miR-212-5p attenuates ferroptotic neuronal death after traumatic brain injury by targeting Ptgs2

Abstract

Ferroptosis, a newly discovered form of iron-dependent regulated cell death, has been implicated in traumatic brain injury (TBI). MiR-212-5p has previously been reported to be downregulated in extracellular vesicles following TBI. To investigate whether miR-212-5p is involved in the ferroptotic neuronal death in TBI mice, we first examined the accumulation of malondialdehyde (MDA) and ferrous ion, and the expression of ferroptosis-related molecules at 6 h, 12 h, 24 h, 48 h and 72 h following controlled cortical impact (CCI) in mice. There was a significant upregulation in the expression of Gpx4 and Acsl4 at 6 h, Slc7a11 from 12 h to 72 h, and Nox2 and Sat1 from 6 h to 72 h post injury. Similarly, an upregulation in the expression of Gpx4 at 6 h, Nox2 from 6 h to 72 h, xCT from 12 h to 72 h, and Sat1 at 72 h after CCI was observed at the protein level. Interestingly, MDA and ferrous ion were increased whereas miR-212-5p was decreased in the CCI group compared to the sham group. Furthermore, we found that overexpression of miR-212-5p attenuated ferroptosis while downregulation of miR-212-5p promoted ferroptotic cell death partially by targeting prostaglandin-endoperoxide synthase-2 (Ptgs2) in HT-22 and Neuro-2a cell lines. In addition, administration of miR-212-5p in CCI mice significantly improved learning and spatial memory. Collectively, these findings indicate that miR-212-5p may protect against ferroptotic neuronal death in CCI mice partially by targeting Ptgs2.

The Potential Value of Targeting Ferroptosis in Early Brain Injury After Acute CNS Disease

“…Inhibiting the ability of PEBP1/15LO complexes to form 15-HpETE-PE may lead to novel anti-ferroptosis approaches and potential neuroprotective drugs. In addition to regulating ferroptosis indicators such as desferrioxamine, vitamin E, U0126, ferrostatin-1, and liproxstatin-1 to regulate ferroptosis, Xiao et al (2019) demonstrated that the administration of miR-212-5p significantly improved learning and spatial memory in a controlled cortical impact model, and the same result was observed in HT-22 and neuro-2a cell lines. The mechanism may reflect miR-212-5p protection against neuronal ferroptosis by targeting Ptgs2 in vivo and in vitro TBI models.…”

Melatonin Enhances the Therapeutic Effect of Plasma Exosomes Against Cerebral Ischemia-Induced Pyroptosis Through the TLR4/NF-κB Pathway

“…On analyzing the miRNA profiles, 12 upregulated and 47 downregulated miRNAs were discovered upon melatonin treatment. Among the upregulated miRNAs (Table 1), miR-212-5p was reported to attenuate ferroptotic cell death partially by targeting Ptgs2 in Neuro-2a cell lines (Xiao et al, 2019). The overexpression of miR-138-5p reduces neurological impairment and confers neuroprotection to astrocytes following ischemic stroke (Deng et al, 2019).…”

Ferroptosis in Acute Central Nervous System Injuries: The Future Direction?

“…Researchers also showed a preponderance of 15-LOX products in CCI-injured adult mice, and increased ACSL4 and 15-LOX2 expression in TBI, when compared with naive groups ( Kenny et al, 2019 ). Moreover, numerous experimental and clinical studies observed the increased levels of MDA and 4-HNE in either the injured brain or serum following TBI ( Hall et al, 2004 ; Readnower et al, 2010 ; Lorente et al, 2015 ; Xiao et al, 2019 ; Xie et al, 2019 ). As for the morphological features, Xie et al (2019) first verifiably identified the ferroptotic features around brain injury lesions of TBI models at 3 days after CCI.…”

“…Moreover, a recent study demonstrated the role of miR-212-5p in suppressing ferroptosis after TBI, partially by targeting PTGS2 ( Xiao et al, 2019 ). Further results showed that intracerebroventricular injection of miR-212-5p agomir improved spatial memory and learning in CCI mice, suggesting that miR-212-5p may serve as a potential ferroptosis inhibitor to be used in treating TBI.…”