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.
Highlights
Neuroinflammation is considered to be a key event in the neurodegeneration process inherent to various aging pathologies
Fisetin (20 mg/kg, i.p. for 2 weeks; 1 week prior to LPS and 1 week co-treated with LPS) supplementation reversed the elevated expression levels in the LPS-treated group compared to LPS-only treated group (p < 0.05) (Figure 7A)
Fisetin treatment significantly enhanced the expression levels of PSD-95 in the Cornu Ammonis 1 (CA1) (p < 0.05) and Cornu Ammonis 3 (CA3) (p < 0.05) regions of the hippocampus, compared to the LPS-only treated group (Figure 9B). These results suggest that fisetin treatment (20 mg/kg, i.p. for 2 weeks; 1 week prior to LPS and 1 week co-treated with LPS) significantly improved synaptic functions associated with the preand post-synaptic proteins in the hippocampi of adult mice
Summary
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. Med. 2019, 8, 850 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 binecfloammemoavteorr-yacmtievdatieadtoarsnd[4,r5e]l.eTasheereelaecvtaivteedolxeyvgeelsnosfpoexcidesat(iRvOe Sst)rtehsastrceasulsteinngeufrroomtoxaincitnycarenadseinditleiavtel aonf iRmOmS upnreodruescptioonns,eavdiaectroelals-leikien rtehceepantotirosx(iTdLanRts)s,ywsthemos,eoarcbtiovtaht,iopnlacyoma cmriutinciaclarteosledionwthnestraegainmg ipnrfloacmesms ataonryd miendiatthoers d[4e,5v]e.loTphme elnetvatoefd ldeevgeelsnoerfaotxivideatidviesesatrseesss r[e6s]u. LtiTnhgefroimnflaanmimncarteoarsyedalegveenlt olifpRoOpSolpyrsoadcuchctairoind,ea (dLePcSre)asise ianntheenadnottioxidnandtesriyvsetedmf,roormbotthhe, polauytearcmriteicmalbrroalneeinotfheGargaimng-npergoacteisvse abnadctienriathaendeivs ealsotpromnegnatcotifvdaetogreonfehraotsitvdeedfeisnesaesreessp[6o]n. Med. 2019, 8, 850 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 binecfloammemoavteorr-yacmtievdatieadtoarsnd[4,r5e]l.eTasheereelaecvtaivteedolxeyvgeelsnosfpoexcidesat(iRvOe Sst)rtehsastrceasulsteinngeufrroomtoxaincitnycarenadseinditleiavtel aonf iRmOmS upnreodruescptioonns,eavdiaectroelals-leikien rtehceepantotirosx(iTdLanRts)s,ywsthemos,eoarcbtiovtaht,iopnlacyoma cmriutinciaclarteosledionwthnestraegainmg ipnrfloacmesms ataonryd miendiatthoers d[4e,5v]e.loTphme elnetvatoefd ldeevgeelsnoerfaotxivideatidviesesatrseesss r[e6s]u. ltiTnhgefroimnflaanmimncarteoarsyedalegveenlt olifpRoOpSolpyrsoadcuchctairoind,ea (dLePcSre)asise ianntheenadnottioxidnandtesriyvsetedmf,roormbotthhe, polauytearcmriteicmalbrroalneeinotfheGargaimng-npergoacteisvse abnadctienriathaendeivs ealsotpromnegnatcotifvdaetogreonfehraotsitvdeedfeisnesaesreessp[6o]n. sTehs.eRiencfleanmt smtuadtoiersysuagegnetstleipdothpaotlythsaecscyhsatermidiec (aLdPmS)inisisatrnateinodnootfoLxPinSdcaeurisveesdinfrfloammmthaetoruyteprrmocemssbesrainethoef bGordaym, -wnhegicahticvaeubseasctdeerlieatearnidouis eaffsetrcotsnign atchteivbartoairnof[7h–o1s3t].dLefPeSnsaedrmesipnoisntrsaetsi.onReicnednutcsetsudmiesmsourgygiemstpedairtmhaetntthseasnydstenmeuicroaidnfmlaimnimstraatitoionnvoifa
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