Synaptic plasticity in area CA1 of rat hippocampal slices following intraventricular application of albumin

Salar, Seda; Lapilover, Ezequiel; Müller, Julia; Hollnagel, Jan‐Oliver; Lippmann, Kristina; Friedman, Alon; Heinemann, Uwe

doi:10.1016/j.nbd.2016.03.008

Cited by 24 publications

(28 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Activated astrocytes further downregulate inward‐rectifier potassium channel and glutamate transporter, resulting in reduced potassium and glutamate buffering, leading to neuronal hyperexcitability . In addition, astrocytic‐mediated alterations in the extracellular matrix, excitatory synaptogenesis, and pathological plasticity contribute to the ongoing process of epileptogenesis …”

Section: Losartanmentioning

confidence: 99%

“…55 In addition, astrocytic-mediated alterations in the extracellular matrix, 56 excitatory synaptogenesis, 57 and pathological plasticity contribute to the ongoing process of epileptogenesis. 58 Losartan inhibits TGFβ signaling by preventing the phosphorylation of intracellular Smad proteins in animal models of chronic renal insufficiency, cardiomyopathy, and connective tissue disorders. [59][60][61] Losartan prevents insult-related epilepsies by blocking the increase in phosphophorylated Smad 2/3 levels following BBB disruption or direct exposure of the cerebral cortex to albumin.…”

Section: Losartanmentioning

confidence: 99%

See 1 more Smart Citation

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

Self Cite

View full text Add to dashboard Cite

Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%‐20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease‐modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N‐acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially “repurposable” medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury–treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose–blood level relationship, brain target engagement, and dose‐response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.

show abstract

Section: Losartanmentioning

confidence: 99%

Section: Losartanmentioning

confidence: 99%

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additional studies have also shown that loss of blood brain barrier (BBB) integrity may be an important link between neuroinflammation and epileptogenesis (Fabene, Navarro Mora, Martinello, Rossi, Merigo, Ottoboni et al 2008, Kim, Kang, Dustin & McGavern 2009, Ransohoff 2009, Bar-Klein, Cacheaux, Kamintsky, Prager, Weissberg, Schoknecht et al 2014, Friedman, Bar-Klein, Serlin, Parmet, Heinemann & Kaufer 2014, Vitaliti, Pavone, Mahmood, Nunnari & Falsaperla 2014, Salar, Lapilover, Muller, Hollnagel, Lippmann, Friedman et al 2016). Overactivated mast cells, which can be potentially activated by stress hormones, such as corticotropin-releasing hormone (CRH), lead to BBB disruption (Theoharides 1990, Esposito, Chandler, Kandere, Basu, Jacobson, Connolly et al 2002, Theoharides & Konstantinidou 2007, Vitaliti, Pavone, Mahmood, Nunnari & Falsaperla 2014).…”

Section: Inflammation and Neuroinflammation: Definitions Targets mentioning

confidence: 99%

Inflammation in Epileptic Encephalopathies

Shandra

Moshé

Galanopoulou

2017

Stress and Inflammation in Disorders

View full text Add to dashboard Cite

West syndrome (WS) is an infantile epileptic encephalopathy (EE) that manifests with infantile spasms, hypsarrhythmia (in ~60% of infants) and poor neurodevelopmental outcomes. The etiologies of WS can be structural-metabolic pathologies (~60%), genetic (12–15%) or of unknown origin. The current treatment options include hormonal treatment [adrenocorticotropic hormone (ACTH) and high dose steroids], the GABA aminotransferase inhibitor vigabatrin, while ketogenic diet can be given as add-on treatment in refractory IS. There is a need to identify new therapeutic targets and more effective treatments for WS. Theories about the role of inflammatory pathways in the pathogenesis and treatment of WS have emerged, being supported by both clinical and preclinical data from animal models of WS. Ongoing advances in genetics have revealed numerous genes involved in the pathogenesis of WS, including genes directly or indirectly involved in inflammation. Inflammatory pathways also interact with other signaling pathways implicated in WS, such as the neuroendocrine pathway. Furthermore, seizures may also activate pro-inflammatory pathways raising the possibility that inflammation can be a consequence of seizures and epileptogenic processes. With this targeted review we plan to discuss the evidence pro and against the following key questions. Does activation of inflammatory pathways in the brain cause epilepsy in WS and does it contribute to the associated comorbidities and progression? Can activation of certain inflammatory pathways be a compensatory or protective event? Are there interactions between inflammation and the neuroendocrine system that contribute to the pathogenesis of West syndrome? Does activation of brain inflammatory signaling pathways contribute to the transition of WS to Lennox-Gastaut syndrome? Are there any lead candidates or unexplored targets for future therapy development for WS targeting inflammation?

show abstract

“…Similarly, recent research has implicated oxidative stress and mitochondrial dysfunction as potential contributing factors to both epileptogenesis and associated cognitive dysfunction. The proinflammatory transforming growth factor beta (TGFβ) signaling was also shown to be activated after injury, and to not only underlie increased excitability and epileptogenesis, but also to be involved in pathologic synaptic plasticity . However, whether the detection of activation of either, few, or all of these pathways may serve as potential biomarkers of cognitive comorbidities in acquired epilepsies remains to be investigated.…”

Section: Potential Molecular Biomarkers Of Comorbiditiesmentioning

confidence: 99%

WONOEP appraisal: Biomarkers of epilepsy‐associated comorbidities

et al. 2016

Self Cite

View full text Add to dashboard Cite

Neurologic and psychiatric comorbidities are common in patients with epilepsy. Diagnostic, predictive, and pharmacodynamic biomarkers of such comorbidities do not exist. They may share pathogenetic mechanisms with epileptogenesis/ictogenesis, and as such are an unmet clinical need. The objectives of the subgroup on biomarkers of comorbidities at the XIII Workshop on the Neurobiology of Epilepsy (WONOEP) were to present the state-of-the-art recent research findings in the field that highlighting potential biomarkers for comorbidities in epilepsy. We review recent progress in the field, including molecular, imaging, and genetic biomarkers of comorbidities as discussed during the WONOEP meeting on August 31-September 4, 2015, in Heybeliada Island (Istanbul, Turkey). We further highlight new directions and concepts from studies on comorbidities and potential new biomarkers for the prediction, diagnosis, and treatment of epilepsy-associated comorbidities. The activation of various molecular signaling pathways such as the "Janus Kinase/Signal Transducer and Activator of Transcription," "mammalian Target of Rapamycin," and oxidative stress have been shown to correlate with the presence and severity of subsequent cognitive abnormalities. Furthermore, dysfunction in serotonergic transmission, hyperactivity of the hypothalamic-pituitary-adrenocortical axis, the role of the inflammatory cytokines, and the contributions of genetic factors have all recently been regarded as relevant for understanding epilepsy-associated depression and cognitive deficits. Recent evidence supports the utility of imaging studies as potential biomarkers. The role of such biomarker may be far beyond the diagnosis of comorbidities, as accumulating clinical data indicate that comorbidities can predict epilepsy outcomes. Future research is required to reveal whether molecular changes in specific signaling pathways or advanced imaging techniques could be detected in the clinical settings and correlate with epilepsy-associated comorbidities. A reliable biomarker will allow a more accurate diagnosis and improved treatment of epilepsy-associated comorbidities.

show abstract

Synaptic plasticity in area CA1 of rat hippocampal slices following intraventricular application of albumin

Cited by 24 publications

References 82 publications

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?

Inflammation in Epileptic Encephalopathies

WONOEP appraisal: Biomarkers of epilepsy‐associated comorbidities

Contact Info

Product

Resources

About