treatment Of Diabetes ◽

Pharmaceutical Industries

Flavonoids are secondary metabolites that are widely distributed in plants. These phenolic compounds are classified into various subgroups based on their structures: flavones, flavonols, isoflavones, flavanones, and anthocyanins. They are known to perform various pharmacological actions like antioxidant, anti-inflammatory, anticancer, antimicrobial, antidiabetic and antiallergic, etc. Diabetes is a chronic progressive metabolic disorder that affects several biochemical pathways and leads to secondary complications such as neuropathy, retinopathy, nephropathy, and cardiomyopathy. Among them, the management of diabetic neuropathy is one of the major challenges for physicians as well as the pharmaceutical industries. Naturally occurring flavonoids are extensively used for the treatment of diabetes and its related complications due to their antioxidant properties. Moreover, flavonoids inhibit various pathways that are involved in the progression of diabetic neuropathy like the reduction of oxidative stress, decrease in glycogenolysis, increase glucose utilization, decrease in the formation of advanced glycation end products, and inhibition of the α-glucosidase enzyme. This review entails current updates on the therapeutic perspectives of flavonoids in the treatment of neuropathic pain. This manuscript explains the pathological aspects of neuropathic pain, the chemistry of flavonoids, and their application in amelioration of neuropathic pain through preclinical studies either alone or in combination with other therapeutic agents.

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The Potential Effects of Phytoestrogens: The Role in Neuroprotection

Molecules ◽

10.3390/molecules26102954 ◽

2021 ◽

Vol 26 (10) ◽

pp. 2954

Author(s):

Justyna Gorzkiewicz ◽

Grzegorz Bartosz ◽

Izabela Sadowska-Bartosz

Keyword(s):

Neuroprotective Effect ◽

Antioxidant Properties ◽

Estrogen Therapy ◽

Neuroprotective Effects ◽

Potential Health ◽

Naturally Occurring ◽

Epigenetic Effects ◽

Estrogen Synthesis ◽

Health Promoting ◽

The Brain

Phytoestrogens are naturally occurring non-steroidal phenolic plant compounds. Their structure is similar to 17-β-estradiol, the main female sex hormone. This review offers a concise summary of the current literature on several potential health benefits of phytoestrogens, mainly their neuroprotective effect. Phytoestrogens lower the risk of menopausal symptoms and osteoporosis, as well as cardiovascular disease. They also reduce the risk of brain disease. The effects of phytoestrogens and their derivatives on cancer are mainly due to the inhibition of estrogen synthesis and metabolism, leading to antiangiogenic, antimetastatic, and epigenetic effects. The brain controls the secretion of estrogen (hypothalamus-pituitary-gonads axis). However, it has not been unequivocally established whether estrogen therapy has a neuroprotective effect on brain function. The neuroprotective effects of phytoestrogens seem to be related to both their antioxidant properties and interaction with the estrogen receptor. The possible effects of phytoestrogens on the thyroid cause some concern; nevertheless, generally, no serious side effects have been reported, and these compounds can be recommended as health-promoting food components or supplements.

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Therapeutics potentiating microglial p21-Nrf2 axis can rescue neurodegeneration caused by neuroinflammation

Science Advances ◽

10.1126/sciadv.abc1428 ◽

2020 ◽

Vol 6 (46) ◽

pp. eabc1428

Author(s):

A. Nakano-Kobayashi ◽

A. Fukumoto ◽

A. Morizane ◽

D. T. Nguyen ◽

T. M. Le ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Neuronal Survival ◽

Disease Model ◽

Neuronal Loss ◽

Induced Pluripotent Stem Cell ◽

Related Factor ◽

Induced Pluripotent ◽

Novel Therapeutic

Neurodegenerative disorders are caused by progressive neuronal loss, and there is no complete treatment available yet. Neuroinflammation is a common feature across neurodegenerative disorders and implicated in the progression of neurodegeneration. Dysregulated activation of microglia causes neuroinflammation and has been highlighted as a treatment target in therapeutic strategies. Here, we identified novel therapeutic candidate ALGERNON2 (altered generation of neurons 2) and demonstrate that ALGERNON2 suppressed the production of proinflammatory cytokines and rescued neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–induced Parkinson’s disease model. ALGERNON2 stabilized cyclinD1/p21 complex, leading to up-regulation of nuclear factor erythroid 2–related factor 2 (Nrf2), which contributes to antioxidative and anti-inflammatory responses. Notably, ALGERNON2 enhanced neuronal survival in other neuroinflammatory conditions such as the transplantation of induced pluripotent stem cell–derived dopaminergic neurons into murine brains. In conclusion, we present that the microglial potentiation of the p21-Nrf2 pathway can contribute to neuronal survival and provide novel therapeutic potential for neuroinflammation-triggered neurodegeneration.

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