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Phytomedicine-Based Potent Antioxidant, Fisetin Protects CNS-Insult LPS-Induced Oxidative Stress-Mediated Neurodegeneration and Memory Impairment

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Phytomedicine-Based Potent Antioxidant, Fisetin Protects CNS-Insult LPS-Induced Oxidative Stress-Mediated Neurodegeneration and Memory Impairment Journal of Clinical Medicine Article Phytomedicine-Based Potent Antioxidant, Fisetin Protects CNS-Insult LPS-Induced Oxidative Stress-Mediated Neurodegeneration and Memory Impairment Ashfaq Ahmad y, Tahir Ali y, Shafiq Ur Rehman y and Myeong Ok Kim * Division of Applied Life Science (BK 21), College of Natural Sciences, Gyeongsang National University, Jinju 52828, Korea; [email protected] (A.A.); [email protected] (T.A.); shafi[email protected] (S.U.R.) * Correspondence: [email protected]; Tel.: +82-55-772-1345; Fax: +82-55-772-2656 These authors contributed equally to this work. y Received: 16 May 2019; Accepted: 11 June 2019; Published: 14 June 2019 Abstract: Phytomedicine based natural flavonoids have potent antioxidant, anti-inflammatory, and neuroprotective activities against neurodegenerative diseases. The aim of the present study is to investigate the potent neuroprotective and antioxidant potential effects of fisetin (natural flavonoid) against central nervous system (CNS)-insult, lipopolysaccharide (LPS)-induced reactive oxygen species (ROS), neuroinflammation, neurodegeneration, and synaptic/memory deficits in adult mice. The mice were injected intraperitoneally (i.p.) with LPS (250 µg/kg/day for 1 week) and a fisetin dosage regimen (20 mg/kg/day i.p. for 2 weeks, 1 week pre-treated to LPS and 1 week co-treated with LPS). Behavioral tests, and biochemical and immunofluorescence assays were applied. Our results revealed that fisetin markedly abrogated the LPS-induced elevated ROS/oxidative stress and activated phosphorylated c-JUN N-terminal Kinase (p-JNK) in the adult mouse hippocampus. Fisetin significantly alleviated LPS-induced activated gliosis. Moreover, fisetin treatment inhibited LPS-induced activation of the inflammatory Toll-like Receptors (TLR4)/cluster of differentiation 14 (CD14)/phospho-nuclear factor kappa (NF-κB) signaling and attenuated other inflammatory mediators (tumor necrosis factor-α (TNF-α), interleukin-1 β (IL1-β), and cyclooxygenase (COX-2). Furthermore, immunoblotting and immunohistochemical results revealed that fisetin significantly reversed LPS-induced apoptotic neurodegeneration. Fisetin improved the hippocampal-dependent synaptic and memory functions in LPS-treated adult mice. In summary, our results strongly recommend that fisetin, a natural potent antioxidant, and neuroprotective phytomedicine, represents a promising, valuable, and therapeutic candidate for the prevention and treatment of neurodegenerative diseases. Keywords: phytomedicine; natural flavonoids; fisetin; central nervous system (CNS) insult; lipopolysaccharide (LPS); oxidative stress; neuroinflammation; neurodegeneration; synaptic and memory functions 1. Introduction Neuroinflammation is considered to be a key event in the neurodegeneration process inherent to various aging pathologies. Within the central nervous system (CNS), microglia are considered a key player in the immune system that trigger various neuroinflammatory responses [1]. Literature reviews suggest that microglial activation plays a pivotal role in various stress conditions including oxidation, neuroinflammation, and neurodegenerative diseases [2,3]. Under varying environmental conditions such as infections and the introduction of toxins and endogenous proteins, microglia J. Clin. Med. 2019, 8, 850; doi:10.3390/jcm8060850 www.mdpi.com/journal/jcm J. Clin. Med. 2019, 8, x FOR PEER REVIEW 2 of 23 J. Clin. Med. 2019, 8, 850 2 of 23 become over-activated and release reactive oxygen species (ROS) that cause neurotoxicity and initiate an immune response via toll-like receptors (TLRs), whose activation communicates downstream becomeinflammatory over-activated mediators and [4,5]. release The reactiveelevated oxygen levels of species oxidative (ROS) stress that resulting cause neurotoxicity from an increased and initiate level anof immuneROS production, response a viadecrease toll-like in receptorsthe antioxidant (TLRs), system, whose or activation both, play communicates a critical role downstreamin the aging inflammatoryprocess and mediatorsin the development [4,5]. The elevated of levelsdegenerat of oxidativeive diseases stress resulting[6]. The from inflammatory an increased agent level oflipopolysaccharide ROS production, a (LPS) decrease is inan the endotoxin antioxidant derived system, from or both, the playouter a criticalmembrane role in of the Gram-negative aging process andbacteria in the and development is a strong activator of degenerative of host defense diseases responses. [6]. The Recent inflammatory studies suggested agent lipopolysaccharide that the systemic (LPS)administration is an endotoxin of LPS derivedcauses inflammatory from the outer processe membranes in the of body, Gram-negative which causes bacteria deleterious and is effects a strong in activatorthe brain of [7–13]. host defense LPS administration responses. Recent induces studies memory suggested impairments that the and systemic neuroinflammation administration via of LPSactivated causes TLR4/NF inflammatoryKB signaling processes and regulates in the body, various which downst causesream deleterious proinflammator effects iny themediators, brain [7 –such13]. LPSas nitric administration oxide (NO), induces prostaglandin memory E2 impairments (PGE2), and and cyclooxygenase neuroinflammation (COX)2, via activatedand proinflammatory TLR4/NFκB signalingcytokines, and including regulates interleukin-1 various downstream (IL-1), IL-6, proinflammatory and tumor necrosis mediators, factor- suchα (TNF- as nitricα) oxide[14]. Recent (NO), prostaglandinstudies have suggested E2 (PGE2), that and among cyclooxygenase the mammalian (COX)2, TLRs and families, proinflammatory TLR4 plays cytokines, an important including role in interleukin-1inflammation (IL-1), pathogenesis. IL-6, and tumor TLR4 necrosis acts as factor- a primaryα (TNF- initiatorα)[14]. Recentof innate studies immune have suggested responses that to amongpathogens the mammalianby activating TLRs a cascade families, of pro-inflamma TLR4 plays antory important events. The role LPS in inflammation administration pathogenesis. triggers the TLR4activation acts asof aTLR4 primary via downstream initiator of innate signaling immune factors, responses such as toadaptor pathogens myeloid by activating differentiation a cascade protein of pro-inflammatory88 (MyD88), leading events. to the The activation LPS administration of nuclear triggersfactor-KB the (NF- activationKB) and of ultimately TLR4 via downstreaminducing the signalingexpression factors, of inflammation-related such as adaptor myeloid genes. di Thefferentiation systematic protein LPS administration 88 (MyD88), leading impaired to the learning activation and ofmemory nuclear performance, factor-κB (NF- increasedκB) and ultimatelyamyloid beta inducing (Aβ)-burden, the expression and diminished of inflammation-related synaptic and memory genes. Thefunctions systematic [13,15,16]. LPS administration impaired learning and memory performance, increased amyloid beta (ATheβ)-burden, epidemiological and diminished comprehensive synaptic surveys and memory reported functions that over [13 the,15 past,16]. few years, it has become a primaryThe epidemiological focus of researchers comprehensive to search for surveys potential reported effective that therapeutic over the past agents few from years, natural it has becomesources ato primary combat focusinflammatory of researchers and neurodegenerative to search for potential diseases. effective Among therapeutic the natural agents sources, from naturalphytomedicine sources toderived combat flavonoids inflammatory are a and primary neurodegenerative focus because diseases. of their Amongpotent biological the natural and sources, therapeutic phytomedicine activities derivedwhich are flavonoids beneficial are for a primaryhealth improvements focus because of[17–20]. their potent Flavonoids biological are andpolyphenolic therapeutic compounds activities whichabundantly are beneficial found in for foods health and improvements vegetables and [17 widely–20]. Flavonoids used as nutritional are polyphenolic supplements compounds for the abundantlytreatment of founddiabetes, in obesity, foods and and vegetables cardiovascular and and widely neurological used as nutritionaldisorders [17,21–24]. supplements Fisetin for (3, the 7, treatment3,4-tetrahydroxyflavone) of diabetes, obesity, (Figure and 1), cardiovascular is a well-known and and neurological potent flavonoid, disorders which [17,21 is –commonly24]. Fisetin found (3, 7, 3,4-tetrahydroxyflavone)in many fruits and vegetables (Figure such1), is as a well-knownapples, grapes, and kiwis, potent strawberries, flavonoid, which onions, is commonlypersimmons, found and incucumbers. many fruits Several and vegetables studies have such suggested as apples, that grapes, fisetin kiwis, is a biochemically strawberries, and onions, physiologically persimmons, active and cucumbers.flavonoid based Several phytomedicine, studies have suggestedshowing various that fisetin strong is a pharmacological biochemically and activities physiologically against cancer, active flavonoidoxidative stress, based phytomedicine,inflammatory bowel showing disease, various and co stronggnitive/ pharmacological ynaptic dysfunctions activities [25–30]. against Similarly, cancer, oxidativewe also recently stress, inflammatoryreported the neuroprotective bowel disease, andeffect cognitive of fisetin/ynaptic against dysfunctions Aβ-induced [neurotoxicity25–30]. Similarly, and wecognitive/synaptic also recently reported dysfunctions the neuroprotective [31]. Therefore,
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