Recent studies have determined that gastrointestinal function contributes to the control of Parkinson's disease (PD). Gastrointestinal dysfunction results in a leaky intestinal barrier, inducing inflammation in the gut. Korean red ginseng (KRG) is widely used for the treatment of numerous afflictions, including inflammation and neurodegenerative disease. We investigated changes in the intestinal tight junctions and proinflammatory cytokines in the colon, and alpha-synuclein (aSyn) in the colon and the substantia nigra (SN) of a PD mouse model. Eight-week-old male C57BL/6 mice were intraperitoneally administered 30 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) once a day for 5 days, and orally given 100 mg/kg of KRG for 12 consecutive days. Alterations in the levels of occludin, zonula occludens-1 (ZO-1), tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) in the colon, and the expressions of aSyn and tyrosine hydroxylase (TH) in the colon and the SN were evaluated. Oral administration of KRG significantly prevents the MPTP-induced motor dysfunction, and suppresses the MPTP-induced disruption of occludin and ZO-1, and suppresses the increase in TNF-α and IL-1β in the colon of mice. In addition, KRG prevents accumulation of aSyn and TH in the colon and the SN. These results suggest that KRG has the potential to prevent MPTP-induced leaky gut barrier, inflammation, and accumulation of aSyn.
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References
1.
SchemannM: Control of gastrointestinal motility by the “gut brain”—the enteric nervous system. J Pediatr Gastroenterol Nutr, 2005; 41Suppl 1:S4–S6.
2.
DevosD, LebouvierT, LardeuxB, et al.: Colonic inflammation in Parkinson's disease. Neurobiol Dis, 2013; 50:42–48.
FangX, XuRS: Protective effect of simvastatin on impaired intestine tight junction protein zo-1 in a mouse model of Parkinson's disease. J Huazhong Univ Sci Technol Med Sci, 2015; 35:880–884.
5.
HouserMC, TanseyMG: The gut-brain axis: Is intestinal inflammation a silent driver of Parkinson's disease pathogenesis?. NPJ Parkinsons Dis, 2017; 3:3.
6.
KellyLP, CarveyPM, KeshavarzianA, et al.: Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease. Mov Disord, 2014; 29:999–1009.
PeelaertsW, BoussetL, Van der PerrenA, et al.: Alpha-synuclein strains cause distinct synucleinopathies after local and systemic administration. Nature, 2015; 522:340–344.
9.
RietdijkCD, Perez-PardoP, GarssenJ, van WezelRJ, KraneveldAD: Exploring Braak's hypothesis of Parkinson's disease. Front Neurol, 2017; 8:37.
10.
StolzenbergE, BerryD, Yang, et al.: A role for neuronal alpha-synuclein in gastrointestinal immunity. J Innate Immun, 2017; 9:456–463.
11.
FitzgeraldE, MurphyS, MartinsonHA: Alpha-synuclein pathology and the role of the microbiota in Parkinson's disease. Front Neurosci, 2019; 13:369.
12.
BuJ, LiuJ, LiuK, WangZ: Diagnostic utility of gut alpha-synuclein in Parkinson's disease: A systematic review and meta-analysis. Behav Brain Res, 2019; 364:340–347.
13.
HengY, ZhangQS, MuZ, HuJF, YuanYH, ChenNH: Ginsenoside Rg1 attenuates motor impairment and neuroinflammation in the MPTP-probenecid-induced parkinsonism mouse model by targeting alpha-synuclein abnormalities in the substantia nigra. Toxicol Lett, 2016; 243:7–21.
14.
ChoiJH, JangM, NahSY, OhS, ChoIH: Multitarget effects of Korean red ginseng in animal model of Parkinson's disease: Antiapoptosis, antioxidant, antiinflammation, and maintenance of blood-brain barrier integrity. J Ginseng Res, 2018; 42:379–388.
15.
KimD, JeonH, RyuS, KooS, HaKT, KimS: Proteomic analysis of the effect of Korean red ginseng in the striatum of a Parkinson's disease mouse model. PLoS One, 2016; 11:e0164906.
16.
JunYL, BaeCH, KimD, KooS, KimS: Korean red ginseng protects dopaminergic neurons by suppressing the cleavage of p35 to p25 in a Parkinson's disease mouse model. J Ginseng Res, 2015; 39:148–154.
17.
RyuS, JeonH, KooS, KimS: Korean red ginseng enhances neurogenesis in the subventricular zone of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice. Front Aging Neurosci, 2018; 10:355.
18.
RyuS, KooS, HaKT, KimS: Neuroprotective effect of Korea red ginseng extract on 1-methyl-4-phenylpyridinium-induced apoptosis in PC12 cells. Anim Cells Syst, 2016; 20:363–368.
19.
AndersonG, NoorianAR, TaylorG, et al.: Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson's disease. Exp Neurol, 2007; 207:4–12.
20.
NataleG, KastsiushenkaO, FulceriF, RuggieriS, PaparelliA, FornaiF: MPTP-induced parkinsonism extends to a subclass of TH-positive neurons in the gut. Brain Res, 2010; 1355:195–206.
21.
JeonH, RyuS, KimD, KooS, HaKT, KimS: Acupuncture stimulation at gb34 restores MPTP-induced neurogenesis impairment in the subventricular zone of mice. Evid Based Complement Alternat Med, 2017; 2017:3971675.
22.
SaitouM, FuruseM, SasakiH, et al.: Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Biol Cell, 2000; 11:4131–4142.
23.
StevensonBR, SilicianoJD, MoosekerMS, GoodenoughDA: Identification of ZO-1: A high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol, 1986; 103:755–766.
24.
HuhE, ChoiJG, NohD, et al.: Ginger and 6-shogaol protect intestinal tight junction and enteric dopaminergic neurons against 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine in mice. Nutr Neurosci, 2020; 23:455–464.
25.
MatsuuraK, KabutoH, MakinoH, OgawaN: Pole test is a useful method for evaluating the mouse movement disorder caused by striatal dopamine depletion. J Neurosci Meth, 1997; 73:45–48.
26.
dela PenaIJI, KimHJ, BotanasCJ, et al.: The psychopharmacological activities of Vietnamese ginseng in mice: Characterization of its psychomotor, sedative-hypnotic, antistress, anxiolytic, and cognitive effects. J Ginseng Res, 2017; 41:201–208.
27.
KellyJR, KennedyPJ, CryanJF, DinanTG, ClarkeG, HylandNP: Breaking down the barriers: The gut microbiome, intestinal permeability and stress-related psychiatric disorders. Front Cell Neurosci, 2015; 9:392.
28.
Perez-PardoP, DodiyaHB, BroersenLM, et al.: Gut-brain and brain-gut axis in Parkinson's disease models: Effects of a uridine and fish oil diet. Nutr Neurosci, 2018; 21:391–402.
29.
SeongMA, WooJK, KangJH, et al.: Oral administration of fermented wild ginseng ameliorates dss-induced acute colitis by inhibiting NF-kappaB signaling and protects intestinal epithelial barrier. BMB Rep, 2015; 48:419–425.
30.
JangSH, ParkJ, KimSH, et al.: Oral administration of red ginseng powder fermented with probiotic alleviates the severity of dextran-sulfate sodium-induced colitis in a mouse model. Chin J Nat Med, 2017; 15:192–201.
31.
GuoM, DingS, ZhaoC, et al.: Red ginseng and Semen Coicis can improve the structure of gut microbiota and relieve the symptoms of ulcerative colitis. J Ethnopharmacol, 2015; 162:7–13.
32.
TruongVL, BakMJ, JeongWS: Chemopreventive activity of red ginseng oil in a mouse model of azoxymethane/dextran sulfate sodium-induced inflammation-associated colon carcinogenesis. J Med Food, 2019; 22:578–586.
33.
ZhuG, WangH, WangT, ShiF: Ginsenoside Rg1 attenuates the inflammatory response in dss-induced mice colitis. Int Immunopharmacol, 2017; 50:1–5.
34.
LeeSY, JeongJJ, EunSH, KimDH: Anti-inflammatory effects of ginsenoside Rg1 and its metabolites ginsenoside Rh1 and 20(s)-protopanaxatriol in mice with TNBS-induced colitis. Eur J Pharmacol, 2015; 762:333–343.
35.
JohEH, LeeIA, JungIH, KimDH: Ginsenoside Rb1 and its metabolite compound k inhibit IRAK-1 activation—the key step of inflammation. Biochem Pharmacol, 2011; 82:278–286.
36.
ShenH, GaoXJ, LiT, et al.: Ginseng polysaccharides enhanced ginsenoside Rb1 and microbial metabolites exposure through enhancing intestinal absorption and affecting gut microbial metabolism. J Ethnopharmacol, 2018; 216:47–56.
37.
LeeIA, HyamSR, JangSE, HanMJ, KimDH: Ginsenoside re ameliorates inflammation by inhibiting the binding of lipopolysaccharide to TLR4 on macrophages. J Agric Food Chem, 2012; 60:9595–9602.
38.
TianM, MaP, ZhangY, MiY, FanD: Ginsenoside Rk3 alleviated dss-induced ulcerative colitis by protecting colon barrier and inhibiting NLRP3 inflammasome pathway. Int Immunopharmacol, 2020; 85:106645.
39.
HeLX, WangJB, SunB, et al.: Suppression of TNF-alpha and free radicals reduces systematic inflammatory and metabolic disorders: Radioprotective effects of ginseng oligopeptides on intestinal barrier function and antioxidant defense. J Nutr Biochem, 2017; 40:53–61.
40.
Perez-PardoP, HartogM, GarssenJ, KraneveldAD: Microbes tickling your tummy: The importance of the gut-brain axis in Parkinson's disease. Curr Behav Neurosci Rep, 2017; 4:361–368.
41.
MaQ, XingC, LongW, WangHY, LiuQ, WangRF: Impact of microbiota on central nervous system and neurological diseases: The gut-brain axis. J Neuroinflammation, 2019; 16:53.
42.
BraakH, de VosRA, BohlJ, Del TrediciK: Gastric alpha-synuclein immunoreactive inclusions in Meissner's and Auerbach's plexuses in cases staged for Parkinson's disease-related brain pathology. Neurosci Lett, 2006; 396:67–72.
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