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

Feng Liang,Jianmin Zhang,Yangxin Wang,Sheng Chen,Jingwei Zheng,Ligen Shi

doi:10.1038/s41598-017-08196-3

Feng Liang, Jianmin Zhang + Show 4 more

Open Access

https://doi.org/10.1038/s41598-017-08196-3

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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.

Highlights

Neuronal apoptosis contributes to the cell loss following traumatic brain injury (TBI)
We demonstrated the neuroprotective effects of CGP3466B and explored a possible PCMT1/Mst[1] signaling pathway following TBI
Neurological Scores. modified neurological severity score (mNss) was measured at 24 h after surgery to confirm the effects of CGP3466B

Summary

Introduction

Neuronal apoptosis contributes to the cell loss following traumatic brain injury (TBI). The present study was performed to investigate the neuroprotective effects of CGP3466B and to determine a potential PCMT1/Mst[1] neuronal antiapoptotic pathway 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-caspase[3]. The anti-apoptotic effects of CGP3466B were abolished by chelerythrine, an Mst[1] activator, without changing PCMT1 levels. Protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) is an enzyme that repairs damaged L-isoaspartyl residues in proteins[5] It is highly expressed in the brain, especially the neuron[6]. As a core component of the Hippo signaling pathway, Mst[1] is involved in a variety of regulatory mechanisms such as apoptosis, cell growth and stress response[13, 14]. Protein-protein interaction between Mst[1] and PCMT1 has been identified in HEK293 cells[11]

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