ACTH and PMX53 recover synaptic transcriptome alterations in a rat model of infantile spasms

Iacobaş, Dumitru A.; Chachua, Tamar; Iacobaş, Sanda; Benson, Melissa J.; Borges, Karin; Velı́šková, Jana; Velı́šek, Libor

doi:10.1038/s41598-018-24013-x

Cited by 25 publications

(33 citation statements)

References 61 publications

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“…CUT (Eq.1) adds correction for the groups of microarray spots probing redundantly the same gene. The corrected Weighted Pathway Regulation (WPR, [33] Like in previous experiments with kidneys [34] and hearts of mice subjected to chronic hypoxia [28,35,36], we computed the pair-wise Pearson correlation coefficient ρij between the expression levels of all pairs of expressed genes i and j in biological replicas of each condition. As speculated in previous papers [37,38], strong expression correlation of two genes may represent a kind of "transcriptomic stoichiometry" aiming to optimize the pathway involving the encoded proteins.…”

Section: Assessment Of Right Ventricular Hypertrophy (Rvh)mentioning

confidence: 99%

Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

Mathew

Huang

Iacobaş

et al. 2019

Preprint

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Pulmonary hypertension (PH) is a serious disorder with high morbidity and mortality rate. We analyzed the right ventricular systolic pressure (RVSP), right ventricular hypertrophy (RVH), lung histology and transcriptomes of six weeks old male rats with PH induced by: 1) hypoxia (HO), 2) administration of monocrotaline (CM) or 3) administration of monocrotaline and exposure to hypoxia (HM). The results in PH rats were compared to those in control rats (CO). After four weeks exposure, increased RVSP and RVH, pulmonary arterial wall thickening, and alteration of the lung transcriptome were observed in all PH groups. The HM group exhibited the largest alterations and also neointimal lesions and obliteration of lumen in small arteries. We found that the PH increased the expression of caveolin1, matrix metallopeptidase 2 and numerous inflammatory and cell proliferation genes. The cell-cycle, vascular smooth muscle contraction and the oxidative phosphorylation pathways, as well as their interplay were largely perturbed. Our results also suggest that the up-regulated Rhoa (ras homolog family member A) mediates its action through expression coordination with several ATPases. The upregulation of antioxidant genes and the extensive mitochondrial damage observed especially in HM group, indicate metabolic shift towards aerobic glycolysis.

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Section: Assessment Of Right Ventricular Hypertrophy (Rvh)mentioning

confidence: 99%

Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

Mathew

Huang

Iacobaş

et al. 2019

Preprint

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“…In the NMDA IS model, the transcription of approximately 30% of hypothalamic genes was altered, with significantly greater changes in males. ACTH and PMX53 both restored these transcriptional changes back to control levels [77].…”

Section: Increased Glutamate Receptor Activation: Prenatal Stress/nmdmentioning

confidence: 89%

“…Evidence linking epilepsy and neuroinflammation has grown over the past decade, providing another potential therapeutic target in IS [76]. PMX53 is a potent inhibitor of the complement factor 5a receptor (C5ar1) and it has shown promise in epilepsy models [77]. Inhibiting this receptor during status epilepticus reduced tumor necrosis factor alpha (TNF-α) [78], a major inflammatory cytokine, which, along with interleukin 1 beta (IL-1β), initiates the immune response in the CNS, leading to neuronal damage and hyperexcitability [79].…”

Section: Increased Glutamate Receptor Activation: Prenatal Stress/nmdmentioning

confidence: 99%

Infantile Spasms: An Update on Pre-Clinical Models and EEG Mechanisms

Janicot¹,

Shao²,

Stafstrom³

2020

Children

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Infantile spasms (IS) is an epileptic encephalopathy with unique clinical and electrographic features, which affects children in the middle of the first year of life. The pathophysiology of IS remains incompletely understood, despite the heterogeneity of IS etiologies, more than 200 of which are known. In particular, the neurobiological basis of why multiple etiologies converge to a relatively similar clinical presentation has defied explanation. Treatment options for this form of epilepsy, which has been described as “catastrophic” because of the poor cognitive, developmental, and epileptic prognosis, are limited and not fully effective. Until the pathophysiology of IS is better clarified, novel treatments will not be forthcoming, and preclinical (animal) models are essential for advancing this knowledge. Here, we review preclinical IS models, update information regarding already existing models, describe some novel models, and discuss exciting new data that promises to advance understanding of the cellular mechanisms underlying the specific EEG changes seen in IS—interictal hypsarrhythmia and ictal electrodecrement.

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“…In a recent study (Iacobas et al, 2018 ) on a rat model of infantile spasms, we have analyzed how the epileptic spasms alter the neurotransmission in the hypothalamic arcuate nucleus and how the ACTH or PMX53 (a potent complement C5ar1 antagonist) treatment recovers most of these alterations. Thus, the question exists whether initiation of the E2 replacement in adult OVX females following the SE would also rescue the deteriorating effects of SE.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Protects Neurotransmission Transcriptome During Status Epilepticus

Iacobaş

Nebieridze

et al. 2018

Front. Neurosci.

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Women with epilepsy commonly have premature onset of menopause. The decrease in estrogen levels is associated with increased occurrence of neurodegenerative processes and cognitive decline. Previously, we found that estradiol (E2) replacement in ovariectomized (OVX) female rats significantly reduced the seizure-related damage in the sensitive hilar region of hippocampal dentate gyrus (DG). However, the complex mechanisms by which E2 empowers the genomic fabrics of neurotransmission to resist damaging effects of status epilepticus (SE) are still unclear. We determined the protective effects of the estradiol replacement against kainic acid-induced SE-associated transcriptomic alterations in the DG of OVX rats. Without E2 replacement, SE altered expression of 44% of the DG genes. SE affected all major functional pathways, including apoptosis (61%), Alzheimer's disease (47%), cell cycle (59%), long-term potentiation (62%), and depression (55%), as well as synaptic vesicle cycle (62%), glutamatergic (53%), GABAergic (49%), cholinergic (52%), dopaminergic (55%), and serotonergic (49%) neurotransmission. However, in rats with E2 replacement the percentage of significantly affected genes after SE was reduced to the average 11% (from 8% for apoptosis to 32% for GABAergic synapse). Interestingly, while SE down-regulated most of the synaptic receptor genes in oil-injected females it had little effect on these receptors after E2-replacement. Our novel Pathway Protection analysis indicated that the E2-replacement prevented SE-related damage from 50% for GABA to 75% for dopaminergic transmission. The 15% synergistic expression between genes involved in estrogen signaling (ESG) and neurotransmission explains why low E2 levels result in down-regulation of neurotransmission. Interestingly, in animals with E2-replacement, SE switched 131 synergistically expressed ESG-neurotransmission gene pairs into antagonistically expressed gene pairs. Thus, the ESG pathway acts like a buffer against SE-induced alteration of neurotransmission that may contribute to the E2-mediated maintenance of brain function after the SE injury in postmenopausal women. We also show that the long-term potentiation is lost in OVX rats following SE but not in those with E2 replacement. The electrophysiological findings in OVX female rats with SE are corroborated by the high percentage of long-term potentiation regulated genes (62%) in oil-injected while only 13% of genes were regulated following SE in E2-replaced rats.

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ACTH and PMX53 recover synaptic transcriptome alterations in a rat model of infantile spasms

Cited by 25 publications

References 61 publications

Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

Infantile Spasms: An Update on Pre-Clinical Models and EEG Mechanisms

Estrogen Protects Neurotransmission Transcriptome During Status Epilepticus

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