A-Type Cinnamon Procyanidin Oligomers Protect Against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Neurotoxicity in Mice Through Inhibiting the P38 Mitogen-Activated Protein Kinase/P53/BCL-2 Associated X Protein Signaling Pathway

Abstract

<jats:title>ABSTRACT</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Parkinson's disease (PD) is a common neurodegenerative disorder. Cinnamon procyanidin oligomers (CPOs) are flavonoids with many claimed health benefits.</jats:p> </jats:sec> <jats:sec> <jats:title>Objective</jats:title> <jats:p>This study aimed to elucidate the neuroprotection of A-type CPOs (CPO-A) and the underlying mechanisms in cultured cell and animal models of PD.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Thirty male mice (C57BL/6, 9-wk old) were assigned to 3 groups (n = 10), and were given daily gavage of saline [control and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) groups] or CPO-A (150 mg/kg, CPO-A group) during days 1–15 and daily intraperitoneal injections of saline (control group) or MPTP (20 mg/kg; MPTP and MPTP + CPO-A groups) during days 11–15. After the motor behavior test, all mice were killed on day 16 to collect the substantia nigra (SN) for assaying the neuroprotective effects of CPO-A. SH-SY5Y cells were treated with 12.5 μM CPO-A for 2 h or 3 activators of stress-related kinases (5–25 μM) for 12–48 h followed by 1 mM 1-methyl-4-phenylpyridinium (MPP+) for assays of viability, morphology, and stress status.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Compared with the control, the MPTP treatment decreased (P &amp;lt; 0.05) locomotor activity by 21%, and tyrosine hydroxylase (TH) positive neurons by 55% and Th mRNA concentration by 51% in the SN. The CPO-A treatment attenuated or restored (P &amp;lt; 0.05) these changes and inhibited (P &amp;lt; 0.05) the MPTP-induced activation of P38 mitogen-activated protein kinase (P38MAPK) and P53, along with the downstream expression of BCL-2 associated X protein (BAX) in the SN. In SH-SY5Y cells, the CPO-A treatment blocked (P &amp;lt; 0.01) the MPP+-induced accumulation of intracellular reactive oxygen species and neurotoxicity. However, this protection was abolished (P &amp;lt; 0.05) by activators of the P38MAPK/P53/BAX pathway.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>CPO-A protected against MPP+-induced cytotoxicity in SH-SY5Y cells and MPTP-induced neurotoxicity in mice by regulating the P38MAPK/P53/BAX signaling. Our findings reveal a novel role and mechanism of a food flavonoid CPO-A in preventing neurodegeneration.</jats:p> </jats:sec>

Neuroprotective potential of cinnamon and its metabolites in Parkinson's disease: Mechanistic insights, limitations, and novel therapeutic opportunities

“…Apart from cinnamaldehyde, cinnamon also contains various polyphenols, exerting significant antioxidant and anti‐inflammatory properties. [ 34 ] Among them, the A‐type cinnamon procyanidin oligomers (CPO‐A) represent the main biologically active polyphenols of cinnamon. [ 34 ] In vitro evidence has shown that treatment of MPP + ‐intoxicated SH‐SY5Y cells with 12.5 μM of CPO‐A may inhibit ROS accumulation and MPP + ‐induced neurotoxicity, via its implication in the P38 MAPK/P53/BCL‐2 associated X protein (BAX) signaling pathway.…”

“…[ 34 ] Among them, the A‐type cinnamon procyanidin oligomers (CPO‐A) represent the main biologically active polyphenols of cinnamon. [ 34 ] In vitro evidence has shown that treatment of MPP + ‐intoxicated SH‐SY5Y cells with 12.5 μM of CPO‐A may inhibit ROS accumulation and MPP + ‐induced neurotoxicity, via its implication in the P38 MAPK/P53/BCL‐2 associated X protein (BAX) signaling pathway. [ 34 ] Stress signals can lead to P38 phosphorylation and subsequent activation.…”

“…[ 34 ] In vitro evidence has shown that treatment of MPP + ‐intoxicated SH‐SY5Y cells with 12.5 μM of CPO‐A may inhibit ROS accumulation and MPP + ‐induced neurotoxicity, via its implication in the P38 MAPK/P53/BCL‐2 associated X protein (BAX) signaling pathway. [ 34 ] Stress signals can lead to P38 phosphorylation and subsequent activation. This further leads to P53 activation which regulates several downstream factors, such as BAX and caspases, contributing to neuroinflammation, mitochondrial impairment, and subsequent neurodegeneration.…”

“…The CPO‐A treatment was also associated with inhibition of dopaminergic neuronal loss in SN and attenuation of locomotor impairment of MPTP‐treated mice, via regulation of the P38/P53/BAX pathway. [ 34 ] Although P38 inhibitors, SB239063 and SB203580, have demonstrated protection against PD in vivo, [ 43 ] several others have been clinically withdrawn because of severe hepatic and neurological side effects. [ 44 ] In this context, plant‐derived compounds may represent an alternative promising approach due to their low toxicity.…”

“…[ 44 ] In this context, plant‐derived compounds may represent an alternative promising approach due to their low toxicity. [ 34 ]…”