Timed fetal inflammation and postnatal hypoxia cause cortical white matter injury, interneuron imbalances, and behavioral deficits in a double-hit rat model of encephalopathy of prematurity

Brain Behavior & Immunity - Health, Journal Year: 2024, Volume and Issue: 40, P. 100817 - 100817

Published: July 5, 2024

Extreme preterm birth-associated adversities are a major risk factor for aberrant brain development, known as encephalopathy of prematurity (EoP), which can lead to long-term neurodevelopmental impairments. Although progress in clinical care infants has markedly improved perinatal outcomes, there currently no curative treatment options available combat EoP. EoP multifactorial etiology, including but not limited pre- or postnatal immune activation and oxygen fluctuations. Elucidating the underlying mechanisms determining efficacy potential therapies relies on valid, clinically translatable experimental models that reflect pathophysiological hallmarks Here, we expand our double-hit rat model be used study disease therapeutic preclinical setting. Pregnant Wistar dams were intraperitoneally injected with 10 μg/kg LPS embryonic day (E)20 offspring was subjected hypoxia (140 min, 8% O

Language: Английский

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Cell-specific vulnerability to metabolic failure: the crucial role of parvalbumin expressing neurons in creatine transporter deficiency

Acta Neuropathologica Communications, Journal Year: 2023, Volume and Issue: 11(1)

Published: March 7, 2023

Abstract Mutations in the solute carrier family 6-member 8 ( Slc6a8 ) gene, encoding protein responsible for cellular creatine (Cr) uptake, cause Creatine Transporter Deficiency (CTD), an X-linked neurometabolic disorder presenting with intellectual disability, autistic-like features, and epilepsy. The pathological determinants of CTD are still poorly understood, hindering development therapies. In this study, we generated extensive transcriptomic profile showing that Cr deficiency causes perturbations gene expression excitatory neurons, inhibitory cells, oligodendrocytes which result remodeling circuit excitability synaptic wiring. We also identified specific alterations parvalbumin-expressing (PV + interneurons, exhibiting a reduction density, hypofunctional electrophysiological phenotype. Mice lacking only PV interneurons recapitulated numerous including cognitive deterioration, impaired cortical processing hyperexcitability brain circuits, demonstrating deficit is sufficient to determine neurological phenotype CTD. Moreover, pharmacological treatment targeted restore efficiency synapses significantly improved activity knock-out animals. Altogether, these data demonstrate critical normal function impairment cells central disease pathogenesis, suggesting novel therapeutic venue

Language: Английский

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Distribution of type 2 diabetes mellitus in chronic hepatitis-c patient; A cross-sectional study conducted in Khyber Teaching Hospital and Khushal Medical Center Peshawar

Deleted Journal, Journal Year: 2025, Volume and Issue: 22(2), P. 76 - 84

Published: Jan. 9, 2025

Background: The prevalence of Hepatitis C virus infections (HCV) and Diabetes Mellitus (DM) is escalating associated with more morbidity mortality. Patient HCV are prone to develop DM this study aims determine the distribution in patients. Methods: This descriptive cross sectional enrolled 160 patients from 27th October 2020 till 26th April 2021 at Medicine Unit, Khyber Teaching Hospital (KTH) Peshawar Khushal Medical Center (KMC) Peshawar. After ethical approval KMC, were screened for DM. detailed interview, blood samples collected subsequently processed glycated hemoglobin A1C (HbA1C). data analyzed using SPSS version 22.0. Results: mean age was 61.1±12.1 years. Similarly, height, weight body mass index (BMI) 71.6±11.4 kg, 166.2±9.7 cm 26.1±4.7 kg/m2 respectively. Family history positive 30.6% while family obesity 23.8% individuals. prevalent 31.3% which 58% newly diagnosed. Statistical significant association observed obese patient than non-obese (p-value 0.03). Furthermore, 12.4 times likely as compared (OR, 95%CI (5.52-28.5). Conclusion: common particularly if obese. It necessary screen control earlier presence type 2 diabetes mellitus also rule out infection among diabetic populations rarely done on population-based studies.

Language: Английский

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The Anticonvulsant and Antioxidant Effect of Rosa Moschata (J) Fruit Extract in Pentylenetetrazole induced Epileptic Mouse Model

Deleted Journal, Journal Year: 2025, Volume and Issue: 22(2), P. 61 - 75

Published: Jan. 9, 2025

Background: Rosa moschata (J) (RM (J)) is widely used as a traditional medicine in different ailments including central nervous system diseases, hepatic and gastrointestinal disease. The current study focused on the anticonvulsant effects memory improvement property of RM fruit extract by modulation oxidative stress markers GABAA receptor pentylenetetrazole (PTZ) induced mice epileptic model. Methods: model was developed using (35 mg/kg). were at doses 50 mg/kg, 100 mg/kg 150 mg/kg. seizure evaluated according to Racine Scale. Cognitive functions Y Maze Morris Water behavioral tests. antioxidant effect measured assessing level lipid peroxidation (LPO), superoxide dismutase (SOD), glutathione (GSH), catalase (CAT). Additionally, expression receptors qPCR. Results: exhibited significant (P<0.5) dose-dependent compared treated with PTZ. Furthermore, significantly increased levels GSH CAT reduced LPO PTZ group. onset time prolong while duration short group Interestingly, there increase groups extract, Conclusions: extracts showed potential due reduction enhanced receptors.

Language: Английский

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A review of the effects of early postnatal hyperoxia exposure on the immature brain

Experimental Neurology, Journal Year: 2023, Volume and Issue: 370, P. 114550 - 114550

Published: Sept. 27, 2023

Preterm birth is a public health priority worldwide, with approximately 15 million premature babies born each year. Oxygen supplementation one of the most common interventions for preterm infants. However, prolonged oxygen inhalation at supraphysiological concentrations can lead to development bronchopulmonary dysplasia (BPD). In addition lifelong pulmonary sequelae, clinical evidence suggests that BPD associated adverse neurodevelopmental outcomes, such as motor impairment, cognitive and behavioral deficits, severely affecting quality life mechanisms underlying combination impairment remain unclear. Therefore, in recent years, attention has also been focused on effects hyperoxia brain this review, we outline pathophysiological injury caused by developmental exposure current animal models briefly describe pharmacological therapies may be applicable injury. Overall, more studies are needed assess immature brain, particularly combined analyses lungs same experimental setting, elucidate potential causes BPD.

Language: Английский

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Melatonin attenuates sevoflurane-induced hippocampal damage and cognitive deficits in neonatal mice by suppressing CypD in parvalbumin neurons

Brain Research Bulletin, Journal Year: 2023, Volume and Issue: 204, P. 110809 - 110809

Published: Nov. 1, 2023

Sevoflurane, a commonly administered inhaled anesthetic, is found to induce synaptic and mitochondrial damage in neonatal mice. Mitochondrial membrane potential (MMP) changes, mediated by Cyclophilin D (CypD), are implicated function. Melatonin, known for its significant neuroprotective properties, was investigated this study elucidate mechanisms mitigating the cognitive impairment caused sevoflurane. The mice were categorized into several groups, including control, vehicle, sevoflurane, vehicle plus melatonin sevoflurane groups. From postnatal day 6 8, or intraperitoneal melatonin. MMP reactive oxygen species (ROS) measured using appropriate detection kits. protein expression levels of PSD95, Synapsin Ⅰ, CypD hippocampus analyzed through western blotting acute prolonged terms. Immunofluorescence staining used assess co-localizations PSD95 parvalbumin (PV) neurons. Cognitive ability evaluated novel object recognition, social interaction experiment, Morris water maze. findings revealed that repeated exposure resulted impairment. Furthermore, administration suppressed ROS expression, enhanced mitochondria PV neurons, ameliorated deficits. Melatonin alleviated sevoflurane-induced deficits suppressing promoting development hippocampal These results provide valuable insights promising therapeutic approach preventing neurotoxic injuries general anesthetics.

Language: Английский

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Mechanistic advances of hyperoxia-induced immature brain injury

Heliyon, Journal Year: 2024, Volume and Issue: 10(9), P. e30005 - e30005

Published: April 22, 2024

The impact of hyperoxia-induced brain injury in preterm infants is being increasingly investigated. However, the parameters and protocols used to study this condition animal models lack consistency. Research further hampered by fact that hyperoxia exerts both direct indirect effects on oligodendrocytes neurons, with precise underlying mechanisms remaining unclear. In article, we aim provide a comprehensive overview conditions induce immature injury. We discuss what known regarding injury, focusing briefly describe therapies may counteract hyperoxia. also identify studies required fully elucidate as well leading therapeutic options.

Language: Английский

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(m) RVD-hemopressin (α) Ameliorated Oxidative Stress, Apoptosis and Damage to the BDNF/TrkB/Akt Pathway Induced by Scopolamine in HT22 Cells

Neurotoxicity Research, Journal Year: 2023, Volume and Issue: 41(6), P. 627 - 637

Published: Nov. 16, 2023

Language: Английский

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Fate of melatonin orally administered in preterm newborns: Antioxidant performance and basis for neuroprotection

Journal of Pineal Research, Journal Year: 2023, Volume and Issue: 76(1)

Published: Dec. 18, 2023

Abstract Preterm infants cannot counteract excessive reactive oxygen species (ROS) production due to preterm birth, leading an excess of lipid peroxidation with malondialdehyde (MDA) production, capable contributing brain damage. Melatonin (ME), endogenous hormone, and its metabolites, act as a free radical scavenger against ROS. Unfortunately, preterms have impaired antioxidant system, resulting in the inability produce release ME. This prospective, multicenter, parallel groups, randomized, double‐blind, placebo‐controlled trial aimed assess: (i) ME very (gestational age ≤ 29 + 6 WE, 28 26 placebo group); (ii) exogenous hormone availability metabolization main metabolite, 6‐OH‐ME after 15 days oral treatment; (iii) difference MDA plasma concentration, marker, treatment. Blood was collected before first administration (T1) (T2). were detected by liquid chromatography tandem mass spectrometry, measured chromatograph fluorescence detection. not detectable group at any study time‐point. absent active T1. In contrast, administration, resulted highly between concentrations T2 versus T1 statistically significant, well treated groups T2. levels seemed stable during treatment both groups. Nevertheless, trend percentage neonates reduced concentration T2/T1 48.1% 38.5% group. We demonstrated that are able their life. Still, following appreciable amounts available. The reduction requires further clinical trials fix dosage, length therapy identify more appropriate indexes demonstrate, biological levels, activity consequent neuroprotectant potential newborns.

Language: Английский

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Oxygen and HIF1α‐dependent SDF1 expression in primary astrocytes

Developmental Neurobiology, Journal Year: 2024, Volume and Issue: 84(3), P. 113 - 127

Published: March 27, 2024

Abstract In the naturally hypoxic in utero fetal environment of preterm infants, oxygen and oxygen‐sensitive signaling pathways play an important role brain development, with hypoxia‐inducible factor‐1α (HIF1α) being regulator. Early exposure to nonphysiological high concentrations by birth room can induce HIF1α degradation may affect neuronal glial development. This involves dysregulation astroglial maturation function, which turn might contribute oxygen‐induced injury. this study, we investigated effects early on and, specifically, stromal cell‐derived factor 1 (SDF1) expression vivo vitro. our neonatal mouse model hyperoxia injury vivo, affected development cortical SDF1 expression. These results were further supported reduced Sdf1 expression, impaired proliferation, decreased total cell number, altered markers astrocytes primary cultures grown under conditions. Moreover, mimic environment, was increased after low vitro, appears be regulated activity. Additionally, knockdown Hif1α revealed HIF1α‐dependent Our indicate oxygen‐dependent chemokine highlight importance conditions for

Language: Английский

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