Dataset Information

Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity.

ABSTRACT: The importance of white matter (WM) injury to stroke pathology has been underestimated in experimental animal models and this may have contributed to the failure to translate potential therapeutics into the stroke clinic. Histone deacetylase (HDAC) inhibitors are neuroprotective and also promote neurogenesis. These properties make them ideal candidates for stroke therapy. In a pure WM tract (isolated mouse optic nerve), we show that pan- and class I-specific HDAC inhibitors, administered before or after a period of oxygen and glucose deprivation (OGD), promote functional recovery of axons and preserve WM cellular architecture. This protection correlates with the upregulation of an astrocyte glutamate transporter, delayed and reduced glutamate accumulation during OGD, preservation of axonal mitochondria and oligodendrocytes, and maintenance of ATP levels. Interestingly, the expression of HDACs 1, 2, and 3 is localized to astrocytes, suggesting that changes in glial cell gene transcription and/or protein acetylation may confer protection to axons. Our findings suggest that a therapeutic opportunity exists for the use of HDAC inhibitors, targeting mitochondrial energy regulation and excitotoxicity in ischemic WM injury.

SUBMITTER: Baltan S

PROVIDER: S-EPMC3061553 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity.

Baltan Selva S Murphy Sean P SP Danilov Camelia A CA Bachleda Amelia A Morrison Richard S RS

The Journal of neuroscience : the official journal of the Society for Neuroscience 20110301 11

The importance of white matter (WM) injury to stroke pathology has been underestimated in experimental animal models and this may have contributed to the failure to translate potential therapeutics into the stroke clinic. Histone deacetylase (HDAC) inhibitors are neuroprotective and also promote neurogenesis. These properties make them ideal candidates for stroke therapy. In a pure WM tract (isolated mouse optic nerve), we show that pan- and class I-specific HDAC inhibitors, administered before ...[more]

PMID: 21411642

Similar Datasets

Project description:Extreme prematurity is a major risk factor for perinatal and neonatal brain injury, and can lead to white matter injury that is a precursor for a number of neurological diseases, including cerebral palsy (CP) and autism. Neuroinflammation, mediated by activated microglia and astrocytes, is implicated in the pathogenesis of neonatal brain injury. Therefore, targeted drug delivery to attenuate neuroinflammation may greatly improve therapeutic outcomes in models of perinatal white matter injury. In this work, we use a mouse model of ischemia-induced neonatal white matter injury to study the biodistribution of generation 4, hydroxyl-functionalized polyamidoamine dendrimers. Following systemic administration of the Cy5-labeled dendrimer (D-Cy5), we demonstrate dendrimer uptake in cells involved in ischemic injury, and in ongoing inflammation, leading to secondary injury. The sub-acute response to injury is driven by astrocytes. Within five days of injury, microglial proliferation and migration occurs, along with limited differentiation of oligodendrocytes and oligodendrocyte death. From one day to five days after injury, a shift in dendrimer co-localization occurred. Initially, dendrimer predominantly co-localized with astrocytes, with a subsequent shift towards microglia. Co-localization with oligodendrocytes reduced over the same time period, demonstrating a region-specific uptake based on the progression of the injury. We further show that systemic administration of a single dose of dendrimer-N-acetyl cysteine conjugate (D-NAC) at either sub-acute or delayed time points after injury results in sustained attenuation of the 'detrimental' pro-inflammatory response up to 9days after injury, while not impacting the 'favorable' anti-inflammatory response. The D-NAC therapy also led to improvement in myelination, suggesting reduced white matter injury. Demonstration of treatment efficacy at later time points in the postnatal period provides a greater understanding of how microglial activation and chronic inflammation can be targeted to treat neonatal brain injury. Importantly, it may also provide a longer therapeutic window.

Dataset Information

Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity.

Publications

Histone deacetylase inhibitors preserve white matter structure and function during ischemia by conserving ATP and reducing excitotoxicity.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets