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. 2017 Dec;1(1):35-46.
Epub 2017 Dec 15.

The microRNA miR-21 conditions the brain to protect against ischemic and traumatic injuries

Mary S Lopez  1   2 , Robert J Dempsey  1   2 , Raghu Vemuganti  1   2   3
Affiliations

The microRNA miR-21 conditions the brain to protect against ischemic and traumatic injuries

Mary S Lopez et al. Cond Med. 2017 Dec.

Abstract

Ischemic and traumatic injuries to CNS remain leading causes of death and disability worldwide, despite decades of research into risk factors, therapies, and preventative measures. Recent studies showed that CNS injuries significantly alter the cerebral microRNAome that impact the secondary brain damage as well as plasticity and recovery. Many microRNA based therapies are currently in various clinical trials for different pathologic conditions indicating their therapeutic potential. In the present review, we discuss the role of miR-21 in acute CNS injuries which is currently thought to be a potent neuroprotective microRNA. We emphasize on the potential of miR-21 in promoting cell and tissue survival and preventing inflammation and apoptosis. We also discussed the role of miR-21 in conditioning the brain to promote ischemic tolerance. Finally, we discussed some of the challenges and difficulties to develop miR-21 as a neuroprotective therapy in humans.

Keywords: CNS injury; Stroke; miR-21; neuroprotection; therapy.

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Figures

Figure 1:
Figure 1:. miR-21 regulates apoptosis
Fas ligand (FasL), programmed cell death protein 4 (PDCD4), and phosphatase and tensin homolog (PTEN) are the best-characterized targets of miR-21. These proteins synergistically promote apoptosis. FasL is either membrane-bound or soluble and physically binds to the Fas death receptor (FasR) to initiate a caspase cleavage cascade resulting in apoptosis. PTEN is a tumor suppressor and a negative regulator of PI3K that phosphorylates PIP2 to form PIP3 that activates Akt pathway leading to cell death. As such, prevention of PTEN by miR-21 can lead to better cell survival following conditions like stroke and TBI. PI3K and Akt also modulate caspase-9 cleavage and hence, PTEN inhibition leads to prevention of apoptosis. Furthermore, PI3K/Akt activates mammalian target of rapamycin (mTOR) that inhibits PDCD4 activity. PDCD4 causes a protein expression bottleneck by inhibiting eukaryotic initiation factor 4a (eIF4a) and the transcription factor activator protein 1 (AP-1). Preventing eIF4a activity causes endoplasmic reticulum stress and inhibiting AP-1 prevents expression of beneficial genes such as vascular endothelial growth factor (VEGF). As inhibition of FasL, PTEN or PDCD4 together is a powerful strategy to prevent apoptosis and hence miR-21 is an attractive therapeutic to protect the post-injury brain. Tipped arrows indicate activation and blunted arrows indicate inhibition.
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