Losartan fails to suppress epileptiform activity in brain slices from resected tissues of patients with drug resistant epilepsy

Reyes-García, Selvin Z.; Scorza, Carla A.; Ortiz‐Villatoro, Nancy N.; Cavalheiro, Ésper A.

doi:10.1016/j.jns.2019.01.008

Cited by 9 publications

(6 citation statements)

References 10 publications

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“…A recent publication suggests that telmisartan, another angiotensin receptor 2 antagonist with anti-TGF-β effects, has the potential to reduce seizure frequency when administered as an add-on antiepileptic drug in dogs with refractory idiopathic epilepsy [343]. However, losartan fails to suppress seizure-like activity in cortical and hippocampal areas of human brain slices of patients with drug-resistant TLE, suggesting that further exploration may be required for losartan as an anticonvulsant drug in clinical trials [344]. The biggest hurdle for losartan clinical translation is the knowledge gap in dosing recommendations.…”

Section: Opportunities and Challenges Of Targeting Tgf-β Signaling In...mentioning

confidence: 99%

TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications

Luo

2022

Biomedicines

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Astrocytes are essential for normal brain development and functioning. They respond to brain injury and disease through a process referred to as reactive astrogliosis, where the reactivity is highly heterogenous and context-dependent. Reactive astrocytes are active contributors to brain pathology and can exert beneficial, detrimental, or mixed effects following brain insults. Transforming growth factor-β (TGF-β) has been identified as one of the key factors regulating astrocyte reactivity. The genetic and pharmacological manipulation of the TGF-β signaling pathway in animal models of central nervous system (CNS) injury and disease alters pathological and functional outcomes. This review aims to provide recent understanding regarding astrocyte reactivity and TGF-β signaling in brain injury, aging, and neurodegeneration. Further, it explores how TGF-β signaling modulates astrocyte reactivity and function in the context of CNS disease and injury.

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Section: Opportunities and Challenges Of Targeting Tgf-β Signaling In...mentioning

confidence: 99%

TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications

Luo

2022

Biomedicines

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“…Losartan was also effecJve at reducing seizures and associated neuronal damage in a mouse model of hypertension and epilepsy (TCHEKALAROVA et al 2016). Conversely, (REYES-GARCIA et al 2019) resported that Losartan did not reduce epilepJform acJvity in resected brain slices from human paJents of drug resistant epilepsy. Since the effect on the BBB integrity in the tadpole model was evenJually overcome, Losartan pharmacokineJcs may play a role in this variability.…”

Section: Neurod2 Crispant Tadpole Brains Appear Morphologically Norma...mentioning

confidence: 99%

Knockdown ofNeuroD2leads to seizure-like behaviour, brain neuronal hyperactivity and a leaky blood-brain barrier in aXenopus laevistadpole model of DEE75

Banerjee,

Szyszka,

Beck

2023

Preprint

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Developmental and Epileptic Encephalopathies (DEE) are a genetically diverse group of severe, early onset seizure disorders. DEE are normally identified clinically in the first six months of life by the presence of frequent, difficult to control seizures and accompanying stalling or regression of development. DEE75 results fromde novomutations of theNEUROD2gene that result in loss of activity of the encoded transcription factor, and the seizure phenotype was shown to be recapitulated inXenopus tropicalistadpoles. We used CRISPR/Cas9 to make a DEE75 model inXenopus laevis, to further investigate the developmental aetiology.NeuroD2.SCRISPR/Cas9 edited tadpoles were more active, swam faster on average, and had more unprovoked escape responses (C-starts) than their sibling controls. Live imaging of Ca2+signalling revealed prolongued, strong signals sweeping through the brain, indicative of neuronal hyperactivity. While the resulting tadpole brain appeared grossly normal, the blood-brain barrier was found to be leakier than that of controls. Additionally, the TGFβ antagonist Losartan was shown to have a short-term protective effect, reducing neuronal hyperactivity and reducing permeability of the blood- brain barrier. Severity of the behavioral phenotype correlated with increased with editing efficiency. Our results support a haploinsufficiency model of DEE75 resulting from reduced NeuroD2 activity during vertebrate brain development, and indicate that a leaky blood- brain barrier contributes to epileptogenesis.

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“…Furthermore, the neuroprotective effects of this drug have been studied in animal models with Post-Traumatic Epilepsy (PTE) (46), kainic acidinduced status epilepticus (47), seizure in animal model with comorbid hypertension and epilepsy (48), pentylenetetrazol (PTZ)kindled seizures (49). In spite of the suppressive role of losartan in different kinds of animal seizure model, it failed to exert effect on epileptiform activity in human brain slices from patients with pharmaco-resistant TLE (50).…”

Section: Brain Bank and Neuropharmacologymentioning

confidence: 99%

The Concept of an Epilepsy Brain Bank

et al. 2020

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Epilepsy comprises more than 40 clinical syndromes affecting millions of patients and families worldwide. To decode the molecular and pathological framework of epilepsy researchers, need reliable human epilepsy and control brain samples. Brain bank organizations collecting and supplying well-documented clinically and pathophysiologically tissue specimens are important for high-quality neurophysiology and neuropharmacology studies for epilepsy and other neurological diseases. New development in molecular mechanism and new treatment methods for neurological disorders have evoked increased demands for human brain tissue. An epilepsy brain bank is a storage source for both the frozen samples as well as the formaldehyde fixed paraffin embedded (FFPE) tissue from epilepsy surgery resections. In 2014, the University of Saskatchewan have started collecting human epilepsy brain tissues for the first time in Canada. This review highlights the necessity and importance of Epilepsy Brain bank that provides unique access for research to valuable source of brain tissue and blood samples from epilepsy patients.

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Losartan fails to suppress epileptiform activity in brain slices from resected tissues of patients with drug resistant epilepsy

Cited by 9 publications

References 10 publications

TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications

TGF-β as a Key Modulator of Astrocyte Reactivity: Disease Relevance and Therapeutic Implications

Knockdown ofNeuroD2leads to seizure-like behaviour, brain neuronal hyperactivity and a leaky blood-brain barrier in aXenopus laevistadpole model of DEE75

The Concept of an Epilepsy Brain Bank

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