The p75 neurotrophin receptor as a novel intermediate in L-dopa-induced dyskinesia in experimental Parkinson's disease

Zhao

et al. 2021

J Neuroinflammation

Background Streptococcus pneumoniae meningitis is a destructive central nervous system (CNS) infection with acute and long-term neurological disorders. Previous studies suggest that p75NTR signaling influences cell survival, apoptosis, and proliferation in brain-injured conditions. However, the role of p75NTR signaling in regulating pneumococcal meningitis (PM)-induced neuroinflammation and altered neurogenesis remains largely to be elucidated. Methods p75NTR signaling activation in the pathological process of PM was assessed. During acute PM, a small-molecule p75NTR modulator LM11A-31 or vehicle was intranasally administered for 3 days prior to S. pneumoniae exposure. At 24 h post-infection, clinical severity, histopathology, astrocytes/microglia activation, neuronal apoptosis and necrosis, inflammation-related transcription factors and proinflammatory cytokines/mediators were evaluated. Additionally, p75NTR was knocked down by the adenovirus-mediated short-hairpin RNA (shRNA) to ascertain the role of p75NTR in PM. During long-term PM, the intranasal administration of LM11A-31 or vehicle was continued for 7 days after successfully establishing the PM model. Dynamic changes in inflammation and hippocampal neurogenesis were assessed. Results Our results revealed that both 24 h (acute) and 7, 14, 28 day (long-term) groups of infected rats showed increased p75NTR expression in the brain. During acute PM, modulation of p75NTR through pretreatment of PM model with LM11A-31 significantly alleviated S. pneumoniae-induced clinical severity, histopathological injury and the activation of astrocytes and microglia. LM11A-31 pretreatment also significantly ameliorated neuronal apoptosis and necrosis. Moreover, we found that blocking p75NTR with LM11A-31 decreased the expression of inflammation-related transcription factors (NF-κBp65, C/EBPβ) and proinflammatory cytokines/mediators (IL-1β, TNF-α, IL-6 and iNOS). Furthermore, p75NTR knockdown induced significant changes in histopathology and inflammation-related transcription factors expression. Importantly, long-term LM11A-31 treatment accelerated the resolution of PM-induced inflammation and significantly improved hippocampal neurogenesis. Conclusion Our findings suggest that the p75NTR signaling plays an essential role in the pathogenesis of PM. Targeting p75NTR has beneficial effects on PM rats by alleviating neuroinflammation and promoting hippocampal neurogenesis. Thus, the p75NTR signaling may be a potential therapeutic target to improve the outcome of PM.

Section: Introductionmentioning

confidence: 99%

Regulation of the p75 neurotrophin receptor attenuates neuroinflammation and stimulates hippocampal neurogenesis in experimental Streptococcus pneumoniae meningitis

Zhao

et al. 2021

J Neuroinflammation

“…A study on the role of p75NTR in LID found that knocking-down striatal p75NTR prevented the development of LID and increased striatal structural plasticity in rat models. In contrast, striatal p75NTR overexpression exacerbated LID and facilitated the loss of striatal dendritic spines in rats [ 28 ]. These results are consistent with the present study and support the idea that NGFR is involved in LID.…”

Section: Discussionmentioning

confidence: 99%

“…The empty AAV vector coding mCherry was used as the control. The shRNA sequence targeting NGFR was 5′-GCAGATGTGCCTATGGCTACT-3′ and the scrambled sequence was 5′-GAAGCAACTCGTCTGGACAGT-3′, which were based on a previous study [ 28 ]. The AAV vector was constructed by HanBio Biotechnology (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

The NONRATT023402.2/rno-miR-3065-5p/NGFR axis affects levodopa-induced dyskinesia in a rat model of Parkinson’s disease

Wang,

Meng

et al. 2023

Cell Death Discov.

Levodopa-induced dyskinesia (LID) is a common motor complication in Parkinson’s disease. However, few studies have focused on the pathogenesis of LID at the transcriptional level. NONRATT023402.2, a long non-coding RNA (lncRNA) that may be related to LID was discovered in our previous study and characterized in rat models of LID. In the present study, NONRATT023402.2 was overexpressed by injection of adeno-associated virus (AAV) in striatum of LID rats, and 48 potential target genes, including nerve growth factor receptor (NGFR) were screened using next-generation sequencing and target gene predictions. The NONRATT023402.2/rno-miR-3065-5p/NGFR axis was verified using a dual luciferase reporter gene. Overexpression of NONRATT023402.2 significantly increased the abnormal involuntary movements (AIM) score of LID rats, activated the PI3K/Akt signaling pathway, and up-regulated c-Fos in the striatum. NGFR knockdown by injection of ShNGFR-AAV into the striatum of LID rats resulted in a significant decrease in the PI3K/Akt signaling pathway and c-Fos expression. The AIM score of LID rats was positively correlated with the expressions of NONRATT023402.2 and NGFR. A dual luciferase reporter assay showed that c-Fos, as a transcription factor, bound to the NONRATT023402.2 promoter and activated its expression. Together, the results showed that NONRATT023402.2 regulated NGFR expression via a competing endogenous RNA mechanism, which then activated the PI3K/Akt pathway and promoted c-Fos expression. This suggested that c-Fos acted as a transcription factor to activate NONRATT023402.2 expression, and form a positive feedback regulation loop in LID rats, thus, aggravating LID symptoms. NONRATT023402.2 is therefore a possible novel therapeutic target for LID.

“…Adult male Sprague-Dawley rats weighing 200-250 g were used, and all rats were kept under standard laboratory conditions as previously described (17). The protocols of this study were reviewed and approved by the Ethical Committee of the Medical School of Shanghai Jiao Tong University (the ethical clearance number: XHEC-NSFC-2019-210).…”

Section: Animals and Establishment Of Parkinson's Disease Modelmentioning

confidence: 99%

“…To establish a rat model of PD, 6-OHDA was injected into the right middle forebrain bundle of each rat. Animal surgical procedures were performed as previously reported (17). Three weeks after the 6-OHDA injection, rats with a rotating frequency >7 turns/min in apomorphine-induced rotation tests were selected as successful PD rat models.…”

Section: Animals and Establishment Of Parkinson's Disease Modelmentioning

confidence: 99%

Network Pharmacology and Absolute Bacterial Quantification-Combined Approach to Explore the Mechanism of Tianqi Pingchan Granule Against 6-OHDA-Induced Parkinson’s Disease in Rats

et al. 2022

Self Cite

Parkinson’s disease (PD) is the second most common neurodegenerative disease. Tianqi Pingchan Granule (TPG) is a clinically effective formula of traditional Chinese medicine to treat PD. However, the therapeutic effect and underlying mechanisms of TPG in PD remain unclear. Based on network pharmacology, the corresponding targets of TPG were identified using the Traditional Chinese Medicine Database and Analysis Platform Database. Differentially expressed genes in PD were obtained from the Therapeutic Target Database, Online Mendelian Inheritance in Man, GeneCards, and DrugBank databases. The protein-protein interaction (PPI) networks of intersected targets were constructed using the STRING database and visualized using Cytoscape. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed, and the pathways directly related to the pathogenesis of PD were integrated manually. Furthermore, in vivo studies were carried out based on network pharmacology. The gut microbiota, peripheral inflammatory cytokines, and glia-mediated neuroinflammation in substantia nigra were evaluated. A total of 99 target genes were intersected between targets of TPG and deferentially expressed genes in PD. The PPI network analysis indicated the proinflammatory cytokine as essential targets. GO and KEGG analyses indicated that inflammatory response and its related signaling pathways were closely associated with TPG-mediated PD treatment. In vivo studies revealed that class Negativicutes and order Selenomonadales decreased, whereas class Mollicutes, order Enterobacteriales, and Mycoplasmatales increased in fecal samples of PD rats via 16S rRNA sequence analysis. Furthermore, the function prediction methods purposely revealed that TPG therapy may be involved in flavonoid biosynthesis, which have anti-inflammatory properties. In addition, in vivo studies revealed that TPG exposure was found to not only attenuate the production of peripheral inflammatory cytokines but also inhibit the activation of microglia and astrocytes in substantia nigra of PD rats. Through network pharmacology and in vivo experiment-combined approach, the mechanisms of TPG in the treatment of PD were revealed, and the role of TPG in the regulation of gut microbiota and inflammatory response was confirmed.