Lycopene ameliorates chronic stress-induced hippocampal injury and subsequent learning and memory dysfunction through inhibiting ROS/JNK signaling pathway in rats
Graphical abstract
Introduction
Chronic stress is a leading cause of brain pathologies, such as depression and Alzheimer's disease (AD), and therefore poses a great threat to public health (Bisht et al., 2018; Dioli et al., 2019). It has been reported that seven million people in China alone have AD, and the annual rate of AD patients is increasing globally by a factor of 1.033 (Jia et al., 2018). The key brain region responsible for learning and memory is the hippocampus, which is susceptible to chronic stress (Nollet et al., 2019). Hippocampal injury caused by chronic stress is important in the pathogenesis of AD, and improving hippocampal injury caused by chronic stress has a therapeutic effect in AD (Dioli et al., 2019; Zhang et al., 2018). Therefore, the exact mechanisms of hippocampal injury caused by chronic stress and its effective therapeutic drugs urgently need to be studied.
Recent studies have shown that oxidative stress and apoptosis are extensively and intricately involved in chronic stress-induced hippocampal injury (Bisht et al., 2018; Mohammadi et al., 2014). When an organism is stimulated by stress, large amounts of reactive oxygen species (ROS) are released, causing an imbalance between oxidation and the antioxidant system, which leads to oxidative stress (Chen et al., 2018). Moreover, excessive generation of ROS is the principal pathological contributor to stress-induced hippocampal injury (Feng et al., 2019; Fontella et al., 2005). Furthermore, oxidative stress can trigger apoptosis (Chen et al., 2018). Mitochondria are the main site of ROS production and are the most vulnerable organelles to ROS (Xu et al., 2019). When mitochondria are attacked by ROS, they release cytochrome c (Cyt-c) into the cytoplasm, thereby activating the caspase cascade reaction to induce apoptosis (Chen et al., 2018; Xu et al., 2019). Apoptosis plays an important role in the progression of hippocampal damage caused by chronic stress (Qing et al., 2018). Conversely, hippocampal damage, cognitive dysfunction, and neurodegenerative diseases can be alleviated by scavenging ROS or inhibiting apoptosis (Ahmad et al., 2019). However, there are currently no safe, effective, and side-effect-free medicines for the prevention and treatment of neurodegenerative diseases.
Lycopene (LYC) is a natural plant carotenoid with a strong antioxidant capacity, and is widely found in red fruits and vegetables, especially ripe tomatoes, carrots, and watermelon (Xu et al., 2019; Yu et al., 2018). Because of its high safety, LYC was approved in 2006 by the joint FAO/WHO Expert Committee on Food Additives for use in various foods as a natural pigment and flavor (Lin et al., 2018; Organization and Organization, 2010). Moreover, because of its strong antioxidant capacity, LYC is widely used in nutritional products and cosmetics (ZQ et al., 2018). Furthermore, dietary LYC supplementation can significantly reduce the risk of chronic diseases associated with oxidative stress (Zhao et al., 2018). Recent studies have demonstrated that LYC can penetrate the blood–brain barrier and improve aging-, hyperinsulinemia-, and toxin-induced brain damage and neurobehavioral defects by inhibiting oxidative stress and apoptosis (Cao et al., 2019; Wang et al., 2018; Zhao et al., 2018). However, the protective effects of LYC on chronic stress-induced hippocampal injury, and their underlying mechanisms, have not yet been reported.
The first aim of the present study was to investigate whether LYC has neuroprotective effects on chronic stress-induced hippocampal injury. The second aim was to explore whether the ROS/c-Jun N-terminal kinase (JNK) signaling pathway is involved in the neuroprotective mechanisms of LYC on chronic stress-induced hippocampal injury, by using a reactive oxygen scavenger (N-acetyl-l-cysteine, NAC) and a JNK inhibitor (SP600125). This study provides a theoretical basis and new perspective for the application of LYC in the prevention and treatment of chronic stress-induced encephalopathy.
Section snippets
Experimental animal and design
All animal procedures were approved by the Animal Ethics Committee of the Northeast Agricultural University (SRM-11, China) and conducted in accordance with Regulations and Recommendations for the Care and Use of Animals in Research (Guillén, 2017).
Ninety-nine male Wistar rats (6–7 weeks old; weighing 200–220 g) were purchased from Harbin Medical University (Harbin, China) and raised in standard laboratory conditions (Zhang et al., 2018). Rats were kept in individual cages (3 rats per cage) and
Effects of LYC pretreatment on body weight and CORT content in CRS rats
The change in rat body weight every 7 days is shown in Fig. 1C. Body weight gain was significantly less in all CRS-exposed rats compared with the CON group at day 14 and day 21 (P < 0.01), while LYC pretreatment led to markedly increased body weight gain compared with the CRS and Vehicle + CRS groups (P < 0.05). These results suggest that LYC pretreatment ameliorates CRS-induced body weight loss in rats.
In terms of CORT content (Fig. 1D), compared with the CON group, CRS significantly increased
Discussion
Chronic stress plays a critical role in the manifestation of AD, such as impaired learning and memory. Millions of people suffer from this cognitive disorder. The US Food and Drug Administration has approved several drugs for the treatment of AD, such as donepezil, galantamine, and memantine. However, current treatments are not satisfactory. It is therefore very important to explore new anti-AD agents. In the present study, we reported for the first time the protective effects and mechanisms of
CRediT authorship contribution statement
Haiyang Zhang: Conceptualization, Methodology, Writing - original draft, Writing - review & editing, Supervision. Mian Wei: Investigation, Visualization, Validation. Qinghong Sun: Conceptualization, Methodology, Writing - original draft, Writing - review & editing, Supervision. Tianyuan Yang: Data curation, Formal analysis, Software. Xiangyu Lu: Investigation, Visualization, Validation. Xiujing Feng: Data curation, Formal analysis, Software. Miao Song: Data curation, Formal analysis, Software.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgments
This study was supported by National Natural Science Foundation of China (Grant No. 31772806 and Grant No. 31802251) and Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, China. We thank Bronwen Gardner, PhD, from Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.
References (47)
- et al.
Chronic stress as a risk factor for Alzheimer's disease: roles of microglia-mediated synaptic remodeling, inflammation, and oxidative stress
Neurobiol Stress
(2018) - et al.
Lycopene attenuates aluminum-induced hippocampal lesions by inhibiting oxidative stress-mediated inflammation and apoptosis in the rat
J. Inorg. Biochem.
(2019) - et al.
Dexmedetomidine ameliorates acute stress-induced kidney injury by attenuating oxidative stress and apoptosis through inhibition of the ROS/JNK signaling pathway
Oxid. Med. Cell. Longev.
(2018) - et al.
Can lycopene be considered an effective protection against cardiovascular disease?
Food Chem.
(2018) - et al.
First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): their fundamental role in the entire antioxidant defence grid
Alexandria J. Med.
(2018) - et al.
The cost of Alzheimer's disease in China and re-estimation of costs worldwide
Alzheimers Dement.
(2018) - et al.
Redox regulation of FoxO transcription factors
Redox Biol.
(2015) - et al.
Necrostatin-1 protects against ischemia/reperfusion injury by inhibiting receptor-interacting protein 1 in a rat flap model
J. Plast. Reconstr. Aesthetic Surg.
(2019) - et al.
Effects of escitalopram and ibuprofen on a depression-like phenotype induced by chronic stress in rats
Neurosci. Lett.
(2019) - et al.
Mineralocorticoid receptor antagonist spironolactone prevents chronic corticosterone induced depression-like behavior
Psychoneuroendocrinology
(2013)
The effects of perindopril on cognitive impairment induced by d-galactose and aluminum trichloride via inhibition of acetylcholinesterase activity and oxidative stress
Pharmacol. Biochem. Behav.
Bone impairment caused by AlCl3 is associated with activation of the JNK apoptotic pathway mediated by oxidative stress
Food Chem. Toxicol.
Aflatoxin B1 induced renal and cardiac damage in rats: protective effect of lycopene
Res. Vet. Sci.
Aluminum trichloride-induced hippocampal inflammatory lesions are associated with IL-1beta-activated IL-1 signaling pathway in developing rats
Chemosphere
Aluminum trichloride caused hippocampal neural cells death and subsequent depression-like behavior in rats via the activation of IL-1β/JNK signaling pathway
Sci. Total Environ.
Aluminium chloride impairs long-term memory and downregulates cAMP-PKA-CREB signalling in rats
Toxicology
Supplementation of lycopene attenuates oxidative stress induced neuroinflammation and cognitive impairment via Nrf2/NF-kappaB transcriptional pathway
Food Chem. Toxicol.
Phytomedicine-based potent antioxidant, fisetin protects CNS-insult LPS-induced oxidative stress-mediated neurodegeneration and memory impairment
J. Clin. Med.
Central role of glucocorticoid receptors in Alzheimer's disease and depression
Front. Neurosci.
JNK phosphorylates the Neh6 domain of Nrf2 and downregulates cytoprotective genes in acetaminophen‐induced liver injury
Hepatology
Chronic stress triggers divergent dendritic alterations in immature neurons of the adult hippocampus, depending on their ultimate terminal fields
Transl. Psychiatry
Neuroprotective effects of curcumin on IL-1beta-induced neuronal apoptosis and depression-like behaviors caused by chronic stress in rats
Front. Cell. Neurosci.
Glucocorticoid-driven NLRP3 inflammasome activation in hippocampal microglia mediates chronic stress-induced depressive-like behaviors
Front. Mol. Neurosci.
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