Effect And Mechanism Of Verbascoside in Treatment Neurodegenerative Diseases

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Abstract: Verbascoside is the active ingredient of Chinese herbs such as Rehmannia glutinosa, Cistanche deserticola, and Forsythia. Studies have shown that verbascoside can antagonize neurotoxicity mediated by amyloid, glutamate, and peroxynitrite ions through Nrf2, ERK, and PI3K/Akt signal transduction, and inhibit mitochondrial pathway apoptosis; through NF-κB And TAK-1/JNK/AP-1 signal transduction regulates immune function, inhibits inflammation; also regulates autophagy. Verbasin has shown therapeutic promise in Alzheimer's disease and Parkinson's disease.

Keywords: Verbasin; Alzheimer's disease; Parkinson's disease

Verbascoside (Verbascoside/Acteoside), alias ergosteroside, Verbasin, belongs to phenylpropanoid glycosides. Studies have shown that five species of Rehmannia glutinosa, Rehmannia glutinosa leaf, Lithoptera lima leaf, Cistanche deserticola, Forsythia suspense, and Sycamore flower contain different amounts of verbascoside, among which Rehmannia glutinosa leaf has the highest content. From a medicinal point of view, Rehmannia glutinosa and Cistanche deserticola are the most commonly used Chinese medicines containing verbasin and are widely used in clinical practice. Verbasin has various physiological functions such as antioxidant, anti-inflammatory response, neuroprotection, immune regulation, anti-tumor, and wound healing. The mechanism of verbascoside in the treatment of common neurodegenerative diseases Alzheimer's disease and Parkinson's disease is introduced.

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1 Pharmacological effect of Verbasin

1. 1 Antioxidative stress, antagonize neurotoxicity, inhibit neuronal apoptosis

1. 1. 1 Up-regulation of HO-1 heme through Nrf2, ERK, and PI3K/Akt pathways

Oxygenase-1 (HO-1) is the rate-limiting enzyme in the process of heme catabolism, catalyzing the conversion of heme into biliverdin, carbon monoxide, and free iron, and converting the above substances into bilirubin to form endogenous protection Substances are key factors in the oxidative damage response. Studies have shown that HO-1 has a neuroprotective effect on oxidative stress-induced neuronal damage. Through experimental studies, HONG et al. found that the expression of HO-1 protein was increased in a time-dependent and concentration-dependent manner after the treatment of PC12 cells by verbasin. In vivo studies showed that verbasin induced the expression of HO-1 protein in SD rats, and the mechanism was mainly due to the activation of Nrf2 by verbasin. transcription factor, and up-regulates HO-1 expression through ERK and PI3K/Akt pathways. Among them, most of the genes encoding phase II detoxification and antioxidant enzymes have an ARE sequence in their promoter region, and Nrf2 is an important transcription factor regulating the expression of ARE-driven HO-1 gene, and its expression product is superoxide dismutase ( SOD), catalase and other antioxidant enzymes and the GSH reduction system are involved in the regulation of oxidative stress in the body; ERK and Akt are both major signal conversion enzymes involved in cell protection from oxidative stress. Therefore, this study believes that Verbasin is an activator of Nrf2 and an inducer of HO-1 expression, and plays an anti-oxidative and alleviating neurotoxicity role through the up-regulation of HO-1.

1. 1. 2 Inhibition of mitochondrial pathway apoptosis

Reactive oxygen species (ROS) are single-electron reduction products of a class of oxygen in the body. They are produced by phagocytes in the body through the respiratory burst mechanism when they are stimulated and are the main mediators for phagocytes to play phagocytosis and killing. However, if an abnormality occurs in the body, reactive oxygen species lose balance and accumulate, which will cause oxidative damage. ROS can be generated in mitochondria, leading to free radical attack of membrane phospholipids and a decrease in mitochondrial membrane potential (MMP), resulting in the release of the intermembrane protein cytochrome c from mitochondria and ultimately activation of Caspase-3. The elevation of Bax, a member of the Bcl-2 family, and its translocation to the mitochondrial membrane play a key role in the mitochondrial apoptosis pathway. After translocating to the mitochondrial membrane, Bax can homodimerize and activate terminal caspases by altering mitochondrial function, resulting in the release of pro-apoptotic factors into the cytoplasm. Bcl-2 inhibited mitochondrial depolarization and ROS production, while Bax induced mitochondrial depolarization and ROS production. Bax and Bcl-2 are related to the apoptosis process induced by ROS-generating agents such as Aβ25-35. Studies have shown that Verbasin inhibits the increase of intracellular ROS and plays an antioxidant role; at the same time, it reduces the ratio of Bax/Bcl-2, because the release of cytochrome c in mitochondria triggers the activation of caspase, blocking this key step will Interfere with the cell death program, thereby saving dying neurons. The study also showed that verbascoside attenuated Aβ25-35-induced mitochondrial dysfunction, which protected SHSY5Y cells from Aβ25-35 neurotoxicity. In addition, some studies have shown that verbasin has a significant neuroprotective effect on MPP +-induced mitochondrial dysfunction-induced apoptosis in PC12 cells, which is related to scavenging free radicals, inhibiting the reduction of mitochondrial membrane potential, and protecting against oxidative stress-induced toxic damage. related.

1. 1. 3 By inhibiting glutamate-induced calcium influx, down-regulating NO production

Glutamate is the main excitatory neurotransmitter in the central nervous system, which is involved in synaptic transmission and is related to neuronal plasticity, learning, and memory. But overactivation causes glutamate-mediated neurotoxicity, which plays a key role in a variety of neurodegenerative diseases. Glutamate-induced excitotoxicity is characterized by the rapid influx of excess calcium ions, followed by activation of a variety of enzymes including NOS, which produces excess NO by increasing the formation of ROS, resulting in neurotoxicity. Since the loss of calcium ion homeostasis can cause mitochondrial depolarization, the membrane potential of the inner mitochondrial membrane can be dissipated, thereby opening the mitochondrial permeability transition pore, resulting in the passage of cytochrome C, apoptosis-inducing factor and other substances, so glutamate causes The influx of calcium ions can produce oxidative damage and pro-apoptotic effects. Studies have shown that verbascoside maintains mitochondrial potential by reducing glutamate-induced calcium influx, enhancing the antioxidant defense system against neurotoxicity.

1. 1. 4 Inhibition of ONOO--induced mitochondrial hyperactivation

ONOO- (peroxynitrite) is produced by the rapid reaction of superoxide anion (O2-) and nitric oxide (NO) generated by the activation of NOPH oxidase and iNOS, respectively, compared with Reactive oxygen species and reactive nitrogen species, ONOO- have stronger membrane penetration and higher cytotoxicity to the CNS [10]. Dynamics-related protein 1 (Drp1) is an important mitotic mediator, ONOO- can mediate the nitration modification and assembly of Drp1, promote mitochondrial recruitment and mitotic activation, and increase mitochondrial membrane permeability, so mitochondria are the main targets of ONOO-. In an experimental study using verbascoside to treat multiple sclerosis model mice, researchers found that verbascoside reduced ONOO- production, down-regulated iNOS, and NADPH oxidase expression, and inhibited ONOO-mediated excess phagocytosis. , protection of neuronal cells from nitrification cytotoxicity suppresses neuronal apoptosis and mitochondrial damage in the mouse spinal cord.

1. 2 Regulate immune function

1. 2. 1 Inhibition of NF-κB activation

NF-κB (nuclear factor-activated B cell κ-light chain enhancement) is an important intracellular nuclear transcription factor, which participates in the body's inflammatory response and immune response, and regulates apoptosis and stress response. , whose hyperactivation is associated with a variety of inflammatory changes. Interleukin-32 (IL-32) is a pro-inflammatory cytokine that can induce macrophages to produce a large amount of tumor necrosis factor-α, which is closely related to the occurrence of chronic inflammation and tumors. Studies have shown that IL-32 induces osteoclast precursor cells to degrade IκB in a time-dependent manner, activates the NF-κB pathway, affects the release of various cytokines and adhesion factors, and produces anti-inflammatory effects. The main mechanism is that IL-32 stimulates nucleotide oligomerization domains 1 and 2, thereby activating serine/threonine kinase receptor-interacting protein 2/RICK/CARDI-AK, resulting in the activation of NF-κB. In recent years, foreign studies have shown that verbascoside inhibits the expression of a series of pro-inflammatory factors (such as IL-1, IL-6, and TNF-α) by blocking IL-32, and blocking the NF-κB pathway, thereby inhibiting the expression of pro-inflammatory cytokines. Activation of macrophage-like cells plays an anti-inflammatory role. In addition to IL-32, TLR4 (Toll-like receptor 4) activates neutrophils through the NF-κB pathway and increases the production of pro-inflammatory cytokines. In an experimental study of intracerebral hemorrhage, we found that by inhibiting TLR4 signaling, verbascoside inhibited microglial activation in a co-culture system and in a mouse model of ICH, thereby reducing neuronal inflammatory toxicity.

1. 2. 1 Inhibit the activation of the TAK-1/JNK/AP-1 signaling pathway

Transforming growth factor b-activated kinase-1 (TAK-1) is a member of the mitogen-activated protein kinase (MAPK) family, which has become an AP-1-activated Key regulator of signal transduction cascades. Multiple lines of evidence support the activation of pro-inflammatory molecules such as bacterial lipopolysaccharides through TAK-1 to activate various protein kinases including p38, JNK, IKK-b, and PKB/Akt. In addition, activation of the transcription factor AP-1 in MAPK phosphorylation has also been reported. These intracellular signaling pathways that control the expression of related genes may mediate the inflammatory response. The protein tyrosine phosphate phase (SHP-1) is an important negative regulator of inflammatory gene expression in the immune system and central nervous system. SHP-1 produces anti-inflammatory functions by promoting the survival of macrophages. In addition, SHP-1 is an important negative regulator of several kinases, such as ERK1/ERK2 MAPKs, p38 MAPK, and JNK, which play a role in IFN-γ and/or LPS-induced nitric oxide production. It has been shown that verbascoside can prevent and inactivate TAK1 phosphorylation caused by lipopolysaccharide, resulting in a significant decrease in the level of JNK protein, resulting in the inactivation of the transcription factor AP-1. The researchers silenced the gene encoding the SHP-1 protein and showed that its transcriptional loss is associated with phosphorylation of the TAK-1/JNK system, resulting in enhanced AP-1 expression, suggesting that the inhibitory effect of verbascoside is dependent on SHP-1. Overall, verbascoside attenuated the activation of the TAK-1/JNK/AP-1 signaling pathway by increasing the phosphorylation of SHP1 and exerted an anti-inflammatory effect.

1. 3 Inhibition of amyloid toxicity

Amyloid β (Aβ) is a polypeptide containing 39 to 43 amino acids produced by the proteolysis of amyloid precursor protein (APP) by β- and γ-secretase. in blood and cerebrospinal fluid. If Aβ accumulates too much, it can be deposited in brain tissue to form senile plaques, which is one of the main pathological markers of Alzheimer's disease. Among them, Aβ1-42 has stronger toxicity and is a key protein in the pathogenesis of AD. Intracerebral injection of Aβ1-42 in AD rats can cause memory impairment, morphological changes in brain tissue and include cholinergic and monoamine nervous systems. neuronal degeneration. Hu Hangjing's research found that verbasin can resist synaptic damage and neuronal apoptosis caused by Aβ1-42 deposition by increasing the expression of SHY (a protein that regulates the release of neurotransmitters) in neurons in the brain. Foreign studies have found that in AD-like animal models, the mechanism by which Aβ1-42 injection into the lateral ventricle leads to memory impairment is closely related to Aβ deposition and subsequent cascade reactions, such as central cholinergic dysfunction, including decreased ACh levels and AChE. activity is up-regulated. Verbasin in 2. 5 to 5. At 0 mg/kg, the level of ACh in the hippocampus can be increased, and the up-regulation of AChE activity in the hippocampus can be inhibited, but only in 5.5. At 0 mg/kg, it can reduce Aβ deposition and reverse the disturbance of cortical Ach level in Aβ1-42 perfused rats. Other studies have shown that verbasin inhibits the aggregation of Aβ42 in a dose-dependent manner, and the catechol part of its molecule plays a key role in this inhibitory activity.

1.4 Regulation of autophagy

The mammalian target of rapamycin (mTOR) is a conserved serine/threonine-protein kinase that regulates the initiation of protein translation. It is involved in signal transduction in multiple signaling pathways, including gene transcription, ribosome biosynthesis, initiation of protein translation, autophagy, and apoptosis. Autophagy is a programmed cell death mode. Moderate autophagy can maintain cell homeostasis and respond to external stimuli, while excessive autophagy may damage organelles and cellular structures, causing abnormal functional changes. Oxidative stress produces a large number of reactive oxygen species and reactive nitrogen, which can inhibit the mTOR signaling pathway, resulting in the blocking of corresponding mRNA translation and protein expression. However, some studies have shown that verbascoside can reduce the formation of autophagosomes, and can also increase the expression of autophagy markers such as Beclin-1, LC3-II, and P62 to activate the mTOR pathway when the body is stimulated by external ischemia and hypoxia. , which indicates that verbasin can not only inhibit excessive autophagy activation, but also maintain a certain autophagy activity, and play a role in protecting neurons by regulating the balance of autophagy.

2 Verascoside in the treatment of neurodegenerative diseases

2. 1 Alzheimer's disease 

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease, characterized by behavioral disturbances such as cognitive dysfunction and neuronal loss, senile plaques, and neurofibrillary tangles. nodal pathological changes. cognition of AD patients

Dysfunction and neurotransmitter disturbances are closely related to the amyloid cascade, amyloid oligomerization, and amyloid cytotoxicity. There are many factors involved in the pathological mechanism of AD, including the Aβ amyloid cascade, hyperphosphorylation of Tau protein, oxidative stress, and inflammatory cascade. According to the existing research, the main cell models used for the treatment of Alzheimer's disease by verbasin are PC12 cells and SH-SY5Y cells, and the animal models are AD rat model perfused with Aβ1-42, d-galactose and scopolamine dementia mice Model and AlCl3 combined inducement

guided mouse aging model [30]. Its therapeutic mechanism can be summarized as follows: ①Reduce Aβ deposition, improve Aβ deposition in the brain of AD patients and improve the normal synaptic activity between neurons blocked by Aβ deposition. ②Reduce the production of ROS mediated by Aβ, regulate apoptosis signaling pathway through Bcl-2 family, cytochrome c and caspase-3, protect nerve cells from oxidative damage and reduce apoptosis. (3) In vitro, it participates in the neuroprotective effect against Aβ neurotoxicity by activating the ERK and PI3 K/Akt signaling pathways and simultaneously causing nuclear translocation of Nrf2 to increase the expression of HO-1. ④ Significantly increased hippocampal neurons and Nissl bodies, shortened the response latency of AD model mice, and reduced the number of errors to alleviate memory impairment.

2. 2 Parkinson's disease 

Parkinson's disease(PD) is the second most common neurodegenerative disease characterized by clinical manifestations such as resting tremor, bradykinesia, myotonia, postural gait disturbance, and nigrostriatal dopaminergic neurons. Degeneration, α-synuclein aggregation, and other pathological changes. The massive degeneration of dopaminergic neurons causes down-regulation of MAP2 and elevation of caspase-3, and these changes may lead to mitochondrial depolarization and aggravate dopaminergic neuron apoptosis. In addition, changes in the expression of tyrosine hydroxylase in the nigrostriatal system are closely related to the occurrence and development of Parkinson's disease. According to the existing research, the main animal models used for the treatment of PD with verbasin are rotenone-induced PD rats and 6-hydroxydopamine (6-OHDA)-induced zebrafish nerve injury models. Its therapeutic mechanism can be summarized as the following aspects: 1) Through penetrating the blood-brain barrier, activating the Nrf2-ARE pathway, increasing the activity of SOD, CAT, GSH-Px, and other antioxidant substances, and reducing the content of MDA to exert detoxification and neuroprotective activities. ②Reduce α-synuclein, reduce its expression by combining with caspase-3, increase the expression of MAP2, and protect neuronal cells damaged by MPP + and glutamate. ③ Significantly increased the expression of tyrosine hydroxylase (TH) mRNA and protein, and the number of tyrosine hydroxylase immunoreactive neurons reduced the loss of TH expression in the substantia nigra in vivo and blocked 6-OHDA in vivo. Damaged substantia nigra dopaminergic neurons die.

3 Conclusion

Common neurodegenerative diseases, Alzheimer's disease, and Parkinson's disease, both appear in the late stage of cognitive dysfunction, which brings a heavy burden to many individuals and families. With the development of medicine, people's research on neurodegenerative diseases has continued to deepen, and multi-channel and multi-targeted treatment has been used to improve the symptoms of patients with neurodegenerative diseases. Verbasic glycoside is the active ingredient of Rehmannia glutinosa, Cistanche, Forsythia, and other traditional Chinese medicines. It antagonizes neurotoxicity mediated by amyloid, glutamate, and peroxynitrite ions through signal transduction such as Nrf2, ERK, and PI3K/Akt. Inhibits mitochondrial pathway apoptosis; regulates immune function and inhibits inflammation through NF-κB and TAK-1/JNK/AP-1 signal transduction; also regulates autophagy. Therefore, verbascoside shows good therapeutic prospects in Alzheimer's disease and Parkinson's disease and is a class of drugs with potential for development.