Limb Remote Ischemic Conditioning Ameliorates Cognitive Impairment in Rats with Chronic Cerebral Hypoperfusion by Regulating Glucose Transport

Ren, Chang­hong; Liu, Yuanyuan; Stone, Christopher; Li, Ning; Li, Sijie; Li, Haiyan; Cheng, Zichao; Hu, Jiangnan; Li, Weiguang; Jin, Kunlin; Ji, Xunming; Ding, Yuchuan

doi:10.14336/ad.2020.1125

Cited by 12 publications

(9 citation statements)

References 47 publications

(57 reference statements)

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“…Although a certain proportion of patients with carotid stenosis display no symptoms, they are at higher risks of mobility and cognitive dysfunction compared with those without stenosis, and this may often be attributed to CCH [ 15 , 16 ]. Progressive brain injuries induced by CCH include metabolic disturbance [ 17 ], white matter injury, neuronal apoptosis and pyroptosis [ 18 ], synaptic plasticity impairment [ 19 ], activated neuroinflammation [ 20 ], and neuroendocrine perturbation [ 21 ]. Despite recent developments in experimental and clinical neuroscience, few options could be adopted to impede CCH-induced brain injury.…”

Section: Introductionmentioning

confidence: 99%

The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids

Xiao

Gao

et al. 2022

Microbiome

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Background Chronic cerebral hypoperfusion (CCH) underlies secondary brain injury following certain metabolic disorders and central nervous system (CNS) diseases. Dysregulation of the microbiota-gut-brain axis can exacerbate various CNS disorders through aberrantly expressed metabolites such as short-chain fatty acids (SCFAs). Yet, its relationship with CCH remains to be demonstrated. And if so, it is of interest to explore whether restoring gut microbiota to maintain SCFA metabolism could protect against CCH. Results Rats subjected to bilateral common carotid artery occlusion (BCCAO) as a model of CCH exhibited cognitive impairment, depressive-like behaviors, decreased gut motility, and compromised gut barrier functions. The 16S ribosomal RNA gene sequencing revealed an abnormal gut microbiota profile and decreased relative abundance of some representative SCFA producers, with the decreased hippocampal SCFAs as the further evidence. Using fecal microbiota transplantation (FMT), rats recolonized with a balanced gut microbiome acquired a higher level of hippocampal SCFAs, as well as decreased neuroinflammation when exposed to lipopolysaccharide. Healthy FMT promoted gut motility and gut barrier functions, and improved cognitive decline and depressive-like behaviors by inhibiting hippocampal neuronal apoptosis in BCCAO rats. Long-term SCFA supplementation further confirmed its neuroprotective effect in terms of relieving inflammatory response and hippocampal neuronal apoptosis following BCCAO. Conclusion Our results demonstrate that modulating the gut microbiome via FMT can ameliorate BCCAO-induced gut dysbiosis, cognitive decline, and depressive-like behaviors, possibly by enhancing the relative abundance of SCFA-producing floras and subsequently increasing SCFA levels.

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Section: Introductionmentioning

confidence: 99%

The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids

Xiao

Gao

et al. 2022

Microbiome

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“…For mice: we performed LRIC as previously described [ 13 ]. Anesthesia was administered intraperitoneally with sodium pentobarbital (30 mg/kg).…”

Section: Methodsmentioning

confidence: 99%

“…In recent years, accumulating evidence has focused on non-drug neuroprotection and recovery of neurological function in stroke therapy [ 11 , 12 ]. The concept of ischemic conditioning refers to the initiation of endogenous protective mechanisms against ischemic injury of multiple organs [ 13 ]. Zhao et al proposed the concept of limb remote ischemic conditioning (LRIC) to protect the brain from ischemic injury.…”

Section: Introductionmentioning

confidence: 99%

Limb Remote Ischemic Conditioning Promotes Neurogenesis after Cerebral Ischemia by Modulating miR-449b/Notch1 Pathway in Mice

Yang

et al. 2022

Biomolecules

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Neurogenesis plays an important role in the prognosis of stroke patients and is known to be promoted by the activation of the Notch1 signaling pathway. Studies on the airway epithelium have shown that miR-449b represses the Notch pathway. The study aimed to investigate whether limb remote ischemic conditioning (LRIC) was able to promote neurogenesis in cerebral ischemic mice, and to investigate the role of the miR-449b/Notch1 pathway in LRIC-induced neuroprotection. Male C57BL/6 mice (22–25 g) were subjected to transient middle cerebral artery occlusion (MCAO), and LRIC was performed in the bilateral lower limbs immediately after MCA occlusion. Immunofluorescence staining was performed to assess neurogenesis. The cell line NE-4C was used to elucidate the proliferation of neuronal stem cells in 8% O2. After LRIC treatment on day 28, mice recovered neurological function. Neuronal precursor proliferation was enhanced in the SVZ, and neuronal precursor migration was enhanced in the basal ganglia on day 7. LRIC promoted the improvement of neurological function in mice on day 28, promoted neuronal precursor proliferation in the SVZ, and enhanced neuronal precursor migration in the basal ganglia on day 7. The neurological function score was negatively correlated with the number of BrdU-positive/DCX-positive cells in the SVZ and striatum. LRIC promoted activated Notch1 protein expression in the SVZ and substantially downregulated miR-449b levels in the SVZ and plasma. In vitro, miR-449b was found to target Notch1. Lentivirus-mediated miR-449b knockdown increased Notch1 levels in NE-4C cells and increased proliferation in the cells. The effects of miR-449b inhibition on neurogenesis were ablated by the application of Notch1 shRNA. Our study showed that LRIC promoted the proliferation and migration of neural stem cells after MCAO, and these effects were modulated by the miR-449b/Notch1 pathway.

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“…The membrane was probed with primary antibody: anti-p-ERK1/2 antibody (Cell Signaling; 1 : 1000 dilution), anti-p-AKT antibody (Cell Signaling; 1 : 1000 dilution), and anti-p-SRC antibody (Cell Signaling; 1 : 1000 dilution). The specific reaction was visualized through the use of a chemiluminescent substrate (GE Healthcare, UK) [ 29 ]. β -Actin was used to verify equal loading.…”

Section: Methodsmentioning

confidence: 99%

Systematic Understanding of Mechanism of Danggui Shaoyao San against Ischemic Stroke Using a Network Pharmacology Approach

Yang

Zhang

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Purpose. Danggui Shaoyao San (DSS) was developed to treat the ischemic stroke (IS) in patients and animal models. The purpose of this study was to explore its active compounds and demonstrate its mechanism against IS through network pharmacology, molecular docking, and animal experiment. Methods. All the components of DSS were retrieved from the pharmacology database of TCM system. The genes corresponding to the targets were retrieved using OMIM, CTD database, and TTD database. The herb-compound-target network was constructed by Cytoscape software. The target protein-protein interaction network was built using the STRING database. The core targets of DSS were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Then, we achieved molecular docking between the hub proteins and the key active compounds. Finally, animal experiments were performed to verify the core targets. Triphenyltetrazolium chloride (TTC) staining was used to calculate the infarct size in mice. The protein expression was determined using the Western blot. Results. Compound-target network mainly contained 51 compounds and 315 corresponding targets. Key targets contained MAPK1, SRC, PIK3R1, HRAS, AKT1, RHOA, RAC1, HSP90AA1, and RXRA FN1. There were 417 GO items in GO enrichment analysis ( p < 0.05 ) and 119 signaling pathways ( p < 0.05 ) in KEGG, mainly including negative regulation of apoptosis, steroid hormone-mediated signaling pathway, neutrophil activation, cellular response to oxidative stress, and VEGF signaling pathway. MAPK1, SRC, and PIK3R1 docked with small molecule compounds. According to the Western blot, the expression of p-MAPK 1, p-AKT, and p-SRC was regulated by DSS. Conclusions. This study showed that DSS can treat IS through multiple targets and routes and provided new insights to explore the mechanisms of DSS against IS.

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Limb Remote Ischemic Conditioning Ameliorates Cognitive Impairment in Rats with Chronic Cerebral Hypoperfusion by Regulating Glucose Transport

Cited by 12 publications

References 47 publications

The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids

The microbiota-gut-brain axis participates in chronic cerebral hypoperfusion by disrupting the metabolism of short-chain fatty acids

Limb Remote Ischemic Conditioning Promotes Neurogenesis after Cerebral Ischemia by Modulating miR-449b/Notch1 Pathway in Mice

Systematic Understanding of Mechanism of Danggui Shaoyao San against Ischemic Stroke Using a Network Pharmacology Approach

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