Cortical Dysplasia in Rats Provokes Neurovascular Alterations, GLUT1 Dysfunction, and Metabolic Disturbances That Are Sustained Post-Seizure Induction

Ghosh, Chaitali; Myers, Rosemary; O'Connor, Christina; Williams, S.P.; Li, Xuefeng; Hossain, Mohammed Kamal; Nemeth, Michael J.; Najm, Imad

doi:10.1007/s12035-021-02624-2

Cited by 6 publications

(2 citation statements)

References 54 publications

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“…Normal human astrocytes (catalog 1800) were purchased from ScienCell Research Laboratories, Inc. (Carlsbad, California) and cultured in poly-D-lysine pre-coated flasks (3 μg/cm 2 ) with appropriate media ( Ghosh et al, 2018 ; Hossain et al, 2020 ). Human dopaminergic neuronal cells (DAN) derived from fetal brain tissues were purchased from ClonExpress (catalog number: DAN 020; Gaithersburg, MD, United States) using the culture media recommended by the manufacturer ( Ghosh et al, 2015 ; Ghosh et al, 2022 ). The neuronal cultures were characterized with anti-human microtubule associated protein 2 (MAP-2) immunohistochemistry (data not shown).…”

Section: Methodsmentioning

confidence: 99%

Cytochrome P450-mediated antiseizure medication interactions influence apoptosis, modulate the brain BAX/Bcl-XL ratio and aggravate mitochondrial stressors in human pharmacoresistant epilepsy

et al. 2022

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Polytherapy with antiseizure medications (ASMs) is often used to control seizures in patients suffering from epilepsy, where about 30% of patients are pharmacoresistant. While drug combinations are intended to be beneficial, the consequence of CYP-dependent drug interactions on apoptotic protein levels and mitochondrial function in the epileptic brain remains unclear. We examined the interactions of ASMs given prior to surgery in surgically resected brain tissues and of three ASMs (lacosamide, LCM; oxcarbazepine, OXC; levetiracetam LEV) in isolated brain cells from patients with drug-resistant epilepsy (n = 23). We divided the patients into groups–those who took combinations of NON-CYP + CYP substrate ASMs, NON-CYP + CYP inducer ASMs, CYP substrate + CYP substrate or CYP substrate + CYP inducer ASMs–to study the 1) pro- and anti-apoptotic protein levels and other apoptotic signaling proteins and levels of reactive oxygen species (reduced glutathione and lipid peroxidation) in brain tissues; 2) cytotoxicity at blood-brain barrier epileptic endothelial cells (EPI-ECs) and subsequent changes in mitochondrial membrane potential in normal neuronal cells, following treatment with LCM + OXC (CYP substrate + CYP inducer) or LCM + LEV (CYP substrate + NON-CYP-substrate) after blood-brain barrier penetration, and 3) apoptotic and mitochondrial protein targets in the cells, pre-and post-CYP3A4 inhibition by ketoconazole and drug treatments. We found an increased BAX (pro-apoptotic)/Bcl-XL (anti-apoptotic) protein ratio in epileptic brain tissue after treatment with CYP substrate + CYP substrate or inducer compared to NON-CYP + CYP substrate or inducer, and subsequently decreased glutathione and elevated lipid peroxidation levels. Further, increased cytotoxicity and Mito-ID levels, indicative of compromised mitochondrial membrane potential, were observed after treatment of LCM + OXC in combination compared to LCM + LEV or these ASMs alone in EPI-ECs, which was attenuated by pre-treatment of CYP inhibitor, ketoconazole. A combination of two CYP-mediated ASMs on EPI-ECs resulted in elevated caspase-3 and cytochrome c with decreased SIRT3 levels and activity, which was rescued by CYP inhibition. Together, the study highlights for the first time that pro- and anti-apoptotic proteins levels are dependent on ASM combinations in epilepsy, modulated via a CYP-mediated mechanism that controls free radicals, cytotoxicity and mitochondrial activity. These findings lead to a better understanding of future drug selection choices offsetting pharmacodynamic CYP-mediated interactions.

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Section: Methodsmentioning

confidence: 99%

Cytochrome P450-mediated antiseizure medication interactions influence apoptosis, modulate the brain BAX/Bcl-XL ratio and aggravate mitochondrial stressors in human pharmacoresistant epilepsy

et al. 2022

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“…The full complement of diverse epilepsy symptoms arises from insults to the underlying functional and genetic networks. After a seizure, pro-inflammatory factors, pro-senescence messengers, and glial activation genes all show an increase in expression from baseline, while pro-survival pathways are down-regulated in damaged neurons (Ghosh et al, 2022). This altered expression state across the brain underlies dysregulation of the neural network that generates seizures and drives cognitive dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of gene expression pathways with dexamethasone and ACTH after early life seizures

Brabec

Ouardouz²,

Mahoney

et al. 2022

Preprint

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Early-life seizures (ELS) are associated with persistent cognitive deficits such as ADHD and memory impairment. These co-morbidities have a dramatic negative impact on the quality of life of patients. Therapies that improve cognitive outcomes have enormous potential to improve patients’ quality of life. Our previous work in a rat flurothyl-induction model showed that administration of adrenocorticotropic hormone (ACTH) at time of seizure induction led to improved learning and memory in the animals despite no effect on seizure latency or duration. Administration of dexamethasone (Dex), a corticosteroid, did not have the same positive effect on learning and memory and has even been shown to exacerbate injury in a rat model of temporal lobe epilepsy. We hypothesized that ACTH exerted positive effects on cognitive outcomes through beneficial changes to gene expression and proposed that administration of ACTH at seizure induction would return gene-expression in the brain towards the normal pattern of expression in the Control animals whereas Dex would not. Twenty-six Sprague-Dawley rats were randomized into vehicle- Control, and ACTH-, Dex-, and vehicle-ELS. Rat pups were subjected to 60 flurothyl seizures from P5 to P15. After seizure induction, brains were removed and the hippocampus and PFC were dissected, RNA was extracted and sequenced, and differential expression analysis was performed using generalized estimating equations. Differential expression analysis showed that ACTH pushes gene expression in the brain back to a more normal state of expression through enrichment of pathways involved in supporting homeostatic balance and down-regulating pathways that might contribute to excitotoxic cell-damage post-ELS.

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GLUT-1 changes in paediatric Huntington disease brain cortex and fibroblasts: an observational case-control study

Tramutola,

Bakels,

Perrone

et al. 2023

eBioMedicine

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Cortical Dysplasia in Rats Provokes Neurovascular Alterations, GLUT1 Dysfunction, and Metabolic Disturbances That Are Sustained Post-Seizure Induction

Cited by 6 publications

References 54 publications

Cytochrome P450-mediated antiseizure medication interactions influence apoptosis, modulate the brain BAX/Bcl-XL ratio and aggravate mitochondrial stressors in human pharmacoresistant epilepsy

Cytochrome P450-mediated antiseizure medication interactions influence apoptosis, modulate the brain BAX/Bcl-XL ratio and aggravate mitochondrial stressors in human pharmacoresistant epilepsy

Differential regulation of gene expression pathways with dexamethasone and ACTH after early life seizures

GLUT-1 changes in paediatric Huntington disease brain cortex and fibroblasts: an observational case-control study

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