Qi Xu1,2, Ziyu Chen1, Borong Zhu3, Gaorui Wang1, Qi Jia3, Yiming Li3, Xiaojun Wu1. 1. Shanghai Key Laboratory of Compound Chinese Medicines, The Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicine, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China. 2. School of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China. 3. School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Abstract
BACKGROUND: Parkinson's disease (PD) is a common neurodegenerative disorder. Cinnamon procyanidin oligomers (CPOs) are flavonoids with many claimed health benefits. OBJECTIVE: 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. METHODS: 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. RESULTS: Compared with the control, the MPTP treatment decreased (P < 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 < 0.05) these changes and inhibited (P < 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 < 0.01) the MPP+-induced accumulation of intracellular reactive oxygen species and neurotoxicity. However, this protection was abolished (P < 0.05) by activators of the P38MAPK/P53/BAX pathway. CONCLUSION: 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.
BACKGROUND:Parkinson's disease (PD) is a common neurodegenerative disorder. Cinnamonprocyanidin oligomers (CPOs) are flavonoids with many claimed health benefits. OBJECTIVE: 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. METHODS: 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. RESULTS: Compared with the control, the MPTP treatment decreased (P < 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 < 0.05) these changes and inhibited (P < 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 < 0.01) the MPP+-induced accumulation of intracellular reactive oxygen species and neurotoxicity. However, this protection was abolished (P < 0.05) by activators of the P38MAPK/P53/BAX pathway. CONCLUSION: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 flavonoidCPO-A in preventing neurodegeneration.