Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA‐derived cell cultures

Scheppingen, Jackelien van; Iyer, Anand M.; Prabowo, Avanita S.; Mühlebner, Angelika; Anink, Jasper J.; Scholl, Theresa O.; Feucht, Martha; Jansen, Floor E.; Spliet, Wim G.M.; Kršek, Pavel; Zámečnı́k, Josef; Buccoliero, Anna Maria; Genitori, Lorenzo; Kotulska, Katarzyna; Jóźwiak, Sergiusz; Jaworski, Jacek; Liszewska, Ewa; Vliet, Erwin A. van; Aronica, Eleonora

doi:10.1002/glia.22983

Cited by 53 publications

(75 citation statements)

References 101 publications

(169 reference statements)

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“…MicroRNAs are essential for the development of astrocytes, and astrogliogenesis can be completely blocked by inhibiting microRNA genesis in the spinal cord [64]. For example, miR-130b, miR-21, miR-146a, miR-155, miR-22, miR-622, and miR-145 can regulate astrocytes proliferation, activation, terminal differentiation, and astrocyte-related inflammation [39, 64, 65].…”

Section: Micrornas and Extrinsic Determinants Of Axon Regenerationmentioning

confidence: 99%

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Extrinsic and Intrinsic Regulation of Axon Regeneration by MicroRNAs after Spinal Cord Injury

Teng

Liu

2016

Neural Plasticity

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Spinal cord injury is a devastating disease which disrupts the connections between the brain and spinal cord, often resulting in the loss of sensory and motor function below the lesion site. Most injured neurons fail to regenerate in the central nervous system after injury. Multiple intrinsic and extrinsic factors contribute to the general failure of axonal regeneration after injury. MicroRNAs can modulate multiple genes' expression and are tightly controlled during nerve development or the injury process. Evidence has demonstrated that microRNAs and their signaling pathways play important roles in mediating axon regeneration and glial scar formation after spinal cord injury. This article reviews the role and mechanism of differentially expressed microRNAs in regulating axon regeneration and glial scar formation after spinal cord injury, as well as their therapeutic potential for promoting axonal regeneration and repair of the injured spinal cord.

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Section: Micrornas and Extrinsic Determinants Of Axon Regenerationmentioning

confidence: 99%

“…For example, miR-130b, miR-21, miR-146a, miR-155, miR-22, miR-622, and miR-145 can regulate astrocytes proliferation, activation, terminal differentiation, and astrocyte-related inflammation [39, 64, 65]. Among these microRNAs, miR-21 is the most well studied (Figure 1) in SCI model [23].…”

Section: Micrornas and Extrinsic Determinants Of Axon Regenerationmentioning

confidence: 99%

Extrinsic and Intrinsic Regulation of Axon Regeneration by MicroRNAs after Spinal Cord Injury

Teng

Liu

2016

Neural Plasticity

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“…Growing knowledge about the molecular relationship between TSC and mTOR [12–15] led to the clinical testing of allosteric mTOR inhibitors. In 2011 Everolimus, a Rapamycin analogon, was approved as an orphan drug for the treatment of TSC patients with SEGAs and/or renal angiomyolipomas at risk for complications, but not amenable to surgery [16–18].…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of Everolimus in children with TSC - associated epilepsy – Pilot data from an open single-center prospective study

Samueli

Abraham

Dressler

et al. 2016

Orphanet J Rare Dis

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BackgroundEpilepsy occurs in up to 90 % of all individuals with tuberous sclerosis complex (TSC). In 67 % disease onset is during childhood. In ≥ 50 % seizures are refractory to currently available treatment options.The mTOR-Inhibitor Everolimus (Votubia®) was approved for the treatment of subependymal giant cell astrocytoma (SEGA) and renal angiomyolipoma (AML) in Europe in 2011. It’s anticonvulsive/antiepileptic properties are promising, but evidence is still limited. Study aim was to evaluate the efficacy and safety of Everolimus in children and adolescents with TSC-associated epilepsies.MethodsInclusion-criteria of this investigator-initiated, single-center, open, prospective study were: 1) the ascertained diagnosis of TSC; 2) age ≤ 18 years; 3) treatment indication for Votubia® according to the European Commission guidelines; 4) drug-resistant TSC-associated epilepsy, 5) prospective continuous follow-up for at least 6 months after treatment initiation and 6) informed consent to participate.Votubia® was orally administered once/day, starting with 4.5 mg/m2 and titrated to achieve blood trough concentrations between 5 and 15 ng/ml. Primary endpoint was the reduction in seizure frequency of ≥ 50 % compared to baseline.ResultsFifteen patients (nine male) with a median age of six (range; 1–18) years fulfilled the inclusion criteria. 26 % (4/15) had TSC1, 66 % (10/15) had TSC2 mutations. In one patient no mutation was found. Time of observation after treatment initiation was median 22 (range; 6–50) months.At last observation, 80 % (12/15) of the patients were responders, 58 % of them (7/12) were seizure free. The overall reduction in seizure frequency was 60 % in focal seizures, 80 % in generalized tonic clonic seizures and 87 % in drop attacks.The effect of Everolimus was seen already at low doses, early after treatment initiation.Loss of efficacy over time was not observed.Transient side effects were seen in 93 % (14/15) of the patients. In no case the drug had to be withdrawn.ConclusionEverolimus seems to be an effective treatment option not only for SEGA and AML, but also for TSC-related epilepsies. Although there are potential serious side effects, treatment was tolerated well by the majority of patients, provided that patients are under close surveillance of epileptologists who are familiar with immunosuppressive agents.

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“…Cells were transfected with mimic pre-miRNA for miR146a or miR147b (mirVana miRNA mimics, Applied Biosystems, Carlsbad, CA) for 24 hr as described previously (van Scheppingen et al, 2016b).…”

Section: Transfection and Stimulation Of Cell Culturesmentioning

confidence: 99%

miR147b:Anovel key regulator of interleukin 1 beta‐mediated inflammation in human astrocytes

Scheppingen

Zimmer

Broekaart

et al. 2018

Glia

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Astrocytes are important mediators of inflammatory processes in the brain and seem to play an important role in several neurological disorders, including epilepsy. Recent studies show that astrocytes produce several microRNAs, which may function as crucial regulators of inflammatory pathways and could be used as therapeutic target. We aim to study which miRNAs are produced by astrocytes during IL-1β mediated inflammatory conditions in vitro, as well as their functional role and to validate these findings in human epileptogenic brain tissue. Sequencing was used to assess miRNA and mRNA expression in IL-1β-stimulated human fetal astrocyte cultures. miRNAs were overexpressed in cell cultures using miRNA mimics. Expression of miRNAs in resected brain tissue from patients with tuberous sclerosis complex or temporal lobe epilepsy with hippocampal sclerosis was examined using in situ hybridization. Two differentially expressed miRNAs were found: miR146a and miR147b, which were associated with increased expression of genes related to the immune/inflammatory response. As previously reported for miR146a, overexpression of miR147b reduced the expression of the pro-inflammatory mediators IL-6 and COX-2 after IL-1β stimulation in both astrocyte and tuberous sclerosis complex cell cultures. miR146a and miR147b overexpression decreased proliferation of astrocytes and promoted neuronal differentiation of human neural stem cells. Similarly to previous evidence for miR146a, miR147b was increased expressed in astrocytes in epileptogenic brain. Due to their anti-inflammatory effects, ability to restore aberrant astrocytic proliferation and promote neuronal differentiation, miR146a and miR147b deserve further investigation as potential therapeutic targets in neurological disorders associated with inflammation, such as epilepsy.

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Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA‐derived cell cultures

Cited by 53 publications

References 101 publications

Extrinsic and Intrinsic Regulation of Axon Regeneration by MicroRNAs after Spinal Cord Injury

Extrinsic and Intrinsic Regulation of Axon Regeneration by MicroRNAs after Spinal Cord Injury

Efficacy and safety of Everolimus in children with TSC - associated epilepsy – Pilot data from an open single-center prospective study

miR147b:Anovel key regulator of interleukin 1 beta‐mediated inflammation in human astrocytes

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