Dataset Information

MicroRNA-103-1 selectively downregulates brain NCX1 and its inhibition by anti-miRNA ameliorates stroke damage and neurological deficits.

ABSTRACT: Na(+)/Ca2+ exchanger (NCX) is a plasma membrane transporter that, by regulating Ca2+ and Na(+) homeostasis, contributes to brain stroke damage. The objectives of this study were to investigate whether there might be miRNAs in the brain able to regulate NCX1 expression and, thereafter, to set up a valid therapeutic strategy able to reduce stroke-induced brain damage by regulating NCX1 expression. Thus, we tested whether miR-103-1, a microRNA belonging to the miR-103/107 family that on the basis of sequence analysis might be a potential NCX1 regulator, could control NCX1 expression. The role of miR-103-1 was assessed in a rat model of transient cerebral ischemia by evaluating the effect of the correspondent antimiRNA on both brain infarct volume and neurological deficits. NCX1 expression was dramatically reduced when cortical neurons were exposed to miR-103-1. This alleged tight regulation of NCX1 by miR-103-1 was further corroborated by luciferase assay. Notably, antimiR-103-1 prevented NCX1 protein downregulation induced by the increase in miR-103-1 after brain ischemia, thereby reducing brain damage and neurological deficits. Overall, the identification of a microRNA able to selectively regulate NCX1 in the brain clarifies a new important molecular mechanism of NCX1 regulation in the brain and offers the opportunity to develop a new therapeutic strategy for stroke.

SUBMITTER: Vinciguerra A

PROVIDER: S-EPMC4428397 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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MicroRNA-103-1 selectively downregulates brain NCX1 and its inhibition by anti-miRNA ameliorates stroke damage and neurological deficits.

Vinciguerra Antonio A Formisano Luigi L Cerullo Pierpaolo P Guida Natascia N Cuomo Ornella O Esposito Alba A Di Renzo Gianfranco G Annunziato Lucio L Pignataro Giuseppe G

Molecular therapy : the journal of the American Society of Gene Therapy 20140623 10

Na(+)/Ca2+ exchanger (NCX) is a plasma membrane transporter that, by regulating Ca2+ and Na(+) homeostasis, contributes to brain stroke damage. The objectives of this study were to investigate whether there might be miRNAs in the brain able to regulate NCX1 expression and, thereafter, to set up a valid therapeutic strategy able to reduce stroke-induced brain damage by regulating NCX1 expression. Thus, we tested whether miR-103-1, a microRNA belonging to the miR-103/107 family that on the basis o ...[more]

PMID: 24954474

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Project description:X-linked adrenoleukodystrophy (ALD) is a genetic disorder that presents neurologically as either a rapid and fatal cerebral demyelinating disease in childhood (childhood cerebral adrenoleukodystrophy; ccALD) or slow degeneration of the spinal cord in adulthood (adrenomyeloneuropathy; AMN). All forms of ALD result from mutations in the ATP Binding Cassette Subfamily D Member (ABCD) 1 gene, encoding a peroxisomal transporter responsible for the import of very long chain fatty acids (VLCFA) and results mechanistically in a complex array of dysfunction, including endoplasmic reticulum stress, oxidative stress, mitochondrial dysfunction, and inflammation. Few therapeutic options exist for these patients; however, an additional peroxisomal transport protein (ABCD2) has been successfully targeted previously for compensation of dysfunctional ABCD1. 4-Phenylbutyrate (4PBA), a potent activator of the ABCD1 homolog ABCD2, is FDA approved, but use for ALD has been stymied by a short half-life and thus a need for unfeasibly high doses. We conjugated 4PBA to hydroxyl polyamidoamine (PAMAM) dendrimers (D-4PBA) to a create a long-lasting and intracellularly targeted approach which crosses the blood-brain barrier to upregulate Abcd2 and its downstream pathways. Across two studies, Abcd1 knockout mice administered D-4PBA long term showed neurobehavioral improvement and increased Abcd2 expression. Furthermore, when the conjugate was administered early, significant reduction of VLCFA and improved survival of spinal cord neurons was observed. Taken together, these data show improved efficacy of D-4PBA compared to previous studies of free 4PBA alone, and promise for D-4PBA in the treatment of complex and chronic neurodegenerative diseases using a dendrimer delivery platform that has shown successes in recent clinical trials. While recovery in our studies was partial, combined therapies on the dendrimer platform may offer a safe and complete strategy for treatment of ALD.

Dataset Information

MicroRNA-103-1 selectively downregulates brain NCX1 and its inhibition by anti-miRNA ameliorates stroke damage and neurological deficits.

Publications

MicroRNA-103-1 selectively downregulates brain NCX1 and its inhibition by anti-miRNA ameliorates stroke damage and neurological deficits.

Similar Datasets

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