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An antagomir to microRNA Let7f promotes neuroprotection in an ischemic stroke model.

ABSTRACT: We previously showed that middle-aged female rats sustain a larger infarct following experimental stroke as compared to younger female rats, and paradoxically, estrogen treatment to the older group is neurotoxic. Plasma and brain insulin-like growth factor-1 (IGF-1) levels decrease with age. However, IGF-1 infusion following stroke, prevents estrogen neurotoxicity in middle-aged female rats. IGF1 is neuroprotective and well tolerated, but also has potentially undesirable side effects. We hypothesized that microRNAs (miRNAs) that target the IGF-1 signaling family for translation repression could be alternatively suppressed to promote IGF-1-like neuroprotection. Here, we report that two conserved IGF pathway regulatory microRNAs, Let7f and miR1, can be inhibited to mimic and even extend the neuroprotection afforded by IGF-1. Anti-mir1 treatment, as late as 4 hours following ischemia, significantly reduced cortical infarct volume in adult female rats, while anti-Let7 robustly reduced both cortical and striatal infarcts, and preserved sensorimotor function and interhemispheric neural integration. No neuroprotection was observed in animals treated with a brain specific miRNA unrelated to IGF-1 (anti-miR124). Remarkably, anti-Let7f was only effective in intact females but not males or ovariectomized females indicating that the gonadal steroid environment critically modifies miRNA action. Let7f is preferentially expressed in microglia in the ischemic hemisphere and confirmed in ex vivo cultures of microglia obtained from the cortex. While IGF-1 was undetectable in microglia harvested from the non-ischemic hemisphere, IGF-1 was expressed by microglia obtained from the ischemic cortex and was further elevated by anti-Let7f treatment. Collectively these data support a novel miRNA-based therapeutic strategy for neuroprotection following stroke.

SUBMITTER: Selvamani A

PROVIDER: S-EPMC3290559 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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An antagomir to microRNA Let7f promotes neuroprotection in an ischemic stroke model.

Selvamani Amutha A Sathyan Pratheesh P Miranda Rajesh C RC Sohrabji Farida F

PloS one 20120229 2

We previously showed that middle-aged female rats sustain a larger infarct following experimental stroke as compared to younger female rats, and paradoxically, estrogen treatment to the older group is neurotoxic. Plasma and brain insulin-like growth factor-1 (IGF-1) levels decrease with age. However, IGF-1 infusion following stroke, prevents estrogen neurotoxicity in middle-aged female rats. IGF1 is neuroprotective and well tolerated, but also has potentially undesirable side effects. We hypothe ...[more]

PMID: 22393433

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Project description:Background and purpose: A major gap in the field of ischemic preconditioning (IPC) is whether or not long-lasting neuroprotection can be achieved. Moreover, the specific mechanisms underlying IPC and how they can be translated into the clinic remain uncertain. To fill these gaps, we tested the hypothesis that IPC exerts long-lasting structural and functional neuroprotection against ischemic stroke through the master gatekeeper of antioxidant defenses, nuclear factor erythroid 2-related factor 2 (Nrf2). We also tested whether the brain could be pharmaceutically preconditioned with a potent and blood-brain barrier-permeable Nrf2 activator, 2-cyano-3,12-dioxo-oleana-1,9(11)-dien-28-trifluoethyl amide (CDDO-TFEA).Methods: IPC was induced by transient middle cerebral artery occlusion (MCAO) for 12 min, and ischemic stroke was generated by MCAO for 60 min in wild-type (WT) or Nrf2 knockout (KO) mice. Sensorimotor function, learning/memory skills, and brain tissue loss were measured up to 35 days after stroke. Primary rodent cortical neurons from wildtype (WT) and Nrf2 KO mice were subjected to lethal oxygen-glucose deprivation (OGD) or a brief OGD episode as a preconditioning (PC) stimulus before OGD. Cell viability/death, lipid electrophile generation, and Nrf2 activation were measured. CDDO-TFEA or its vehicle was administered in vivo for three consecutive days before MCAO. Tissue loss and neurological tests were performed 35 days after stroke.Results: IPC significantly reduced sensorimotor deficits, post-stroke cognitive impairments, and brain tissue loss, 35 days after MCAO in WT mice. These enduring protective effects of IPC were inhibited in Nrf2 KO mice. In neuronal cultures, PC also endowed primary neurons with ischemic tolerance against OGD-induced cell death, an effect that was abolished by loss of Nrf2 expression in KO neurons. PC induced the generation of low levels of lipid electrophiles and led to activation of the Nrf2 pathway. The mechanism underlying IPC may be translatable, as exogenous administration of the Nrf2 activator CDDO-TFEA significantly reduced neurological dysfunction and ischemic brain damage after MCAO.Conclusions: IPC provides long-lasting neuroprotection against ischemic brain injury and post-stroke cognitive dysfunction. Nrf2 activation plays a key role in this beneficial outcome and is a promising therapeutic target for the attenuation of ischemic brain injury.

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An antagomir to microRNA Let7f promotes neuroprotection in an ischemic stroke model.

Publications

An antagomir to microRNA Let7f promotes neuroprotection in an ischemic stroke model.

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