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Sci Rep. 2017 Aug 23;7(1):9201. doi: 10.1038/s41598-017-08196-3.

Neuroprotective Effects of CGP3466B on Apoptosis Are Modulated by Protein-L-isoaspartate (D-aspartate) O-methyltransferase/Mst1 Pathways after Traumatic Brain Injury in Rats.

Author information

1
Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
2
Department of Orthopaedics, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China.
3
Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, China. zjm135@vip.sina.com.

Abstract

Neuronal apoptosis chiefly contributes to the cell loss following traumatic brain injury (TBI). CGP3466B is a compound related to the anti-Parkinsonism drug R-(-)-deprenyl. Previous studies have illuminated anti-apoptosis effects of CGP3466B in different cell lines, but the underlying mechanisms have not been fully elucidated. Mammalian sterile 20 (STE20)-like kinase1 (Mst1) is a core component of the Hippo signaling pathway. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) is an enzyme that repairs damaged L-isoaspartyl residues in proteins. The present study was performed to investigate the neuroprotective effects of CGP3466B and to determine a potential PCMT1/Mst1 neuronal anti-apoptotic pathway after TBI. Double immunofluorescence staining demonstrated that PCMT1 and Mst1 are co-located in neurons. Administration of CGP3466B improved neurological function, downregulated the ROS level and alleviated brain edema at 24 h after TBI. CGP3466B alleviates neuronal apoptosis by increasing PCMT1 expression and subsequently inhibiting MST1 activation, resulting in changing the expression levels of Bax, Bcl-2 and active-caspase3. The TUNEL staining results also support the anti-apoptosis effects of CGP3466B. The anti-apoptotic effects of CGP3466B were abolished by chelerythrine, an Mst1 activator, without changing PCMT1 levels. In conclusion, our findings suggest CGP3466B may have a promising therapeutic potential by modulating PCMT1/Mst1 signaling pathway after TBI injury.

PMID:
28835703
PMCID:
PMC5569064
DOI:
10.1038/s41598-017-08196-3
[Indexed for MEDLINE]
Free PMC Article

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