Traditional Chinese Medicine for Senile Dementia

Traditional Chinese Medicine (TCM) has a 3000 years' history of human use. A literature survey addressing traditional evidence from human studies was done, with key result that top 10 TCM herb ingredients including Poria cocos, Radix polygalae, Radix glycyrrhizae, Radix angelica sinensis, and Radix rehmanniae were prioritized for highest potential benefit to dementia intervention, related to the highest frequency of use in 236 formulae collected from 29 ancient Pharmacopoeias, ancient formula books, or historical archives on ancient renowned TCM doctors, over the past 10 centuries. Based on the history of use, there was strong clinical support that Radix polygalae is memory improving. Pharmacological investigation also indicated that all the five ingredients mentioned above can elicit memory-improving effects in vivo and in vitro via multiple mechanisms of action, covering estrogen-like, cholinergic, antioxidant, anti-inflammatory, antiapoptotic, neurogenetic, and anti-Aβ activities. Furthermore, 11 active principles were identified, including sinapic acid, tenuifolin, isoliquiritigenin, liquiritigenin, glabridin, ferulic acid, Z-ligustilide, N-methyl-beta-carboline-3-carboxamide, coniferyl ferulate and 11-angeloylsenkyunolide F, and catalpol. It can be concluded that TCM has a potential for complementary and alternative role in treating senile dementia. The scientific evidence is being continuously mined to back up the traditional medical wisdom.


Introduction
Cognitive impairment or dementia in elderly is associated with many disorders [1]. Alzheimer's disease (AD) is the principal type of dementia and represents about 70% of the dementia patients.
The pathologic hallmarks of AD are senile plaques, neurofibrillary tangles, dystrophic neurites, and neuronal loss. The development of AD may be due to the improper biochemical processing of amyloid precursor protein (APP) leading to subsequent accumulation of β-amyloid (Aβ). The amyloid and tangle cascade hypothesis is the dominant explanation for the pathogenesis of AD [2]. Other relevant factors, including cholinergic dysfunction [3], neuroinflammation [4,5], oxidative stress [6], and disturbance of neuronal plasticity [7], age-related loss of sex hormones [8,9], are important and contribute to the understanding of AD pathology.
The 2nd most common form of dementia is vascular dementia (VD) or multi-infarct dementia, which accounts for about 15% of dementia cases [10,11]. VD may fol-low after a succession of acute cerebrovascular events or, less commonly, a single major stroke. The compromised cerebrovascular circulation causes ischemia that leads to damage of the brain structure, for example, formation of white matter lesions or silent brain infarctions. VD is often related to the loss of fine motor control besides memory impairment.
Lots of folk plants in traditional medicine are being used in age-related brain disorders for improvement of memory and cognitive function [14][15][16]. In China, a number of herb ingredients known from Traditional Chinese Medicine (TCM) have a long history of use for mental health. In this study, we exploited the empirically driven TCM lore and surveyed scientific data to back up the cognitive benefits, claimed by TCM.

Ancient Records on TCM for Cognitive Decline
The term "senile dementia" refers to a clinical syndrome seen in the elderly characterized by impairment of memory and cognition. So in a search of the ancient literature of TCM, the etiology, pathogenesis, and treatment for "dementia or amnesia" have been used for the survey in detail.

Etiology and Pathogenesis
2.1.1. Deficiency of Energy. Deficiency of energy is similar to "Qi" deficiency in TCM. According TCM lore Qi is the essential substance that makes up the body and maintains various physiological activities, similar to flow of energy in the body. The energy is mainly from the kidney, heart, and spleen, especially from the kidney. In TCM, the energy from the kidney is called kidney essence which can produce marrow including cerebral marrow, spinal cord, and bone marrow. The cerebral marrow can nourish the brain and maintain the physiological functions of the brain. If the kidney essence is insufficient, the production of cerebral marrow will be reduced, leading to various symptoms, such as headache, dizziness, amnesia, and retard response [17].

Blood Stasis.
Normally the blood is pumped by the heart to flow in the vessels. If blood circulation is stagnated or slowed down by certain factors such as cold, emotional disorder, aging, consumptive disease, and overstrain, it will result in retention of blood flow in the vessels or organs, a pathological condition named blood stasis. The cognitive function will decline, due to long-term global hypo-perfusion in cerebral blood flow or acute focal stroke in memory-related cerebral parenchyma [17].

Toxin.
As the function of internal organs in the elderly decline, the balance between host defense and external toxins in the body is disrupted. Pathological or physiological products occur and form toxin including waste of "water" and "endogenous fire", which result from the poor digestion, accumulates into phlegm and retention of fluid, and caused by mental disorder, attack from pathological factors, and imbalance within the body, respectively. If such toxins can not be eliminated quickly the blood circulation and mental acuity will be affected, eventually contributing to the onset of dementia. In this study, 27 ancient TCM books were selected, which could be divided into 3 types, namely, Pharmacopoeias, formulae monographs and renowned TCM doctor's case studies.
A database was established to determine the frequency of herbs in these documents. Totally 236 formulae for improving cognitive function were identified among 27 books mentioned above (Table 1); 139 herbs were gathered from those 236 formulae and 10 TCM herbs were prioritized due to the highest frequency over 50 times (Table 2).
According to specification documented in Chinese Pharmacopeia [18], (i) Poria cocos is a diuretic with capacity to invigorate spleen function and calm the mind. Clinically, it is applicable for memory decline due to spleen deficiency and phlegm blockage; (ii) Radix polygalae is able to anchor the mind and eliminate the phlegm, and indicated in forgetfulness and insomnia; (iii) Radix glycyrrhizae is a qi tonic to invigorate the stomach and spleen, resolve phlegm, and clear away heat and toxin; (iv) Radix Angelica sinensis, as a vital blood tonic and antithrombotic agent, is especially used to treat stroke and poststroke vascular dementia induced by blood stasis; (v) Radix rehmanniae is another tonic used to reinforce kidney essence and marrow. Because of functionality to invigorate the energy, activate blood circulation, or eliminate the toxin, these herbs can be prescribed along or combined to exhibit a good therapeutic effect for senile dementia, for example, Zhi Ling Tang [19].

Evidence-Based Efficacy of TCM Herbs on
Cognitive Decline

Functionality/Efficacy.
There is suggestive evidence that P. cocos is memory improving regardless of absence of available clinical reports. Pharmacological research exhibited that the water extract of P. cocos enhanced hippocampal long-term potentiation (LTP) and improved scopolamineinduced spatial memory impairment in rats ( [20,21], Table 3).

Functionality/Efficacy.
There is strong support that thinleaf milkwort root is memory improving. BT-11, the extract of dried root of Radix polygalae, was developed in Korea as a functional diet with cognitive enhancing activity. Elderly with subjective memory impairment and mild cognitive impairment ascend with oral BT-11 at 300 mg/d for 4-8 weeks. Except for mild dyspepsia, no adverse events were reported [32,33].
(1) Isoliquiritigenin also has the protective potential against transient middle cerebral artery occlusioninduced focal cerebral ischemia in rats, at the doses of 5, 10, and 20 mg/kg. Its protection may be attributed to amelioration of cerebral energy metabolism and antioxidant property.
(2) Liquiritigenin, a plant-derived highly selective estrogen receptor β agonist has been identified to alleviate the cognitive recession in the elders.
(3) Glabridin appears to be an active isoflavone as it improved learning and memory in mice at 1, 2, and 4 mg/kg, through targeting at ChE. Glabridin had a protective effect on cerebral ischemia injury, and neuron insult induced by staurosporine at 5, 25 mg/kg (i.p). Its underlying mechanism is probably linked to antioxidant and antiapoptotic activity.

Mechanism of Action and Active Principles
(1) Ferulic acid has been identified to be an active principle because it may reverse memory deficits induced by a variety of toxins, including dl-buthionine-(S,R)sulfoximine, trimethyltin, glutamate, Aβ1-42, scopolamine, and cycloheximide. Multiple mechanisms are probably implicated into its cognitive benefits, including inhibition on oxidative stress, activation of ChAT or enhance the cholinergic activities, competitive N-methyl-D-aspartate (NMDA) receptor antagonism, suppression on immunoreactivities of the astrocyte, and facilitation of cerebral blood flow ( [66][67][68][69][70], Table 6(b), Figure 3).
(2) Z-ligustilide has been identified to be another active component from volatile of Radix Angelica sinensis. It may protect brain and cognition especially against focal and global ischemia induced by permanent common carotid arteries occlusion (CCAO) and transient middle cerebral artery occlusion (MCAO) [71][72][73], (Table 6(b), Figure 3).

Radix rehmanniae. Radix rehmanniae is the roots of
(b) Memory-improving and neuro-protective effects of active components from Radix Angelica sinensis
Recently, catalpol has been identified as a vital active with robust cognitive potential (Figure 4). Behaviour studies exhibited that catalpol reversed brain damage and memory deficits in mice induced by lipopolysaccharide (LPS) and D-galactose and in gerbils by cerebral ischemia. The nootropic and neuroprotective efficacy of catalpol probably resulted from a variety of underlying molecular mechanisms (Table 7).
(iii) Neurogenetic activity: catalpol can enhance axonal growth of cortical neurons cultured in vitro from 24 h newly born rat, at 1-5 mg/mL and ameliorate agerelated presynaptic proteins decline (synaptophysin and GAP-43), and neuroplasticity loss in the hippocampus of the aged rats, by upregulating protein kinase C (PKC) and brain-derived neurotrophic factor (BDNF) [85,88].
(iv) Antiapoptotic activity: catalpol not only suppressed the downregulation of Bcl-2, upregulation of Bax, and the release of mitochondrial cytochrome c to cytosol, but also attenuated caspase-3 activation, poly-ADP-ribose polymerase (PARP) cleavage, and eventually protected against H 2 O 2 -induced apoptosis in PC12 cells and in the ischemic dorsal hippocampus of gerbils subject to CCAO [82][83][84]90].
(v) In addition, the function to stimulate the production of adrenal cortical hormones, which increases the production of sex hormones, is likely implicated into the cognitive benefit of catalpol in menopausal women [92].

Discussion and Conclusion
TCM has a long history of human use for mental health. The current literature survey addressing traditional evidence from human studies has been primarily carried out. The top 10 TCM herb ingredients were identified. Poria, thinleaf milkwort, licorice, Chinese Angelica, and Rehmannia were further prioritized to have the highest potential benefit to dementia intervention, due to their highest frequency of use in 236 formulae collected from 29 ancient Pharmacopoeias, ancient formula books, or historical archives on ancient renowned TCM doctors, over the past 10 centuries. In TCM philosophy, AD is assumed to be induced by kidney essence vacuity and toxin (turbid phlegm). The amnestic mild cognitive impairment in elderly population has been disclosed in a clinical investigation to correlate with kidney essence vacuity and turbid phlegm blocking upper orifices. The whole cognitive function may worsen because of the aggravation of kidney essence vacuity, deficiency of blood and qi, phlegm and heat toxin and may eventually lead to multiple cognitive domains impairment, even dementia [93].
Based on the history of use, there is strong clinical support that Radix polygalae is memory improving since its efficacy has been demonstrated in elderly with mild cognitive decline [32,33]. There is suggestive evidence that Poria cocos, Radix glycyrrhizae, Radix Angelica sinensis, or Radix rehmanniae are memory improving, though modern clinical reports concerning the four herbs are absent yet.
Furthermore, pharmacological investigations in 39 animal studies and 18 in vitro studies also indicated that the five ingredients can elicit memory-improving effects via multiple mechanisms of action, covering estrogen-like, cholinergic, antioxidant, anti-inflammatory, antiapoptotic, Neurogenetic, and anti-Aβ activities. These mechanisms are in well accordance with modern pharmacotherapy for AD and VD, by prescribing ChEIs, anti-inflammatory mediations, antioxidants, estrogen, neurotrophic factors, and nootropics, depending on difference situations.
In the meantime, 11 active molecules have also been identified, including sinapic acid, tenuifolin, isoliquiritigenin, liquiritigenin, glabridin, ferulic acid, Z-ligustilide, N-methyl-beta-carboline-3-carboxamide, coniferyl ferulate and 11-angeloylsenkyunolide F, and catalpol. Most of them are lipophilic compounds with comparatively low-molecular weight (200 ∼ 700) and likely to be absorbed into blood and distributed to brain according to Lipinski rule of 5 [94]. The 11 compounds can serve as active markers for characterisation and standardization of corresponding TCM herbal extracts and pharmacokinetics markers for bioavailability study. In drug discovery, these phyto-chemicals can also be used as candidates to optimize derivatives [95].
Taken together, it is concluded that TCM could have a complementary and alternative role in preventing and treating cognitive disorder in the elderly. The scientific evidence is being continuously mined to back up the traditional medical wisdom and product innovation in the healthcare sectors.