Cholecystokinin and glucagon-like peptide-1 analogues regulate intestinal tight junction, inflammation, dopaminergic neurons and α-synuclein accumulation in the colon of two Parkinson's disease mouse models.

Parkinson's disease (PD) is the second most common neurodegenerative disease, and no treatment is available to stop its progression. Studies have shown that the colonic pathology of PD precedes that of the brain. The 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model and the human A53T α-synuclein (α-syn) transgenic PD mouse model show colonic pathology and intestinal dopaminergic neuronal damage, which is comparable to the intestinal pathology of PD. Cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1), which are brain-gut peptides, have neurotrophic and anti-inflammatory properties. Two GLP-1R agonists have already shown robust effects in phase II trials in PD patients. However, whether they have beneficial effects on colonic pathology in PD remains unclear. In this study, MPTP-treated mice and human A53T α-syn transgenic mice were intraperitoneally injected with a CCK analogue or Liraglutide, a GLP-1 analogue, once a day for 5 weeks. Levels of colonic epithelial tight junction proteins including occludin and zonula occludens-1 (ZO-1), inflammatory biomarkers including inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-α), brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH) and α-syn were analyzed. The results show that the CCK analogue and Liraglutide both restored the disruption of intestinal tight junction, reduced colonic inflammation, inhibited colonic dopaminergic neurons reduction and the accumulation of α-syn oligomers in the colon of both PD mice models. This study suggested that CCK or GLP-1 analogues could be beneficial to the improvement of leaky gut barrier, inflammation, dopaminergic neuron impairment and accumulation of α-syn in the colon of PD patients.

Su Y ，Liu N ，Zhang Z ，Li H ，Ma J ，Yuan Y ，Shi M ，Liu J ，Zhao Z ，Zhang Z ，Holscher C ... -  《-》

Korean Red Ginseng Regulates Intestinal Tight Junction and Inflammation in the Colon of a Parkinson's Disease Mouse Model.

Jeon H ，Kim HY ，Bae CH ，Lee Y ，Kim S ... -  《-》

[Bmal1 mediates the neuroprotective effect of sodium butyrate in a mouse model of Parkinson's disease].

Wang F ，Zhang Z ，Sun Y ，Yang L ，Guo T ，Pan Y ，Ding S ，Jiang L ，Liu H ... -  《-》

Korean red ginseng suppresses 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced inflammation in the substantia nigra and colon.

Parkinson's disease (PD) is a neurodegenerative disease involving dopaminergic neuronal death in the substantia nigra (SN); recent studies have shown that interactions between gut and brain play a critical role in the pathogenesis of PD. In this study, the anti-inflammatory effect of Korean red ginseng (KRG) and the changes in gut microbiota were evaluated in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. Male nine-week-old C57BL/6 mice were injected intraperitoneally with 30 mg/kg of MPTP at 24-h intervals for 5 days. Two hours after the daily MPTP injection, the mice were orally administered 100 mg/kg of KRG, which continued for 7 days beyond the MPTP injections, for a total of 12 consecutive days. Eight days after the final KRG administration, the pole and rotarod tests were performed and brain and colon samples of the mice were collected. Dopaminergic neuronal death, activation of microglia and astrocytes, α-synuclein and expressions of inflammatory cytokines and disruption of tight junction were evaluated. In addition, 16S ribosomal RNA gene sequencing of mouse fecal samples was performed to investigate microbiome changes. KRG treatment prevented MPTP-induced behavioral impairment, dopaminergic neuronal death, activation of microglia and astrocytes in the nigrostriatal pathway, disruption of tight junction and the increase in α-synuclein, interleukin-1β and tumor necrosis factor-α expression in the colon. The 16S rRNA sequencing revealed that MPTP altered the number of bacterial species and their relative abundances, which were partially suppressed by KRG treatment. Especially, KRG suppressed the abundance of the inflammation-related phylum Verrucomicrobia and genera Ruminococcus and Akkermansia (especially Akkermansia muciniphila), and elevated the abundance of Eubacterium, which produces the anti-inflammatory substances. These findings suggest that KRG prevents MPTP-induced dopaminergic neuronal death, activation of microglia and astrocytes, and accumulation of α-synuclein in the SN, and the regulation of inflammation-related factors in the colon may influence the effect.

Jeon H ，Bae CH ，Lee Y ，Kim HY ，Kim S ... -  《-》

[Preliminary study on time-dependent changes of intestinal tract and brain-gut axis in mice model of Parkinson's disease induced by paraquat].

Wang KD ，Zhang BY ，Zhang BF ，Huang M ... -  《-》