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

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Summary

Introduction

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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Conclusion

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