Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion

Cao, Jie; Yao, Di; Li, Rong; Guo, Xuequn; Hao, Jiahuan; Xie, Mingxing; Li, Jia; Pan, Dengji; Luo, Xiang; Yu, Zhiyuan; Wang, Minghuan; Wang, Wei

doi:10.1007/s12264-021-00772-y

Cited by 29 publications

(24 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Experimental data also suggested hypoperfusion-induced white matter injury [ 74 , 91 ]. Using a model of chronic cerebral hypoperfusion, impaired glymphatic transport was associated with decreased cerebral perfusion, and treatment of digoxin-rescued cerebral perfusion and glymphatic transport [ 92 ]. It suggested that glymphatic dysfunction played a vital role in linking hypoperfusion, CSVD, and cognitive impairment.…”

Section: The Underlying Role Of the Glymphatic And Meningeal Lymphati...mentioning

confidence: 99%

The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease

et al. 2022

View full text Add to dashboard Cite

There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main contributor to VCI. Several potential physiopathologic mechanisms have been proven to be involved in the process of CSVD, such as blood-brain barrier damage, small vessels stiffening, venous collagenosis, cerebral blood flow reduction, white matter rarefaction, chronic ischaemia, neuroinflammation, myelin damage, and subsequent neurodegeneration. However, there still is a limited overall understanding of the sequence and the relative importance of these mechanisms. The glymphatic system (GS) and meningeal lymphatic vessels (mLVs) are the analogs of the lymphatic system in the central nervous system (CNS). As such, these systems play critical roles in regulating cerebrospinal fluid (CSF) and interstitial fluid (ISF) transport, waste clearance, and, potentially, neuroinflammation. Accumulating evidence has suggested that the glymphatic and meningeal lymphatic vessels played vital roles in animal models of CSVD and patients with CSVD. Given the complexity of CSVD, it was significant to understand the underlying interaction between glymphatic and meningeal lymphatic transport with CSVD. Here, we provide a novel framework based on new advances in main four aspects, including vascular risk factors, potential mechanisms, clinical subtypes, and cognition, which aims to explain how the glymphatic system and meningeal lymphatic vessels contribute to the progression of CSVD and proposes a comprehensive insight into the novel therapeutic strategy of CSVD.

show abstract

Section: The Underlying Role Of the Glymphatic And Meningeal Lymphati...mentioning

confidence: 99%

The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The red channel was GFAP, the green channel was AQP4, and the blue channel was DAPI. Based on previous studies (Zeppenfeld et al, 2017;Cao et al, 2022), DAPI and GFAP immunostaining surrounded the voids as capillaries. Then, we drew a region of interest (ROI) within 3 µm from the capillary; the green fluorescence in this area represented the fluorescence intensity of AQP4 in the perivascular space.…”

Section: Aquaporin-4 Polarization Analysismentioning

confidence: 76%

The mechanisms underlying the actions of Xuefu Zhuyu decoction pretreatment against neurological deficits after ischemic stroke in mice: The mediation of glymphatic function by aquaporin-4 and its anchoring proteins

Gao²,

Lv³

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

Ischemic stroke (IS) has been associated with an impairment in glymphatic function. Xuefu Zhuyu Decoction (XFZYD) is widely used in the prevention and treatment of ischemic stroke. We hypothesized that Xuefu Zhuyu decoction pretreatment could attenuate early neurological deficits after ischemic stroke by enhancing the function of the glymphatic system. To prove our hypothesis, we carried out temporary middle cerebral artery occlusion and reperfusion surgery on C57BL/6 mice and then measured neurological score, infarct size and performed hematoxylin-eosin staining to assess stroke outcomes after 24 h of reperfusion. Subsequently, we injected fluorescent tracers in to the cisterna magna and evaluated tracer distribution in coronal brain sections. The polarization of aquaporin-4 (AQP4), colocalization of aquaporin-4, α-dystroglycan, β-dystroglycan and agrin were determined by immunofluorescence. Our research showed that pretreatment with Xuefu Zhuyu decoction significantly alleviated neurological scores, neurological deficits and pathological abnormalities in a mouse model of ischemic stroke. Importantly, Xuefu Zhuyu decoction pretreatment enhanced cerebrospinal fluid influx, protected aquaporin-4 depolarization and promoted the colocalization of aquaporin-4 with its anchoring proteins in the brain. Our findings highlight novel mechanisms underlying the neuroprotective effect of Xuefu Zhuyu decoction pretreatment on ischemic stroke-induced brain damage through the glymphatic system. Xuefu Zhuyu decoction pretreatment may offer a promising approach to slow the onset and progression of ischemic stroke.

show abstract

“…In a rat MMI model mimicking the VCI state by multiple microinfarcts, multiple microinfarcts (MMIs) lead to delayed infiltration of CSF into the brain parenchyma through perivascular pathways and delay in waste clearance, resulting in glymphatic system dysfunction, which may play an important role in MMI-induced axonal damage and cognitive deficits (Venkat et al, 2017 ). In addition, chronic cerebral hypoperfusion is also associated with significant white matter damage, cognitive impairment, and impaired glymphatic function (Cao et al, 2022 ). Furthermore, we found in our study that in the context of prior ischemic stroke, patients with cognitive deficits had significant differences in glymphatic function compared with those with normal cognition; this suggests an essential role of glymphatic function in the occurrence of PSCI.…”

Section: Discussionmentioning

confidence: 99%

Structural network efficiency mediates the association between glymphatic function and cognition in mild VCI: a DTI-ALPS study

Song

Ruan

Gao

et al. 2022

Front. Aging Neurosci.

View full text Add to dashboard Cite

Background and objective: Vascular cognitive impairment (VCI) can be caused by multiple types of cerebrovascular pathology and is considered a network disconnection disorder. The heterogeneity hinders research progress in VCI. Glymphatic failure has been considered as a key common pathway to dementia recently. The emergence of a new method, Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS), makes it possible to investigate the changes of the glymphatic function in humans non-invasively. We aimed to investigate alterations of glymphatic function in VCI and its potential impact on network connectivity.Methods: We recruited 79 patients with mild VCI, including 40 with cerebral small vessel disease cognitive impairment (SVCI) and 39 with post-stroke cognitive impairment (PSCI); and, 77 normal cognitive (NC) subjects were recruited. All subjects received neuropsychological assessments and multimodal magnetic resonance imaging scans. ALPS-index was calculated and structural networks were constructed by deterministic tractography, and then, the topological metrics of these structural connectivity were evaluated.Results: The ALPS-index of VCI patients was significantly lower than that of NC subjects (P < 0.001). Multiple linear regression analysis showed that ALPS-index affects cognitive function independently (β = 0.411, P < 0.001). The results of correlation analysis showed that the ALPS-index was correlated with overall vascular risk factor burden (r = −0.263, P = 0.001) and multiple cerebrovascular pathologies (P < 0.05). In addition, global efficiency (Eg) of network was correlated with ALPS-index in both SVCI (r = 0.348, P = 0.028) and PSCI (r = 0.732, P < 0.001) patients. Finally, the results of mediation analysis showed that Eg partially mediated in the impact of glymphatic dysfunction on cognitive impairment (indirect effect = 7.46, 95% CI 4.08–11.48).Conclusion: In both major subtypes of VCI, the ALPS-index was decreased, indicating impaired glymphatic function in VCI. Glymphatic dysfunction may affect cognitive function in VCI by disrupting network connectivity, and, may be a potential common pathological mechanism of VCI. ALPS-index is expected to become an emerging imaging marker for VCI.

show abstract

Digoxin Ameliorates Glymphatic Transport and Cognitive Impairment in a Mouse Model of Chronic Cerebral Hypoperfusion

Cited by 29 publications

References 63 publications

The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease

The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease

The mechanisms underlying the actions of Xuefu Zhuyu decoction pretreatment against neurological deficits after ischemic stroke in mice: The mediation of glymphatic function by aquaporin-4 and its anchoring proteins

Structural network efficiency mediates the association between glymphatic function and cognition in mild VCI: a DTI-ALPS study

Contact Info

Product

Resources

About