Commentary: Therapeutic Potential of Targeting the Auto-Inhibition of ASIC1a for Neuroprotection Against Ischemic Brain Injury

MicroRNAs (miRs) are small endogenous RNA molecules that repress gene translation by hybridizing to 3’-UTRs of mRNAs. Accumulating evidence has shown that miRs play a critical regulatory role in the pathogenesis of ischemic stroke. MiR-15a and miR-16-1 are two highly conserved miRs, which act similarly by binding to their common mRNA targets, thus forming both a structural and functional cluster. Dysregulated plasma levels of miR-15a/16-1 have been reported in stroke patients. Inhibition of miR-15a has been shown to protect against myocardial infarction and selected by pharmaceutical companies as one of the most attractive miR-based therapeutics. Up to now, the essential role and therapeutic potential of the miR-15a/16-1 cluster in ischemic stroke are poorly understood. In this study, adult male miR-15a/16-1 knockout and wildtype mice were subjected to 45 min of middle cerebral artery occlusion (MCAO) and 72h of reperfusion. In a separate experiment, miR-15a/16-1 specific inhibitor (antagomir, 30 pmol/g) was injected into tail vein of stroke mice and the animals were allowed to survive for 72h. The neurological scores, brain infarct volume, and edema content were then evaluated and analyzed. To explore the underlying mechanism, inflammatory factors were measured by qPCR or ELISA and anti-apoptotic proteins were examined by western blotting. We found that genetic deletion of miR-15a/16-1 or intravenous delivery of miR-15a/16-1 antagomir significantly reduced cerebral infarct size, decreased brain edema and improved neurological outcomes in stroke mice. Mechanistically, treatment of miR-15a/16-1 antagomir significantly ameliorated the expression of several key inflammatory factors and increased the Bcl-2 and Bcl-w levels in the ischemic brain regions. These results demonstrated that pharmacological inhibition of miR-15a/16-1 reduces ischemic brain injury via both anti-apoptotic and anti-inflammatory mechanisms and the miR-15a/16-1 cluster is a novel therapeutic target for ischemic stroke.

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Therapeutic Potential of Neurotrophic Factors and Neural Stem Cells Against Ischemic Brain Injury

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200010000-00001 ◽

2000 ◽

Vol 20 (10) ◽

pp. 1393-1408 ◽

Cited By ~ 153

Author(s):

Koji Abe

Keyword(s):

Stem Cells ◽

Brain Injury ◽

Neural Stem Cells ◽

Neurotrophic Factors ◽

Therapeutic Potential ◽

Stem Cell Differentiation ◽

Adult Brain ◽

Ischemic Brain Injury ◽

Ischemic Brain

Development of neuronal and glial cells and their maintenance are under control of neurotrophic factors (NTFs). An exogenous administration of NTFs protects extremely sensitive brain tissue from ischemic damage. On the other hand, it is now known that neural stem cells are present in normal adult brain, and have a potential to compensate and recover neural functions that were lost due to ischemic stroke. These stem cells are also under control of NTFs to differentiate into a certain species of neural cells. Thus, the purpose of this review is to summarize the present understanding of the role of NTFs in normal and ischemic brain and the therapeutic potential of NTF protein itself or gene therapy, and then to summarize the role of NTFs in stem cell differentiation and a possible therapeutic potential with the neural stem cells against ischemic brain injury.

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Faculty Opinions recommendation of Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1030318.360571 ◽

2006 ◽

Author(s):

Stephen Helfand

Keyword(s):

Cell Death ◽

Brain Injury ◽

Therapeutic Potential ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Nonapoptotic Cell Death

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Faculty Opinions recommendation of Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1030318.323430 ◽

2005 ◽

Author(s):

Eui-Ju Choi

Keyword(s):

Cell Death ◽

Brain Injury ◽

Therapeutic Potential ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Nonapoptotic Cell Death

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Extended Therapeutic Window and Functional Recovery after Intraarterial Administration of Neuregulin-1 after Focal Ischemic Stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600212 ◽

2005 ◽

Vol 26 (4) ◽

pp. 527-535 ◽

Cited By ~ 55

Author(s):

Zhenfeng Xu ◽

DaJoie R Croslan ◽

Adalynn E Harris ◽

Gregory D Ford ◽

Byron D Ford

Keyword(s):

Brain Injury ◽

Functional Recovery ◽

Therapeutic Potential ◽

Infarct Volume ◽

Neuroprotective Effect ◽

Artery Occlusion ◽

Therapeutic Window ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Neuregulin 1

We have previously shown that neuregulin-1 (NRG-1) protects neurons from ischemic brain injury if administered before focal stroke. Here, we examined the therapeutic window and functional recovery after NRG-1 treatment in rats subjected to 90 mins of middle cerebral artery occlusion (MCAO) and 24 h of reperfusion. Neuregulin-1 (2.5 ng/kg bolus, 1.25 ng/kg/min infusion) reduced infarct volume by 89.2% ± 41.9% (mean ± s.d.; n = 8; P < 0.01) if administered immediately after the onset of reperfusion. Neuroprotection was also evident if NRG-1 was administered 4 h (66.4% ± 52.6%; n = 7; P < 0.01) and 12 h (57.0% ± 20.8%; n = 8; P < 0.01) after reperfusion. Neuregulin-1 administration also resulted in a significant improvement of functional neurologic outcome compared with vehicle-treated animals (32.1% ± 5.7%; n 9; P < 0.01). The neuroprotective effect of the single administration of NRG-1 was seen as long as 2 weeks after treatment. Neurons labeled with the neurodegeneration marker dye Fluoro-JadeB were observed after MCAO in the cortex, but the numbers were significantly reduced after NRG-1 treatment. These results indicate that NRG-1 is a potent neuroprotective compound with an extended therapeutic window that has practical therapeutic potential in treating individuals after ischemic brain injury.

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Erratum: Corrigendum: Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury

Nature Chemical Biology ◽

10.1038/nchembio0905-234a ◽

2005 ◽

Vol 1 (4) ◽

pp. 234-234 ◽

Cited By ~ 1

Author(s):

Alexei Degterev ◽

Zhihong Huang ◽

Michael Boyce ◽

Yaqiao Li ◽

Prakash Jagtap ◽

...

Keyword(s):

Cell Death ◽

Brain Injury ◽

Therapeutic Potential ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Nonapoptotic Cell Death

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Abstract W P243: Multiple Therapeutic Effects of Progranulin on Experimental Acute Ischemic Stroke

Stroke ◽

10.1161/str.46.suppl_1.wp243 ◽

2015 ◽

Vol 46 (suppl_1) ◽

Author(s):

Masato Kanazawa ◽

Kunio Kawamura ◽

Tetsuya Takahashi ◽

Minami Miura ◽

Yoshinori Tanaka ◽

...

Keyword(s):

Brain Injury ◽

Cerebral Ischemia ◽

Growth Factor ◽

Therapeutic Potential ◽

Focal Cerebral Ischemia ◽

Dynamic Change ◽

Therapeutic Effects ◽

Ischemic Brain Injury ◽

In Vivo Models ◽

Ischemic Brain

Introduction: In central nervous system, progranulin (PGRN), a glycoprotein growth factor, is considered to play crucial roles in maintaining physiological functions, and mutations in PGRN gene cause TAR DNA-binding protein-43 (TDP-43)-positive frontotemporal lobar degeneration. Although several studies reported that PGRN plays protective roles against ischemic brain injury, it remains unknown the precise mechanisms by which PGRN exerts protective effects on the ischemic brain injury. Methods: We determined the temporal changes of expression and localization of PGRN after ischemia as well as therapeutic effects of PGRN on ischemic brain injury using in vitro and in vivo models. Results: First, we demonstrated a dynamic change of PGRN expression in ischemic Sprague-Dawley rats, including increased levels of PGRN expression in microglia within the ischemic core, and increased level of PGRN expression in survived neurons as well as induction of PGRN expression in endothelial cells within the ischemic penumbra. Second, we demonstrated that PGRN could protect against acute focal cerebral ischemia by variety of mechanisms including via attenuation of blood-brain barrier disruption, suppression of neuroinflammation, and neuroprotection: we found that PGRN may regulate vascular permeability via vascular endothelial growth factor (VEGF), that PGRN may suppress neuroinflammation after ischemia via anti-inflammatory interleukin-10 (IL-10) in microglia, and that neuroprotective effect of PGRN may be explained in part by inhibition of cytoplasmic redistribution of TDP-43 using PGRN knock-out mice (C57Bl/6 background). Finally, we demonstrated the therapeutic potential of PGRN against acute focal cerebral ischemia using a rat autologous thromboembolic model with delayed tissue plasminogen activator (tPA) treatment. Intravenously administered recombinant PGRN reduced volumes of cerebral infarct and edema, suppressed hemorrhagic transformation, and improved motor outcome (P = 0.007, 0.038, 0.007, and 0.004, respectively). Conclusions: PGRN may be a novel therapeutic target that provides vascular protection, anti-neuroinflammation, and neuroprotection related in part to VEGF, IL-10, and TDP-43, respectively.

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