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

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.

Apoptosis and its Role in Parkinson’s Disease

“…CGP3466B suppresses neuronal apoptosis by upregulating protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1), which is an enzyme that repairs damaged L-isoaspartyl residues in intracellular proteins. Upregulated PCMT1 leads to overexpression of the antiapoptotic Bcl-2 and underexpression of the proapoptotic Bax and active-caspase3, and thus inhibiting mitochondria-dependent apoptosis (133). Concomitantly, it prevents dopaminergic cell death both in vitro and in rodent models of Parkinson' s disease, and it consequently inhibits the development of MPTP-and 6-OHDA-induced motor symptoms (131,132).…”

The emerging role of Hippo signaling in neurodegeneration

“…Hence, this Src‐MST1‐IκBα signaling forms the critical player in microglial activation and ultimately neuronal death (Zhao et al, ). Hyperactivation of Hippo signaling has also been associated with several other stroke‐like conditions including traumatic brain injury (TBI) (Liang et al, ), subarachnoid hemorrhage (SAH) (Qu et al, ), and intracerebral hemorrhage (ICH) (Zhang et al, ).…”

“…Administration of CGP3466B, a compound related to the anti‐Parkinsonism drug R‐(−)‐deprenyl was found to alleviate brain edema, downregulate ROS levels, and enrich neurological function 24‐hr post‐TBI. Additionally, CGP3466B treatment rescued neuronal apoptosis by increasing PCMT1 (protein‐ l ‐isoaspartate ( d ‐aspartate) O‐methyltransferase) expression, which inhibits MST1 expression, subsequently leading to reduced expression of proapoptotic proteins like Bax and active caspase‐3 (Liang et al, ). Suppressing MST1 expression rescues neuronal apoptosis in various injury‐induced neurodegenerative disorders like stroke and hemorrhage as well.…”

“…Hyperactivation of Hippo signaling has also been associated with several other stroke-like conditions including traumatic brain injury (TBI) (Liang et al, 2017), subarachnoid hemorrhage (SAH) (Qu et al, 2018), and intracerebral hemorrhage (ICH) .…”

Induction of Neuronal PI3Kγ Contributes to Endoplasmic Reticulum Stress and Long-Term Functional Impairment in a Murine Model of Traumatic Brain Injury

“…Early neuronal apoptosis induced by TBI was examined at 3 days after TBI. Double labeling staining of TUNEL and NeuN was performed to colocalize apoptotic neurons as described previously [31]. Serial coronal sections (10 μm thick) at the level of the dorsal hippocampus (− 1.4 to − 2.1 mm from the bregma) at 100-μm intervals were selected for staining.…”