Chinese Herbal Medicine against Alzheimer’s Disease

Alzheimer’s disease (AD), the most common neurodegenerative disorder associated with dementia, not only severely decreases the quality of life for its victims, but also brings a heavy economic burden to the family and society. Unfortunately, few chemical drugs designed for clinical applications have reached the expected preventive or therapeutic effect so far, and combined with their significant side-effects, there is therefore an urgent need for new strategies to be developed for AD treatment. Traditional Chinese Medicine has accumulated many experiences in the treatment of dementia during thousands of years of practice; modern pharmacological studies have confirmed the therapeutic effects of many active components derived from Chinese herbal medicines (CHM).

Radix Ginseng Extracts

Radix Ginseng (Renshen) is one of the perennial plants, which are in genus Panax and family Araliaceae. Ginsenosides are believed to be the active compounds of ginseng herbs. Renshen can reinforce vital energy, as described in Sheng Nong’s Herbal Classic’ (100AD). More than 31 types of ginsenosides have been extracted and each possesses a variety of biological activities. A number of studies have shown that ginsenosides can prevent and treat Alzheimer’s disease via regulating neurite outgrowth and synaptic plasticity, neuroprotection, anti-inflammatory effects andregulation of Aβ production and β-secretase activity. Ginsenoside Rg1 can significantly reduce the level of Aβ in the hippocampus of AD model mice brains, reverse the load of Aβ plaques in the cerebral cortex and hippocampus, protect cholinergic neurons and synapses, and improve spatial learning and memory function. Rg1 can inhibit the activity of secretase through activation of the PKA/CREB signaling pathway. It can also a neuroprotective effect by inhibiting the apoptosis of neuron cells, increasing the activity of neurons and decreasing the release of lactate dehydrogenase (LDH), reducing the expression of cytochrome C and increase the ratio of Bcl-2/Bax. Other monomers extracted from Radix Ginseng, like ginsenosides Rg3 and Rb1, can protect neurons by inhibiting the inflammatory response and hyperphosphorylation of tau protein. Ginsenoside Rg3 can reduce the expression of cellular factors associated with inflammation in the hippocampus, like tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and cyclooxygnasis-2 (COX-2), so as to improve the defects of learning and memory in rats. Another study demonstrated the neuroprotective effects of ginsenoside Rb1 against Aβ1_42 toxicity in cultured cortical neurons; the mechanism may be associated with inhibiting of tau hyperphosphorylation, increasing the levels of phospho-Ser (473)-Akt and down-regulating GSK-3β activity by PI3K activation, as well as reversing the Aβ1_42 induced decrease in phosphorylation cyclic AMP response element binding (CREB) protein.

Radix Salviae Miltiorrhize (Salvia Miltiorrhiza Bunge) Extracts

The active components and monomers extracted from Radix Salviae miltiorrhizecae (Danshen) can be divided into two main categories according to their solubility: lipophilic compounds like Tanshinone IIA and hydrophilic compounds like Salvianolic acid B. Many of these active components and monomers have protective effects on neurons, and can be used to treat Alzheimer’s disease. Tanshinone IIA can increase the viability and reduce the number of apoptotic of PC-12 cells by PI3K/Akt activation and GSK3β phosphorylation. Tanshinone IIA can also protect neurons from regulating the activity of calpain via the Bcl-xl and P35/CDK5 signaling pathway. Oxidative stress may play an important role in the occurrence and development of AD; tanshinone IIA has been shown to protect against oxidative stress and cell death by significantly decreasing the activities of malondialdehyde (MDA) and superoxide dismutase (SOD), increasing the level of glutathione peroxidase (GSH-PX), reducing the intracellular reactive oxygen species (ROS) level and increasing the mitochondrial membrane potential, reducing the caspase-3 activity, cytochrome c translocation and increasing the ratio of Bcl-2/Bax in Aβ25_35-induced cortical neurons. Danshensu, a hydrophilic compound of Danshen, can act as a protector of AD via antioxidative stress; it can enhance heme oxygenase-1 (HO-1) expression to suppress 6-hydroxydopamine (6-OHDA)-induced oxidative damage via PI3K/Akt/Nrf2 signaling pathways. Other studies have shown that monomers extracted from Danshen like Salvianolic acid B, Tanshinone I, Dihydrotanshinone I have neuron protective effects. Salvianolic acid B can inhibit the uptake of calcium and reduce the release of LDH. Cryptotanshinone and Dihydrotanshinone I can act as the cholinesterase inhibitors.

Radix Scutellariae (Scutallaria Baicalensis Georgi) Extracts

The active components and monomers extracted from Radix Scutellariae (Huangqin), thedry root of Scutellaria baicalensis Georgi, such as baicalin, baicalein and other flavonoids, showed significant biological activities such as antioxidation, free radicals scavenging, anti-inflammation, antitumor, antimicrobial effect. Baicalin, the main flavonoid extracted from Radix Scutellariae, can interact with copper directly and inhibit Aβ1_42 aggregation, as well as decrease H2O2 production, so as to inhibit Aβ aggregation and protect neurons. Baicalin could ameliorate Aβ1-42 protein-induced cognitive dysfunction, attenuate glia activation, TNF-α and IL-6 expression in AD model mice, its mechanism may be related to the inhibition of the JAK2/ STAT3 signaling pathway. Baicalein, another flavonoid isolated from the roots of Radix Scutellariae, has been found in vivo and vitro to promote nonamyloidogenic processing of APP, thereby reducing Aβ production and improving cognitive performance by activating gama-aminobutyric acid A (GABAA) receptors. Baicalein can also break down the aggregated amyloid beta fibrils, and the effect is time and dose-dependent. Chen Y C and colleagues examined the protective mechanism of Baicalein on hydrogenperoxide (H2O2)-induced cell death in rat glioma C6 cells and found that it can inhibit the activity of caspase 3, 8 and 9, modulate the activation of ERKs and induce heme oxygenase-1 (HO-1) expression, so as to inhibit cell apoptosis.

Ginkgo Leaf (Folium Ginkgo) Extracts

Ginkgo bilobais one of the oldest living tree species on the planet. The standardized extract from the leaves of the Ginkgo biloba tree, labeled EGb761, contains 24% flavonoid glycosides (containing quercetin, kaempferol, isorhamnetin, etc.), 6% terpenoids (in which 3.1% are ginkgolides A, B, C, and J and 2.9% is bilobalide), and 5–10% organic acids, EGb761 has been demonstrated to possess neuroprotective effects in the treatment and prevention of AD, and the mechanisms involve antioxidant activity, protective effects on mitochondrial function, anti-apoptotic effect, anti-inflammatory effect, and protective effects against amyloidogenesis and Aβ aggregation. However, clinical trials of Ginkgo biloba leaf extracts on AD produced very different results. One study enrolled 2854 participants and found that long-term use of standardized Ginkgo biloba extract did not reduce the risk of progression to Alzheimer’s disease compared to theplacebo. Another clinical trial implemented by Ihl R and colleagues  found that EGB761 can improve cognitive functioning, neuropsychiatric symptoms and functional abilities in AD. Systematic review and meta-analysis of efficacy and tolerability of Ginkgo biloba extract EGb 761 in dementia indicated that Ginkgo biloba extract has good clinical effect on mild and moderate Alzheimer’s disease, furthermore, it was well tolerated. The research of the mechanisms of Ginkgo biloba extract in the treatment of AD is also widespread. Jahanshahi and colleagues found that Ginkgo biloba extract may protect neuron cells, can significantly reduce the apoptosis of the cells in CA1, CA3 and dentate gyrus areas of hippocampus of rat. Ginkgo biloba extract also manifests anti-inflammation effects, can reduce the number of microglia, decrease the expression of inflammation associated cytokines such as tumor necrosis factor α (TNF-α), Chemokine CCL-2 and the transcription of both proinflammatory and antiinflammatory genes (TNF-α, IL-1β, CCL-2 and IL-10) was markedly decreased in the hippocampus, and improve the cognitive function and preserves synaptic structure proteins in AD model mice. Antioxidation is another effect of Ginkgo biloba extract. EGb761 may increase the levels of superoxide dismutase (SOD) and glutathione (GSH), reduce the level of malondialdehyde (MDA), the expression of Bax, cytochrome c and caspase-9/3 in hippocampus of rats.

Herba Epimedii (Epimedium Herb) Extracts

Herba Epimedii (Yinyanghuo) can improve the function of the nervous system. Icariin, one kind of flavonoid, is the main active ingredient extracted from Herba Epimedii. The therapeutic effects of icariin have been found to target the pathological basis of Alzheimer’s disease, such as β-amyloid proteins, phosphorylation of tau proteins, the apoptosis of neuron cells, oxidative stress and so on. Lan Zhang and colleagues found that Icariin can reduce the Aβ burden and amyloid plaque deposition in the hippocampus of APP transgenic mice by decreasing the amyloid precursor protein (APP) and β-secretion, and thus improve learning and memory functions. Icariin can also increase the cell viability and decrease apoptosis in cultured rat pheochromocytoma PC12 cells induced by amyloid beta protein fragment 25-35(Aβ25_35), the mechanism may be associated with the activation of the PI3K/Akt signaling pathway, downregulation of proapoptotic factors Bax and Caspase3, and upregulation of antiapoptotic factor Bcl-2. Icariin may protect neurons by inhibiting oxidative stress and hyperphosphorylation of tau protein, as well as activating PI3K/Akt signaling pathway, resulting in an inhibitory effect on glycogen synthase kinase (GSK)-3β, which is an important kinase response for tau protein hyperphosphorylation in the development of AD, icariin also can attenuate LDH leakage, reduce GSH depletion, prevent DNA oxidation damage and inhibit subsequent activation of caspase-3 and p53. These effects may associated with its inhibitory effect on the JNK/p38 MAPK pathways. Phosphodiesterase-5 (PDE5) inhibitors have been recently shown to have a potential therapeutic effect for the treatment of Alzheimer’s disease, Icariin acts as a PDE5 inhibitor and can decrease the levels of amyloid precursor protein (APP), Aβ1_40, Aβ1_42 and PDE5 mRNA and protein levels in the hippocampus and cortex of the AD model mice and thus improve learning and memory functions significantly, and the mechanism may be associated with the stimulation of the NO/cGMP signaling pathway.

Huperzia serrata Extracts

Huperzine A, derived from the Chinese herb the Huperzia serrata, is considered to be a reversible, selective inhibitor of acetylcholinesterase (AChE), and can be used for the treatment of Alzheimer’s disease. A large number of clinical studies, systematic reviews and meta-analyses have found that huperzine A can significantly improve memory, cognitive function and daily living abilities of patients with AD, without serious side effects. Recent studies have found that huperzine A not only acts as a cholinesterase inhibitor, but also involves other mechanisms. Chun-Yan Wang and colleagues found that huperzine A also has antioxidant effects that can increase ADAM10, decrease BACE1 and APP695 protein levels and reduce Aβ levels and Aβ burden, as well as increase the activity of α secreted enzyme in cerebral cortex and hippocampus of transgenic AD mice through activating of the Wnt/β-Catenin signaling pathway. By reducing the contents of iron element in the brain, Huperzine A can reduce the production of Aβ and hyperphosphorylation of tau protein in the cerebral cortex and hippocampus of transgenic AD mice. Another study found that huperzine A can promote hippocampal neurogenesis in adult mice, suggesting that huperzine A may improve hippocampus-dependent functions.

Curcuma Longa Extracts

Curcumin is derived from the herb Curcuma Longa, more commonly known as turmeric that is used in curries and other spicy dishes from India, Asia and the Middle East. Many studies have reported that curcumin has various beneficial properties, such as antioxidant, antiinflammatory, and antitumor.  The structure of curcumin is largely composed of a carbon chain linking two aryl groups. Researchers have found the phenolic OH groups attached to the aryl groups to be able to scavenge reactive oxygen species (ROS), contributing to its anti-oxidative effect.  Recent reports have suggested therapeutic potential of curcumin in the pathophysiology of Alzheimer’s disease (AD). A growing body of evidence indicates that oxidative stress, free radicals, beta amyloid, cerebral deregulation caused by bio-metal toxicity and abnormal inflammatory reactions contribute to the key event in Alzheimer’s disease pathology.   In in vivo studies, oral administration of curcumin has resulted in the inhibition of Aβ deposition, Aβ oligomerization, and tau phosphorylation in the brains. These findings suggest that curcumin might be one of the most promising compounds for the development of AD therapies.