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Am J Transl Res 2012;4(3):316-332
Original Article
Post-insult valproic acid-regulated microRNAs: potential targets for
cerebral ischemia
Joshua G Hunsberger, Emily B Fessler, Zhifei Wang, Abdel G Elkahloun, De-Maw Chuang
Molecular Neurobiology Section, National Institute of Mental Health (NIMH), National Institutes of Health,
Bethesda, MD; Microarray Core Facility, National Human Genome Research Institute (NHGRI), National Institutes
of Health, Bethesda, MD, USA.
Received July 6, 2012; accepted July 22, 2012; Epub July 25, 2012; Published August 15, 2012
Abstract: Stroke is a devastating brain injury that is a leading cause of adult disability with limited treatment
options. Using a rat model of middle cerebral artery occlusion (MCAO) to induce cerebral ischemia, we profiled
microRNAs (miRNAs), small non-protein coding RNAs, in the ischemic cortex. Many miRNAs were confirmed by
qPCR to be robustly upregulated 24 hours following MCAO surgery including miR-155, miR-297a, miR-466f,
miR-466h, and miR-1224. In addition, we treated MCAO rats with valproic acid (VPA), a mood stabilizer and
histone deacetylase inhibitor. This post-insult treatment was shown to improve neurological deficits and motor
performance following MCAO. To provide mechanistic insight into the potential targets and pathways that may
underlie these benefits, we profiled miRNAs regulated following this VPA treatment. Two promising post-insult
VPA-regulated candidates were miR-331 and miR-885-3p. miR-331 was also regulated by VPA pre-treatment in
rat cortical neuronal cultures subjected to oxygen-glucose deprivation, an in vitro ischemic model. The predicted
targets of these miRNAs analyzed by Ingenuity Pathway Analysis (IPA) identified networks involved in
hematological system development, cell death, and nervous system development. These predicted networks
were further filtered using IPA and showed significant associations with neurological diseases including
movement disorders, neurodegenerative disorders, damage to cerebral cortex, and seizure disorders among
others. Collectively, these data support common disease mechanisms that may be under miRNA control and
provide exciting directions for further investigations aimed at elucidating the miRNA mechanisms and targets that
may yield new therapies for neurological disorders. (AJTR1207001).
Keywords: Cerebral ischemia, valproic acid, microRNA, oxygen-glucose deprivation, neuroprotection
Address all correspondence to:
Dr. De-Maw Chuang
Section on Molecular Neurobiology
National Institute of Mental Health
National Institutes of Health
Bethesda, MD 20892-1363, USA.
Tel: 301.496.4915; Fax: 301-480-9290
E-mail: chuang@mail.nih.gov
Original Article
Post-insult valproic acid-regulated microRNAs: potential targets for
cerebral ischemia
Joshua G Hunsberger, Emily B Fessler, Zhifei Wang, Abdel G Elkahloun, De-Maw Chuang
Molecular Neurobiology Section, National Institute of Mental Health (NIMH), National Institutes of Health,
Bethesda, MD; Microarray Core Facility, National Human Genome Research Institute (NHGRI), National Institutes
of Health, Bethesda, MD, USA.
Received July 6, 2012; accepted July 22, 2012; Epub July 25, 2012; Published August 15, 2012
Abstract: Stroke is a devastating brain injury that is a leading cause of adult disability with limited treatment
options. Using a rat model of middle cerebral artery occlusion (MCAO) to induce cerebral ischemia, we profiled
microRNAs (miRNAs), small non-protein coding RNAs, in the ischemic cortex. Many miRNAs were confirmed by
qPCR to be robustly upregulated 24 hours following MCAO surgery including miR-155, miR-297a, miR-466f,
miR-466h, and miR-1224. In addition, we treated MCAO rats with valproic acid (VPA), a mood stabilizer and
histone deacetylase inhibitor. This post-insult treatment was shown to improve neurological deficits and motor
performance following MCAO. To provide mechanistic insight into the potential targets and pathways that may
underlie these benefits, we profiled miRNAs regulated following this VPA treatment. Two promising post-insult
VPA-regulated candidates were miR-331 and miR-885-3p. miR-331 was also regulated by VPA pre-treatment in
rat cortical neuronal cultures subjected to oxygen-glucose deprivation, an in vitro ischemic model. The predicted
targets of these miRNAs analyzed by Ingenuity Pathway Analysis (IPA) identified networks involved in
hematological system development, cell death, and nervous system development. These predicted networks
were further filtered using IPA and showed significant associations with neurological diseases including
movement disorders, neurodegenerative disorders, damage to cerebral cortex, and seizure disorders among
others. Collectively, these data support common disease mechanisms that may be under miRNA control and
provide exciting directions for further investigations aimed at elucidating the miRNA mechanisms and targets that
may yield new therapies for neurological disorders. (AJTR1207001).
Keywords: Cerebral ischemia, valproic acid, microRNA, oxygen-glucose deprivation, neuroprotection
Address all correspondence to:
Dr. De-Maw Chuang
Section on Molecular Neurobiology
National Institute of Mental Health
National Institutes of Health
Bethesda, MD 20892-1363, USA.
Tel: 301.496.4915; Fax: 301-480-9290
E-mail: chuang@mail.nih.gov
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