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Yi-Zhi-Fang-Dai Formula Exerts Neuroprotective Effects Against Pyroptosis and Blood-Brain Barrier-Glymphatic Dysfunctions to Prevent Amyloid-Beta Acute Accumulation After Cerebral Ischemia and Reperfusion in Rats.

ABSTRACT: Background: The dysfunctional blood-brain barrier (BBB)-glymphatic system is responsible for triggering intracerebral amyloid-beta peptide (Aβ) accumulation and acts as the key link between ischemic stroke and dementia dominated by Alzheimer's disease (AD). Recently, pyroptosis in cerebral ischemia and reperfusion (I/R) injury is demonstrated as a considerable mechanism causing BBB-glymphatic dysfunctions and Aβ acute accumulation in the brain. Targeting glial pyroptosis to protect BBB-glymphatic functions after cerebral I/R could offer a new viewpoint to prevent Aβ accumulation and poststroke dementia. Yi-Zhi-Fang-Dai formula (YZFDF) is an herbal prescription used to cure dementia with multiple effects of regulating inflammatory responses and protecting the BBB against toxic Aβ-induced damage. Hence, YZFDF potentially possesses neuroprotective effects against cerebral I/R injury and the early pathology of poststroke dementia, which evokes our current study. Objectives: The present study was designed to confirm the potential efficacy of YZFDF against cerebral I/R injury and explore the possible mechanism associated with alleviating Aβ acute accumulation. Methods: The models of cerebral I/R injury in rats were built by the method of middle cerebral artery occlusion/reperfusion (MCAO/R). First, neurological function assessment and cerebral infarct measurement were used for confirming the efficacy of YZFDF on cerebral I/R injury, and the optimal dosage (YZFDF-H) was selected to conduct the experiments, which included Western blotting detections of pyroptosis, Aβ_1-42 oligomers, and NeuN, immunofluorescence observations of glial pyroptosis, aquaporin-4 (AQP-4), and Aβ locations, brain water content measurement, SMI 71 (a specific marker for BBB)/AQP-4 immunohistochemistry, and Nissl staining to further evaluate BBB-glymphatic functions and neuronal damage. Results: YZFDF obviously alleviated neurological deficits and cerebral infarct after cerebral I/R in rats. Furthermore, YZFDF could inactivate pyroptosis signaling via inhibiting caspase-1/11 activation and gasdermin D cleavage, ameliorate glial pyroptosis and neuroinflammation, protect against BBB collapse and AQP-4 depolarization, prevent Aβ acute accumulation and Aβ_1-42 oligomers formation, and reduce neuronal damage and increase neurons survival after reperfusion. Conclusion: Our study indicated that YZFDF could exert neuroprotective effects on cerebral I/R injury and prevent Aβ acute accumulation in the brain after cerebral I/R associated with inhibiting neuroinflammation-related pyroptosis and BBB-glymphatic dysfunctions.

SUBMITTER: Lyu Z

PROVIDER: S-EPMC8714930 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:There is yet no effective drug for Alzheimer's disease (AD) which is one of the world's most common neurodegenerative diseases. The Qin-Zhi-Zhu-Dan Formula (QZZD) is derived from a widely used Chinese patent drug-Qing-Kai-Ling Injection. It consists of Radix Scutellariae, Fructus Gardeniae, and Pulvis Fellis Suis. Recent study showed that QZZD and its effective components played important roles in anti-inflammation, antioxidative stress and preventing brain injury. It was noted that QZZD had protective effects on the brain, but the mechanism remained unclear. This study aims to investigate the mechanism of QZZD in the treatment of AD combining network pharmacology approach with experimental validation. In the network pharmacology analysis, a total of 15 active compounds of QZZD and 135 putative targets against AD were first obtained. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were then applied to clarify the biological mechanism. The anti-inflammatory mechanism of QZZD was proved, and a synthetic pathway-TNFR1-ERK1/2-NF-κBp65 signaling pathway was obtained. On the basis of the above discoveries, we further validated the protective effects QZZD on neurons with an APP/PS1 double transgenic mouse model. Weight change of the mice was monitored to assess QZZD's influence on the digestive system; water maze experiment was used for evaluating the effects on spatial learning and memory; Western blotting and immunohistochemistry analysis were used to detect the predicted key proteins in network pharmacology analysis, including Aβ, IL-6, NF-κBp65, TNFR1, p-ERK1/2, and ERK1/2. We proved that QZZD could improve neuroinflammation and attenuate neuronal death without influencing the digestive system in APP/PS1 double transgenic mice with dementia. Combining animal pharmacodynamic experiments with network pharmacology analysis, we confirmed the importance of inflammation in pathogenesis of AD, clarified the pharmacodynamic characteristics of QZZD in treating AD, and proved its neuroprotective effects through the regulation of TNFR1-ERK1/2-NF-κBp65 signaling pathway, which might provide reference for studies on treatment of AD in the future.

Project description:BackgroundJian-Pi-Yi-Qi-Fang (JPYQF) is a traditional Chinese medicine (TCM) herbal formula for treating chronic atrophic gastritis (CAG) in the clinic; however, its related mechanism remains unclear. The purpose of this study was to explore the potential mechanisms of JPYQF in treating CAG by examining proteins and genes related to the proliferation and differentiation of gastric stem cells and Wnt signaling.MethodsA CAG model was established in Sprague-Dawley (SD) rats which were induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and ranitidine. We randomly divided 25 CAG rats into 5 groups: the model group, positive drug group, low-dose group of JPYQF (JPYQF-L), middle-dose group of JPYQF (JPYQF-M), and high-dose group of JPYQF (JPYQF-H), with 5 rats of the same age classified into the control group. The body weight of rats was measured and their gastric morphology was visually assessed. Furthermore, pathological analysis of rat gastric tissue was performed. The expression levels of proteins and genes associated with the proliferation and differentiation of gastric stem cells and Wnt signaling were measured via immunohistochemistry and reverse transcription quantitative polymerase chain reaction (RT-qPCR).ResultsCompared with the model group, treatment with JPYQF increased the body weight of the rats, and relieved the gastric atrophy and inflammation. Compared with the control group, the protein and messenger RNA (mRNA) expression levels of gastric stem cell proliferation and differentiation markers Lgr5, Sox2, Ki67, PCNA, Muc5AC, and Wnt signaling initiator Wnt3A and enhancer R-spondin-1 (Rspo1) were decreased in the model group. Treatment with JPYQF increased the protein and mRNA expression levels of these markers.ConclusionsThe Wnt signaling of CAG rats may be in a low activation state, which inhibits the proliferation and differentiation of gastric stem cells, so that gland cells cannot be replenished in time to repair the damaged gastric mucosa. The TCM formula JPYQF could enhance Wnt signaling to promote the restricted proliferation and normal differentiation of gastric stem cells, thereby improving gastric mucosal atrophy in CAG rats, which provides a novel and robust theoretical basis for CAG treatment.

Project description:Background: Qinzhi Zhudan Formula (QZZD), optimized from Angong Niuhuang Wan, consists of Radix Scutellariae, Fructus Gardeniae and Pulvis Fellis Suis. We had investigated the neuroprotective effects of QZZD and its active components, and demonstrated that it could treat cerebral ischemia and dementia through multiple pathways and mechanisms. Nevertheless, toxicological data on this formula still remains limited. In the study, we sought to examine the toxicological effects of QZZD during the treatment and recovery periods. Methods: We investigated potential toxicities of QZZD in Sprague-Dawley (SD) rats via 28-day gavage administration. SD rats were randomly divided into control group and treatment groups of A (0.5 g/kg/d QZZD), B (1.5 g/kg/d QZZD), and C (5.0 g/kg/d QZZD). The 56-day course includes treatment period (administration with water or QZZD once a day for 28 consecutive days) and recovery period (28 days). The rats received daily monitoring of general signs of toxicity and mortality, as well as weekly determination of body weight and food consumption. Moreover, the complete blood cell count, biochemistry, coagulation, and urine indicators, organ weights, and histopathological report were analyzed respectively at the end of the treatment and recovery periods. Results: There was no death related to the active pharmaceutical ingredients of QZZD during the treatment period. The maximum no observed adverse effect level (NOAEL) was 0.5 g/kg/d, which is approximately 16.7 times of the equivalent dose of clinical dose in rats. In group TB (1.5 g/kg/d QZZD) and TC (5.0 g/kg/d QZZD), there were adverse effects of blue coloring of tail skin, weight loss, a significant increase of total bilirubin (TBIL), blackening of liver and kidney in gross examination, hyperplasia of bile duct and karyomegaly of hepatocytes in histopathological examination. Besides, in females rats, the food consumption was reduced, while in male rats, there was decrease in triglycerides (TG) and slight increase in white blood cell (WBC) count and neutrophils. In group TC (5.0 g/kg/d QZZD), the indicators of red blood cell (RBC) count, hemoglobin (HGB) and hematocrit (HCT) were decreased slightly, while the platelet count (PLT) was increased. However, these changes were not considered to be toxicologically significant because they resolved during the recovery period. Conclusion: Overall, QZZD exhibited a good safety profile. The maximum no observed adverse effect level was 0.5 g/kg/d, and no target organs toxicity were identified. The present findings might confirm the safety of QZZD in clinical practices.

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Yi-Zhi-Fang-Dai Formula Exerts Neuroprotective Effects Against Pyroptosis and Blood-Brain Barrier-Glymphatic Dysfunctions to Prevent Amyloid-Beta Acute Accumulation After Cerebral Ischemia and Reperfusion in Rats.

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