Vascular dementia (VD) is construed as a progressive disorder resulting from reduced cerebral blood flow and it severely impacts cognitive abilities, especially executive functions, which accounts for approximately 17–20% of dementia cases, making it the 2nd prevalent form of dementia (Venkat et al., 2015). Patients with VD typically present symptoms of memory loss, attention deficits, and dysfunction of task execution, such as disorientation, slowed thinking, diminished abilities to plan, reason, and judge, and reduced capacities of solving problems (Sun, 2018). However, the improvement in VD treatment remains slow due to the uncertainty in disease classification and diagnostic criteria, controversy in terms of the exact relation between cerebrovascular pathologies and cognitive insults, and a paucity of identifiable therapy targets, and therefore the mortality rate due to cerebrovascular and cardiovascular causes remains considerably high in VD, with an average survival of only 3–5 years (O'Brien and Thomas, 2015). Even worse, the upsurge in the prevalence of cardio-metabolic risk factors and the increase in aging population have greatly increased the risk of VD (Romay et al., 2019). The harsh reality places an urgent demand on researchers to comprehend the complicated pathogenesis, find potent and tractable targets, and develop appropriate treatment modalities for VD management.

With the extensive introduction of traditional Chinese medicine (TCM) in treating various disorders, herbal therapy is increasingly becoming a promising approach for VD management (Ghorani-Azam et al., 2018). In the context of TCM, nourishing the kidney and filling the essence, activating blood circulation and removing stasis, calming and nourishing the mind, as well as strengthening the spleen and replenishing Qi are regarded as vital models of treating VD (Bai and Zhang, 2021). In particular, Zishen Huoxue (nourishing the kidney and activating blood circulation) Decoction can efficiently ameliorate cognitive decline in rats manifesting cerebral hypoperfusion, showing therapeutic potential for VD treatment (Ye et al., 2014). The decoction also has vital abilities to stabilize plaque, regulate lipid metabolism, protect vascular endothelial function, and impede inflammation and thrombosis, thus mitigating myocardial ischemia (Liu et al., 2020). Yi-Qi-Huo-Xue exerts an imperative role in the treatment of cerebral hemorrhage by promoting hematoma absorption, reducing neuroinflammation, and alleviating neurological deficits in rats (Li et al., 2020). Nonetheless, the exact therapeutic mechanism of Zishen Huoxue Recipe in VD remains largely unknown.

The neurovascular unit (NVU) is primarily composed of neurons, glial cells, and microvessels that confer an integrated role in maintaining brain homeostasis and function by modifying blood flow to support the energy demand of neural activity as well as sustaining the integrity of blood-brain barrier (BBB) (Bernier et al., 2021). The injury in NVU is identified as a root cause of VD and the altered integrity of NVU in the context of vascular stenosis or occlusion can result in cognitive impairment, self-care inability, and even death (Li et al., 2021). Indeed, aberrant neuronal cell death, especially pyroptosis, is tightly associated with diverse neurological diseases (Moujalled et al., 2021). Pyroptosis is a type of inflammatory-programmed cell death mediated by caspase activation and inflammasomes, particularly the activation of caspase-1 and gasdermin-D (GSDMD), which occurs mainly downstream of the nucleotide oligomerization domain-like receptor protein (NLRP) inflammasome activation (Fricker et al., 2018; Li et al., 2022). The aforementioned evidence implies that attenuating NVU injury, especially pyroptosis, may offer a preferred target for therapeutic strategies in VD.

Additionally, microRNAs (miRNAs) have been well-documented as potential novel biomarkers and therapeutic targets in dementia (Viegas et al., 2017). Meanwhile, miRNAs play roles in regulatory activities taking place in cells, and exert effects on various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (Bisht et al., 2020). Specifically, miR-124-3p is highly expressed in neuron-derived exosomes as well as immune cells and organs and is a key modulator to immunity and inflammation (Jiang et al., 2020; Men et al., 2019; Qin et al., 2016). An existing study reveals that miR-124-3p suppresses neuronal inflammation caused by scratch injury by suppressing the mTOR signaling (Huang et al., 2018). However, the precise role of miR-124-3p in VD has not been elucidated yet. Therefore, combined with the involvement of miR-124-3p, the study investigated the protective role of Zishen Huoxue Recipe against neuronal injury in the NVU of VD rats by interfering with the inflammatory cascade-induced pyroptosis.