Intracerebroventricular injection of miR-146a relieves seizures in an immature rat model of lithium-pilocarpine induced status epilepticus

Wang, Xiaole; Yin, Fei; Linhong, Li; Kong, Huimin; You, Baiyang; Zhang, Weixi; Chen, Shuyuan; Peng, Jing

doi:10.1016/j.eplepsyres.2017.10.006

Cited by 19 publications

(14 citation statements)

References 42 publications

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“…This matches the effects of Ant-134 at a similar dose in studies in which seizures were reduced in adult mice treated with intraamygdala KA 18 and pilocarpine 19 Thus, the effective anti-seizure dose for Ant-134 is similar regardless of age and model. The anti-seizure effects of Ant-134 appear to be superior when compared with another miRNA targeting strategy in juvenile rodents, where over-expression of miR-146a in P21-P28 rats only increased the latency to SE by roughly 20% in a lithium-pilocarpine model 34 . www.nature.com/scientificreports/…”

Section: Discussionmentioning

confidence: 99%

Antagomir-mediated suppression of microRNA-134 reduces kainic acid-induced seizures in immature mice

Campbell

Morris

Heller

et al. 2021

Sci Rep

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MicroRNAs are short non-coding RNAs that negatively regulate protein levels and perform important roles in establishing and maintaining neuronal network function. Previous studies in adult rodents have detected upregulation of microRNA-134 after prolonged seizures (status epilepticus) and demonstrated that silencing microRNA-134 using antisense oligonucleotides, termed antagomirs, has potent and long-lasting seizure-suppressive effects. Here we investigated whether targeting microRNA-134 can reduce or delay acute seizures in the immature brain. Status epilepticus was induced in 21 day-old (P21) male mice by systemic injection of 5 mg/kg kainic acid. This triggered prolonged electrographic seizures and select bilateral neuronal death within the CA3 subfield of the hippocampus. Expression of microRNA-134 and functional loading to Argonaute-2 was not significantly changed in the hippocampus after seizures in the model. Nevertheless, when levels of microRNA-134 were reduced by prior intracerebroventricular injection of an antagomir, kainic acid-induced seizures were delayed and less severe and mice displayed reduced neuronal death in the hippocampus. These studies demonstrate targeting microRNA-134 may have therapeutic applications for the treatment of seizures in children.

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Section: Discussionmentioning

confidence: 99%

Antagomir-mediated suppression of microRNA-134 reduces kainic acid-induced seizures in immature mice

Campbell

Morris

Heller

et al. 2021

Sci Rep

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“…The miR-15a-5p inhibitor was injected into the lateral ventricle of the SD rats using the stereotactic method [21]. Briefly, the rats were anesthetized and then they were intubated and injected with 50 μL of the miR-15a-5p inhibitor or NC via the intracerebroventricular route.…”

Section: Intracerebroventricular Injectionmentioning

confidence: 99%

Propofol inhibited apoptosis of hippocampal neurons in status epilepticus through miR-15a-5p/NR2B/ERK1/2 pathway

et al. 2020

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Although a previous study reported that propofol had a therapeutic effect in status epilepticus (SE), the mechanisms underlying the effect of propofol in SE remain unclear. The aim of this study was to explore the regulatory mechanisms underlying propofol-induced inhibition of SE.A rat SE model was established using the lithium-pilocarpine injection method. A qRT-PCR and Western blot were utilized to detect the expression of relative molecules. Cell apoptosis was evaluated by a flow cytometry assay. The interaction between miR-15a-5p and NR2B was assessed using a luciferase reporter assay.Propofol inhibited cell apoptosis and increased miR-15a-5p expression both in hippocampal tissues of SE rats and low Mg 2+ -induced hippocampal neurons. Propofol-induced attenuation of apoptosis of low Mg 2+ -induced hippocampal neurons was mediated by miR-15a-5p. miR-15a-5p targeted NR2B and negatively regulated its expression. Propofol downregulated NR2B expression, mediated by miR-15a-5p. In terms of the mechanism of action, propofol suppressed the apoptosis of Mg 2+ -induced hippocampal neurons through the miR-15a-5p/NR2B/ERK1/2 pathway. In vivo experiment suggested that propofol inhibited the apoptosis of hippocampal neurons in SE rats by upregulating miR-15a-5p.In terms of the molecular mechanism of propofol, it appears to inhibit apoptosis of hippocampal neurons in SE through the miR-15a-5p/NR2B/ERK1/2 pathway. The findings provide theoretical support for propofol treatment of SE.

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“…Accordingly, inhibitors of this signaling pathway (e.g., IL-1 receptor antagonist, IL-1Ra; caspase-1 inhibitors; TLR4 antagonists; and anti-HMGB1 monoclonal antibodies), and a negative regulator of this pathway (synthetic oligonucleotide analog of microRNA[miR]-146a), mediate significant anti-seizure effects also when seizures do not respond to clinical antiseizure drugs (ASDs). 21,23,[32][33][34][35][36][37][38][39][40][41] These therapeutic effects were associated with reduced BBB dysfunction and neuroprotection.…”

Section: Cytokines and Danger Signalsmentioning

confidence: 99%

Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

Ravizza

Vezzani

2018

Epilepsia Open

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SummaryIncreasing evidence supports a pathogenic role of unabated neuroinflammation in various central nervous system (CNS) diseases, including epilepsy. Neuroinflammation is not a bystander phenomenon of the diseased brain tissue, but it may contribute to neuronal hyperexcitability underlying seizure generation, cell loss, and neurologic comorbidities. Several molecules, which constitute the inflammatory milieu in the epileptogenic area, activate signaling pathways in neurons and glia resulting in pathologic modifications of cell function, which ultimately lead to alterations in synaptic transmission and plasticity. Herein we report the up‐to‐date experimental and clinical evidence that supports the neuromodulatory role of inflammatory mediators, their related signaling pathways, and involvement in epilepsy. We discuss how these mechanisms can be harnessed to discover and validate targets for novel therapeutics, which may prevent or control pharmacoresistant epilepsies.

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Intracerebroventricular injection of miR-146a relieves seizures in an immature rat model of lithium-pilocarpine induced status epilepticus

Cited by 19 publications

References 42 publications

Antagomir-mediated suppression of microRNA-134 reduces kainic acid-induced seizures in immature mice

Antagomir-mediated suppression of microRNA-134 reduces kainic acid-induced seizures in immature mice

Propofol inhibited apoptosis of hippocampal neurons in status epilepticus through miR-15a-5p/NR2B/ERK1/2 pathway

Pharmacological targeting of brain inflammation in epilepsy: Therapeutic perspectives from experimental and clinical studies

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