Dementia and other neurodegenerative diseases represent a rapidly escalating global health crisis. The number of people with dementia is projected to soar from 57 million in 2021 to 81.1 million by 2040 and ultimately to 139 million by 2050. Dementia is a leading cause of disability and death, disproportionately affecting women. As the most prevalent form of dementia, Alzheimer’s disease (AD) cases are expected to nearly double in the U.S. by 2060. This crisis carries an immense economic burden, with global costs projected to reach $2.8 trillion by 2030. Despite the scale, persistent stigma leads many to view dementia as a normal part of aging, hindering crucial early diagnosis and support [1–5].

AD is a complex brain disorder first documented in 1906. While decades of research have led to eight FDA-approved drugs, with the efficacy of recent antibody-based drugs still debated [6, 7], a cure remains elusive. Current treatments have limited efficacy, often due to the difficulty of drugs to cross the blood-brain barrier (BBB) and also due to their significant side effects [8, 9]. The disease’s pathology is multifaceted, with several leading hypotheses (Figure 1). The amyloid hypothesis suggests that plaques formed by amyloid-beta (Aβ) proteins are a hallmark cause [10, 11]. The tau hyperphosphorylation hypothesis indicates that neurofibrillary tangles (NFTs) disrupt brain cell function [12]. The cholinergic hypothesis links AD to a deficiency in acetylcholine, a neurotransmitter crucial for memory [13]. Additionally, factors like neuroinflammation [14], mitochondrial dysfunction [15], oxidative stress [16], vascular dysfunction [17], insulin signaling abnormalities [18], cholesterol [19], cell cycle deregulation [20], and gut microbiota dysbiosis [21, 22] are also being explored. Genetically, mutations in the PSEN genes are also known to cause the disease [23], which is clinically defined by a progressive decline in memory, cognitive function, emotional changes, and even psychiatric symptoms [24].

Current research seeks safe, effective therapies for AD. Oxidative stress is a key factor linking various pathogenic mechanisms and thus leading to the exploration of natural flavonoids with antioxidant properties, a focus of study. These compounds offer promising outcomes by inhibiting Aβ aggregation, tau hyperphosphorylation, and promoting mitochondrial autophagy [25]. Complementary and alternative medicine (CAM) is also gaining attention for preventing neurodegenerative diseases. However, more research, including advances in genomics and proteomics, is needed to validate their quality, safety, and efficacy, and to understand their mechanisms and potential drug interactions [26, 27].

BI (7.98%) and BE (0.1–1.5%) are flavonoids found in the roots of the Chinese herb Scutellaria baicalensis Georgi (Huangqin or Ogon), a plant grown in several European countries and native to several East Asian countries, including the Russian Federation [28–31]. These compounds are also present in other Scutellaria species, including S. lateriflora, S. galericulata, and S. rivularia Wall, Oroxylum indicum (L.), the fungus Trametes versicolor, Astragalus membranaceus, and Taxus chinensis fruit (TCF) [28, 32–42].

BI (BE-7-O-β-D-glucuronic acid) must first be hydrolyzed by gut microbiota’s β-glucuronidase enzymes to yield BE for absorption. This conversion is a crucial, rate-limiting step [43, 44]. After absorption, BE can be reconverted to BI in the liver, leading to enterohepatic circulation that prolongs its effects [45]. BE (C₁₅H₁₀O₅), the aglycone form derived from chrysin, has a unique molecular structure that gives it diverse biological activities [43] (Figure 2). While highly permeable, its poor aqueous solubility and rapid, extensive metabolism through glucuronidation limit its oral bioavailability (13–23% in monkeys). It is quickly converted to BI and other conjugated metabolites in the liver and intestines, meaning that oral BE administration results in low concentrations of the parent compound in the blood [46]. It has shown no toxic effects in human clinical trials at doses up to 2,800 mg [47]. Thus, key differences in the chemical structure of both moieties and the way they are processed by the body impart them distinct pharmacological profiles, which have significant implications for human therapy [48]. The distinct metabolic pathways of these two compounds have significant clinical implications. BI’s effectiveness depends heavily on an individual’s gut microbiome composition for its conversion to BE [49]. Conversely, BE’s poor bioavailability makes it less ideal for oral delivery, prompting research into advanced delivery systems to improve its absorption and therapeutic potential. The interplay between these two forms and their metabolism is vital to comprehend their neuroprotective and other pharmacological roles. Thus, for a detailed PK/PD overview of both moieties, a comparative table of PK/PD is provided in Table S1.

Experimental models for AD provide a comprehensive framework for drug development and are crucial for understanding its mechanisms. These are categorized into three types (Figure 3).

i.

In vitro models use cell lines like neuroblastoma (SHSY-5Y) [50–53], neuroblast (N2a), microglia (SIM-A9) [54], along with yeast cells [55, 56]. These in vitro models, such as cell lines and yeast, are cost-effective for high-throughput screening [56] and identifying therapeutic targets [50, 51]. However, they lack a full physiological context, failing to replicate the brain’s complex environment.

Since no single model can fully capture the complexity of AD, a multi-model approach is essential. Combining in vitro, in vivo, and in silico methods allows researchers to overcome individual limitations, creating a more comprehensive understanding of the disease and increasing the potential for successful treatment development.

BE and BI, prominent bioflavonoids primarily derived from Scutellaria baicalensis (commonly known as Chinese skullcap or Huang-Qin), exhibit a wide array of pharmacological properties. These compounds are promising candidates for treating and preventing various chronic ailments. Their extensively investigated properties include anti-cancer activities, liver protection (hepatoprotection), broad-spectrum antibacterial and antiviral effects, powerful antioxidant capabilities, and significant anticonvulsant and neuroprotective benefits [29, 49, 69–73]. They have been extensively utilized in traditional medicine, particularly in China and South Korea, for anti-inflammatory and cancer disorders [74, 75].

Both BE and BI exhibit similar pharmacological effects, but with differences in potency and specific mechanisms [76]. BE is often considered more potent in certain contexts, such as inhibiting inflammatory mediators like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) [77]. In terms of anticancer activity, both compounds induce apoptosis and inhibit proliferation, but their specific efficacy can vary depending on the cancer type and the signaling pathways involved. Some research suggests BE has a stronger antiproliferative effect on cancer cells [78]. These differences have significant implications for human therapy. BE’s higher potency could make it a better choice for conditions requiring a rapid, strong anti-inflammatory response, provided its low bioavailability is addressed. Conversely, the enterohepatic circulation of BI and its metabolites might be more suitable for therapeutic applications requiring sustained, long-term effects. The choice between the two, or using a combination, must be tailored to the specific disease and desired biological outcome [79].

It is interesting to note that BE and BI achieve their dual neuroprotective and anticancer effects by modulating a common set of critical signaling pathways (PI3K/AkT, NF-κB, Nrf2, MAPK) as given in Figure 4. Their distinct outcomes are determined by the cellular context; they can be anti-inflammatory and cytoprotective in normal and neuronal cells, but pro-apoptotic and antiproliferative in cancer cells. The difference in their chemical structure and metabolism also impacts their potency, with BE often showing more potent effects in direct cellular assays due to its higher bioavailability.

Our understanding of AD evolved to recognize it as a complex, multifactorial disorder, and the need for therapeutic agents that could simultaneously target multiple pathological pathways became paramount. BE and BI emerged as promising candidates in this regard, exhibiting broad neuroprotective effects against AD through a wide array of mechanisms (Figure 5). Preclinical studies consistently showed that these compounds ameliorated memory deficits, reduced amyloid plaques, and modulated tau phosphorylation in various AD models (Table 1). Both BE and BI improved mitochondrial function, synaptic plasticity, and neuronal survival, ultimately preventing cell death and enhancing cognition [103–112].

Recent research leveraging advanced modalities such as network pharmacology, bioinformatics, molecular simulations, and metabolomics further elucidated the multifaceted mechanisms through which these flavonoids exert their neuroprotective effects. The following subsections present a comprehensive detail of the various investigations that illuminated the multifaceted neuroprotective mechanisms and effects of BE and BI, incorporating the key findings from literature reports.

This review lays a foundation for future research on the bioactive flavonoids BE and BI from Scutellaria baicalensis, exploring their applications and mechanisms for neuroprotection, particularly against AD. These compounds demonstrate vital antioxidant, anti-inflammatory, and neuroprotective properties, suggesting significant preclinical promise in mitigating AD pathology.

However, despite this potential, their therapeutic utility has been significantly challenged by limitations in solubility and brain delivery. To overcome these hurdles, innovative formulation strategies are crucial. These range from TCM decoctions, which leverage synergistic herbal interactions, to modern nanocarriers like liposomes and solid lipid nanoparticles. These advanced delivery systems are essential for enhancing the bioavailability, stability, and brain targeting of BE and BI, thereby maximizing their therapeutic potential for AD.

While preclinical studies consistently show promising results and a good safety profile, the full clinical relevance, especially regarding efficacy, safety, and appropriate dosages in humans, remains to be established. The clinical application of BE and BI is currently limited by insufficient human data. Therefore, comprehensive human clinical trials are imperative to fully understand their therapeutic utility and confirm their safety profile before they can be recommended for AD treatment. This review’s insights can serve as a guide for future research to define disease markers and optimize dosing, emphasizing therapeutic drug monitoring. Furthermore, studies on their interaction with various signaling pathways, including ADME processes, are crucial. Continued interdisciplinary research in pharmaceutical science and neuroscience, incorporating modern approaches like transcriptomics, systems biology, and metabolomics, should guide the design of novel formulations, enhance bioavailability via varied routes for maximum efficacy, investigate drug interactions, and establish long-term toxicity, pharmacokinetic, and pharmacodynamic profiles of these phytocompounds, both alone and in combination with other drugs.