Abstract
Oxidative stress is implicated in the pathogenesis of neurodegeneration and other aging-related diseases. Previous studies have found that the whole herb of Centipeda minima has remarkable antioxidant activities. However, there have been no reports on the neuroprotective effects of C. minima, and the underlying mechanism of its antioxidant properties is unclear. Here, we examined the underlying mechanism of the antioxidant activities of the ethanol extract of C. minima (ECM) both in vivo and in vitro and found that ECM treatment attenuated glutamate and tert-butyl hydroperoxide (tBHP)-induced neuronal death, reactive oxygen species (ROS) production, and mitochondria dysfunction. tBHP-induced phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinases (JNK) was reduced by ECM, and ECM sustained phosphorylation level of extracellular signal regulated kinase (ERK) in SH-SY5Y and PC12 cells. Moreover, ECM induced the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and the upregulation of phase II detoxification enzymes, including heme oxygenase-1 (HO-1), superoxide dismutase-2 (SOD2), and NAD(P)H quinone oxidoreductase-1 (NQO-1) in both two cell types. In a D-galactose (D-gal) and aluminum muriate (AlCl3)-induced neurodegenerative mouse model, administration of ECM improved the learning and memory of mice in the Morris water maze test and ameliorated the effects of neurodegenerative disorders. ECM sustained the expression level of postsynaptic density 95 (PSD95) and synaptophysin (SYN), activated the Nrf2 signaling pathway, and restored the levels of cellular antioxidants in the hippocampus of mice. In addition, four sesquiterpenoids were isolated from C. minima to identify the bioactive components responsible for the antioxidant activity of C. minima; 6-O-angeloylplenolin and arnicolide D were found to be the active compounds responsible for the activation of the Nrf2 signaling pathway and inhibition of ROS production. Our study examined the mechanism of C. minima and its active components in the amelioration of oxidative stress, which holds the promise for the treatment of neurodegenerative disease.
Highlights
Aging is a complex molecular process that is associated with many life-threatening diseases, such as neurodegenerative disease, diabetes, and cardiovascular disease [1, 2]
These results indicated that extract of C. minima (ECM) exerted neuroprotective effects through the attenuation of oxidative stress
The phosphorylation level of extracellular signal regulated kinase (ERK) was significantly decreased in cells exposed to tert-butyl hydroperoxide (tBHP), while ECM pretreatment increased the phosphorylation level of ERK (Figures 3(a) and 3(b)). These results suggest that alteration of the phosphorylation level of MAPK kinase can mediate the antioxidant activity of ECM, and that p38 MAPK and ERK may play different role in mediating the antioxidant effects of ECM
Summary
Aging is a complex molecular process that is associated with many life-threatening diseases, such as neurodegenerative disease, diabetes, and cardiovascular disease [1, 2]. Donepezil is one of the most commonly used drugs approved for dementia; Oxidative Medicine and Cellular Longevity adverse side effects could be induced by long-term and highdose treatment [7,8,9]. Mitochondrial dysfunction, and carbonyl toxification have been widely accepted as the primary causes for the development of aging processes, especially the pathogenesis of most neurodegenerative disorders [10, 11]. Several studies have shown that HO-1 and NQO-1 exert neuroprotective effects by directly reducing oxidative stress and maintaining the integrity of the mitochondria [21, 22]. Nrf overexpression has been shown to protect against neurotoxicity caused by amyloid fibrils [25, 26], indicating that phase II detoxification enzymes have an indispensable role in alleviating the pathogenesis of neurodegenerative disease. Stimulation of the Nrf signaling pathway could be a valuable tool for amelioration of oxidative stress and treatment of neurodegenerative diseases
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