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, Aβ1-42 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 Aβ1-42 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.
Highlights
Alzheimer’s disease (AD), a common neurodegenerative disease, comprises the major type of dementia and is causing a high socioeconomic impact with the advancement of world population aging (Alzheimer’s Association, 2021)
Endfeet of astrocytes are the main components of both the blood–brain barrier (BBB) and glymphatic system which contribute to maintain the homeostasis of brain microenvironments, and aquaporin-4 (AQP-4) on astrocytic endfeet is a water channel protein with high polarization and essential for neurovascular coupling and glymphatic flow to facilitate the clearance of metabolites such as Aβ (Nakada et al, 2017)
The result in the present study showed that Yi-Zhi-Fang-Dai formula (YZFDF) treatment could reduce the raised immunofluorescent co-staining of gasdermin D (GSDMD) and ionized calcium-binding adapter molecule-1 (Iba-1) in ischemic cortex and hippocampus-CA1 areas (Figures 5A,B) and downregulate the expression levels of Iba-1, IL-6, and cleaved IL-1β after reperfusion (Figures 5C,D), indicating that YZFDF could exert inhibitory effects on inflammatory responses during cerebral ischemia and reperfusion (I/R) by regulating microglial overactivation and pyroptosis
Summary
Alzheimer’s disease (AD), a common neurodegenerative disease, comprises the major type of dementia and is causing a high socioeconomic impact with the advancement of world population aging (Alzheimer’s Association, 2021). Maintaining the clearance of Aβ after cerebral I/R could offer a new therapeutic approach to prevent poststroke cognitive impairment and development into dementia (Goulay et al, 2020). In cerebral I/R injury, the loss of AQP-4 polarization on astrocytic endfeet is considered as an important factor of BBB–glymphatic dysfunctions that are the vital pathological change causing the onset and development of dementia (Verheggen et al, 2018; Goulay et al, 2020). 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). 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. YZFDF potentially possesses neuroprotective effects against cerebral I/R injury and the early pathology of poststroke dementia, which evokes our current study
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