TCM plays an essential role in medical diagnosis and treatments. Based on the TCM theory. Chinese formulas contain a mixture of herbs, which combined the following compatibility principle "monarch, minister, assistant, and guide," meaning herbs play a primary, secondary, auxiliary, or harmonic roles, respectively [18]. The primary herbs are substances that provide the main therapeutic thrust. The second primary herbs enhance or assist the therapeutic actions of the first. The rest serve one of the following functions: treat accompanying symptoms, moderate the harshness or toxicity of the primary ones, guide the medicine to the proper organs, or exert a harmonizing effect [19]. In HLJDD, CR acts as the monarch role. SR plays the minister role. PCC and GF were the assistant and guide role. However, this compatibility is not suitable for treating BPSD. Our research studied drugs from the molecular perspective, which provides a novel method for the compatibility of formulas. Our results showed that SR and PCC are the principal herbs, CR and GF are the assistant herbs.
BPSD is a critical neuropsychiatric feature in Alzheimer’s disease [4]. In Alzheimer’s disease, abnormal accumulation of amyloid-β released from amyloid precursor protein and neuroinflammation are the partially pathologic hallmarks. Accumulation of amyloid-β also causes indirect injury to neurons by inducing neuroinflammation [20]. Microglia, the resident innate immune cells in the brain, is pivotal for the immune response observed in AD, acting as sentinel and protective cells, but may become inappropriately reactive in AD to drive neuropathology [21]. Lipopolysaccharide (LPS) is a gram-negative bacterial endotoxin released from the cell wall component that contributes to inflammation in the body. LPS is involved in the regulation of the expression of potent inflammatory factors [22]. Studies showed that with age, microglia exhibit enhanced sensitivity to inflammatory stimuli, similar to that observed in brains with ongoing neurodegeneration [23]. An increasing number of data has linked schizophrenia with neuroinflammatory conditions and microglia, which have been related to the pathogenesis of schizophrenia. Evidence suggests that neuroinflammatory changes observed in schizophrenia involve abnormal astrocyte functions [24]. In our research, Scutellaria baicalensis has anti-inflammatory roles in the biological process of treating BPSD, including regulating neuroinflammatory response, mediating lipopolysaccharide-mediated signaling pathway, cellular response to interleukin-6, and regulation of interferon - α production. GF can regulate amyloid-beta formation in treating BPSD.
Smooth muscle cell proliferation, especially vascular smooth muscle cells, is essential during cell growth or injury [25]. Blood vessels composed of vascular smooth muscle cells play a crucial role in normal brain function for its integrity structure and function and supplying adequate blood. Cerebral blood flow shortfalls and blood-brain barrier dysfunction are early findings in neurodegenerative disorders. Cerebral blood flow reductions, impaired cerebrovascular reactivity, and impaired hemodynamic responses are increasingly recognized in AD's early stages [26]. Platelet, a critical factor for blood flow, is an anucleate cell in blood, whose principal function is to stop bleeding by forming aggregates for hemostatic reactions. Platelet aggregates are also involved in pathological thrombosis and play an essential role in inflammation [27]. Nitric oxide (NO) is a small free radical molecule with an endothelium-derived relaxing factor. Its adequate production levels in the vascular endothelium are critical for regulating blood flow and vasodilation. Besides, NO plays a vital neuronal signaling role [28]. Cadmium, a metal that resembles zinc and calcium, is also crucial for neuronal signaling. Cadmium exposure is linked to neurodegenerative diseases like Alzheimer's disease. It can alter neurotransmitters' release, cause oxidative stress, damage mitochondrion, and induce apoptosis [29]. In our study, SR can positively regulate smooth muscle cell proliferation, positively regulate the endothelial cell proliferation, and positively regulate the blood vessel endothelial cell migration. CR can mediate cellular response to cadmium ion. PCC can regulate platelet activation. GF can regulate the nitric oxide biosynthetic process.
Macroautophagy is an evolutionarily conserved dynamic pathway that functions primarily in a degradative manner. A wide range of diseases is associated with dysregulation of macroautophagy. Macroautophagy has a critical role in cellular homeostasis. Either insufficient or excessive macroautophagy can seriously compromise cell physiology, and thus, it needs to be regulated appropriately [30]. CR can negatively regulate macroautophagy. PCC can regulate the glial cell apoptotic process.
Research showed that Nicotine might be involved in the pathophysiology of psychosis. Smoking has a relationship with depression. In animal models, Nicotine shows anxiolytic properties. Depression people are more likely to smoke and more likely to develop severe depressive episodes upon smoking cessation. Nicotine has also been observed to produce similar cognitive improvements in AD patients [31]. However, the relationship between smoking and AD is still debatable [32]. In our herbs, CR, PCC has the function to respond to Nicotine.
It has been demonstrated that serotoninergic, dopaminergic, and cholinergic systems are mainly involved in the pathogenesis of BPSD, and the role of HTR2A and DRD2 as therapeutic targets appear to be evident [16]. Our research utilized molecular docking to find potential active ingredients with good binding activities to DRD2 and HTR2A. The best-docked compound was beta-sitosterol. The free binding energy of beta-sitosterol with DRD2 and HTR2A was − 9.58 kcal/mol, -8.2 kcal/mol, respectively. Stigmasterol, chelerythrine, and campesterol also have good binding activities. Beta-sitosterol, Stigmasterol, chelerythrine, and campesterol are the active ingredients of PCC. It is the only herb containing these five ingredients.
The TCM theory verifies our results. Triple energizers mean upper, middle, and lower energizer in TCM theory. They are the birth and channel to run for Qi, blood, thin, thick fluids, and essence. Moreover, they also contact five Zang-organs and six Fu-organs. SR affects the upper energizer, which is the brain and heart. PCC works on the lower energizer that is the kidney and liver. CR influences the middle energizer that consists of the spleen and stomach. Kidney essence deficiency is a primary syndrome differentiation of AD in TCM theory. "Liver fire" is the largest contributor to BPSD due to the imbalance between yin and yang of liver function [33, 34]. PCC acts on the lower energizer can purge the liver fire. "Su Wen" puts forward that "the mind is the monarch's official, and the gods come out of it." In the compendium of Materia Medica, Shizhen Li of the Ming Dynasty proposed that "the brain is the house of primordial God." SR works on the heart and brain, belongs to the upper energizer, is beneficial for the heart and brain. In conclusion, SR and PCC are HLJDD's primary herbs based on the TCM theory.