|Ahead of print publication
Anti-inflammatory and memory-enhancing properties of Chinese herbal extracts: The possible application in Alzheimer's disease
Peeraporn Varinthra1, Pavithra Suresh1, Prithiviraj Chokkalingam2, Ayooluwa Gabriel Ibiayo1, Ingrid Y Liu1
1 Institute of Medical Sciences, College of Medicine, Tzu Chi University, Hualien, Taiwan
2 Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien, Taiwan
|Date of Submission||10-May-2022|
|Date of Decision||06-Jun-2022|
|Date of Acceptance||13-Jul-2022|
|Date of Web Publication||05-Sep-2022|
Ingrid Y Liu,
Institute of Medical Sciences, Tzu Chi University, 701, Zhongyang Road, Section 3, Hualien
Source of Support: None, Conflict of Interest: None
Alzheimer's disease (AD) is a progressive brain disease that causes cognitive impairment in seniors. The beta-amyloid (Aβ) deposition and intracellular neurofibrillary tangles are two pathological hallmarks of AD. The increase of AD hallmarks causes inflammatory response enhancement, reduction of synaptic plasticity, and impaired cognition. The percentage of the aging population is growing along with the number of AD patients; however, effective treatment of AD is still limited. Therefore, developing preventive and therapeutic drugs for AD with fewer adverse side effects is urgently needed. The crude extracts from herbs such as Centella asiatica, Dendrobium catenatum, Litsea cubeba, Nardostachys jatamansi, Convolvulus pluricaulis, Melissa officinalis, Magnolia officinalis, Withania somnifera, and Nigella sativa improved memory performance and reduced inflammation response in various diseases. In addition, herbal blends usually have minimum aversive effects and can be mixed into diet and served as nutritional supplements. Hence, it is promising to develop Chinese herbal extracts to prevent or treat early AD. This review article highlights the currently available treatments of AD and the therapeutic effects of a group of crude extracts from Chinese herbs that can prevent cognitive decline and reduce the excessive inflammatory response. The possible clinical use of these Chinese herbal extracts in AD is also discussed.
Keywords: Alzheimer's disease, Anti-inflammation, Herbal medicine, Memory
|How to cite this URL:|
Varinthra P, Suresh P, Chokkalingam P, Ibiayo AG, Liu IY. Anti-inflammatory and memory-enhancing properties of Chinese herbal extracts: The possible application in Alzheimer's disease. Tzu Chi Med J [Epub ahead of print] [cited 2022 Oct 6]. Available from: https://www.tcmjmed.com/preprintarticle.asp?id=355612
| Introduction|| |
Severity and prevalence of Alzheimer's disease
Alzheimer's disease (AD) is a disease that slowly impairs memory performance and cognitive functions. It has become the 6th leading cause of death among neurodegenerative diseases . However, in-market drugs that apply to middle or late AD patients are limited and have aversive side effects. Therefore, preventive and therapeutic drugs for AD from natural products with fewer adverse side effects are necessary. More than 4.6 million new AD patients are diagnosed every year. The number is expected to double by 2030 and possibly triple by 2050 . From 2002 to 2012, data showed that 3%–7% of the Europe and US population were diagnosed with AD, including France (3%), the United Kingdom (4.9%), Italy (3%), Spain (6.4%), and the USA (5%–7%) . The prevalence of AD in East Asia is about 6% of the elderly population aged ≥65 years in Taiwan, 3% in Japan, 5% in China, and 9% in South Korea . AD has become a severe medical issue that heavily increases the societal burden locally and worldwide. Moreover, advanced medical health care and a nursing home are required for about 43% of patients . Therefore, finding a preventive treatment from nature is more practical and costs less than developing a therapeutic drug for AD.
Signs and symptoms of Alzheimer's disease
AD's signs and symptoms can be classified into three stages : (1) in the early stage, the patients demonstrate disorientation, forgetfulness, and confusion with time, usually considered a typical aging process and often neglected. (2) The signs and symptoms become more apparent in the middle stage. Most patients have difficulties in personal communication, remembering the names of people and events, and exhibiting behavioral changes such as reiterating the questions and wandering that can obstruct their daily lives. (3) In the late stage, intensive medical care is necessary for AD patients because of declined awareness of recent experiences, inability to recognize familiar people, and changes in physical abilities such as difficulties in eating, swallowing, walking, sitting, and being vulnerable to infections . The progression of AD is irreversible and worsens over time; therefore, the early preventive treatments of AD before the onset of the late stage are essential.
| Pathology of Alzheimer's disease|| |
Several types of memory impairment are associated with AD, including working memory, episodic memory, semantic memory, procedural memory , and fear memory . Fear response is an essential emotion for survival and is highly conserved across species . Previous studies have reported that defective fear memory appears in the early stage of AD, mild cognitive impairment (MCI) patients . Working memory is the brain process with limited capacity to store necessary information for responding to complicated tasks such as learning, understanding, and reasoning . Reduced working memory is a common symptom in AD patients. A previous study found that theta-gamma coupling recording by electroencephalography is defective in AD patients in the N-back working memory task . The functional magnetic resonance imaging examination during a visuospatial associative working memory task demonstrated working memory impairment in MCI patients . Episodic memory is associated with learning, storing, and retrieval of information for specific events in daily life. Semantic memory is linked with general world knowledge such as word meaning, fact, language, math, color, and names . For the early stage of AD patients, episodic and semantic memory deficits can be identified using the five-word test , traditional semantic memory measures, and a nonverbal test . Although AD affects various types of memory, effective treatments that could prevent and reverse memory impairments in AD are still limited.
Amyloid beta (Aβ) and tau
AD's two pathological hallmarks are known to be Aβ and neurofibrillary tangle (NFT) in the brain. Deposits of accumulated Aβ peptide were found within the interstitial space in the brains of AD patients. Aβ monomers can form higher-order assemblies to become dimers, trimers, tetramers, oligomers, and fibrils . Accumulating Aβ can propagate excitatory synaptic alterations and loss of synaptic plasticity potential , which induces an inflammatory response, neurotransmission dysfunction, neuronal loss, and memory impairment . Tau proteins are proteins that stabilize microtubules. They are abundant in the neurons of the central nervous system (CNS). The excessive or abnormal phosphorylation of tau results in the transformation of normal tau into NFTs. NFTs phosphorylated at S262 were found in the early pathological process of AD, which is more toxic to neurons than phosphorylation at other sites .
Neuroinflammation is a significant early pathology of AD, which can be initiated by Aβ aggregation and the formation of NFTs . On the other hand, increased inflammatory responses in the CNS caused by trauma, infection, and toxins can also stimulate the progressive activation of astrocytes and microglia, leading to the accumulation of Aβ and NFTs . Microglia are present in the brain with different activation states according to its function and morphology, including resting, activated, and phagocytic microglia. The microglia cells protect and maintain CNS by acting on injury repair and pathogen infection. The imbalance of proinflammatory (M1)/immunosuppressive (M2) ratio is associated with neuronal dysfunction and neuronal loss in AD . Aβ aggregation can stimulate microglia to acquire M1 phenotype and release interleukin-1β (IL-1β), IL-1, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), etc., to induce acute inflammation response to avoid neuronal damage. The increase of proinflammatory molecules such as IL-1β, TNF-α, and IFN-γ also interfere with the microglia's capacity to remove Aβ by suppressing microglial endocytic  and phagocytic activities . In modulating acute inflammation to react properly, M2 microglia produces anti-inflammatory cytokines such as IL-4 and IL-10 to prevent the CNS inflammation mechanism from overreacting . It suggests that suppressing neuroinflammation before the onset of AD may be a promising approach to preventing the progression of the disease.
Current treatment of Alzheimer's disease
Effective treatments to prevent and cure AD are limited. Up to date, only five medicines have been approved for AD treatment, including donepezil, galantamine, rivastigmine (cholinesterase inhibitors) , memantine (N-methyl-D-aspartate receptor [NMDAR] antagonist) , and aducanumab (anti-Aβ) . These medicines only delay progressive symptoms of AD but do not prevent neuronal death. The side effects also elicit many concerns. Those patients who took cholinesterase inhibitors showed nausea, vomiting, diarrhea, abdominal cramp, and increased rates of syncope and bradycardia . The side effect of NMDAR antagonist has also been reported, including dizziness, occasional restlessness/agitation, constipation, ocular effects (cataracts, conjunctivitis), nausea, dyspnea, confusion, headache, fatigue, rash, diarrhea, and urinary incontinence . Moreover, the adverse effects of anti-Aβ are related to imaging abnormalities with brain effusion or hemorrhage, confusion or altered mental status, nausea, dizziness, and visual disturbances . Many efforts have been invested in developing amyloid-targeting drugs, and some of them have gone through various phases of clinical trials. However, clearing beta-amyloid may be like putting out a forest fire, which is very difficult to be effective in the late stage of AD. Therefore, shifting to other approaches for AD treatments with fewer side effects, such as reducing chronic inflammation response before onset, would be hopeful.
Chinese herbal extracts
Chinese herbal extracts have been widely used for memory enhancement and inflammation alleviation in East Asian countries, and they are affordable, easy to obtain, natural, and produce fewer side effects . Many Chinese herbal extracts appear to be effective in enhancing memory performance , preventing cognitive decline , and reducing inflammation response . Since the chronic inflammatory response is a cause of learning and memory impairment in AD, Chinese herbal extracts with anti-inflammatory properties [Table 1] reviewed in the following paragraphs may be promising to become preventive treatments for AD.
|Table 1: The Chinese herbal extract's effects on memory and anti-inflammation|
Click here to view
Centella asiatica (C. asiatica), also known as Indian Pennywort, is a member of the plant family Apiaceae. It is well known as an enhancer of cognitive functions . Several studies have demonstrated CA's effect on antidepression, anticonvulsant, neuroprotection, and anti-inflammation . In vitro and in vivo studies showed that C. asiatica effectively improves memory impairment in AD models. C. asiatica extracted with water attenuated the behavioral deficit in AD mouse models ,,. Prolonged treatment of C. asiatica significantly alters Nicotinamide, glycerophospholipid, and purine metabolism associated with AD . C. asiatica's antioxidative property was explored in attenuating AD symptoms , and normal aging . C. asiatica treatment lowered the lipid peroxidation , ROS levels, rescued mitochondrial dysfunction , and restored levels of antioxidative enzymes in the brain. A randomized control study using C. asiatica on healthy elderly population showed improvement in age-related cognitive deficit and mood . Similarly, another study showed improvement in MCI, depression, insomnia, and loss of appetite . Recently, C. asiatica has been included in clinical research to find its effect on the cognitive functions of the elderly; the results are yet to be analyzed . Since C. asiatica is edible, it can be mixed into a diet or served as a nutritional supplement for AD prevention.
Dendrobium catenatum (D. catenatum), also known as D. officinale, is a traditional Chinese medicine and wildly distributed in many countries, including India, Japan, the US, Australia, and China . D. catenatum appears to be safe, indicated with acute toxicity test (12.0 g/kg), genetic toxicity test (Ames test; 1000, 2000, and 4000 mg/kg), and feeding test for 90 days with 1.08, 1.67, and 5.00 g/kg in rats . Previous studies reported that D. catenatum has anti-inflammation ,, anti-aging , and antioxidation effects. D. catenatum treatment could also attenuate ERK, p38 MAPK, and NF-κB signaling pathways in the lung of a chronic obstructive pulmonary disease rat model . In the ovariectomy mouse models, D. catenatum administration could improve memory deficits tested with Morris water maze and decrease Iba-1, IL-1β, and TNF-α expression via activation of Nrf2/HO-1 pathway . In traditional Chinese medicine, D. catenatum was used to remove arthralgia, relieve fever and pain, reinforce kidney function, attenuate irritable bowel syndrome, and build muscles . These studies suggest that the effect of D. catenatum is a potential candidate for preventing AD.
Litsea cubeba (L. cubeba) or Lauraceae is a medicinal plant widely distributed in India, Southeast Asia, southern China, Taiwan, and Japan . It is called “Shan Cang Zi or shan jiao ji” in China and “makauy” in Taiwan. The indigenous people in Taiwan used the essential oil of L. cubeba to cure headaches, inflammation, intoxication, bronchitis, and dyspepsia . The effect of L. cubeba essential oil has been studied in Aβ-induced AD mice and revealed decreasing oxidative stress, brain atrophy, and Aβ plaques. Besides, oral administration of L. cubeba (30.2 mg/day) for 8 weeks could improve spatial and working learning and memory deficit in Aβ-induced AD mice . The L. cubeba essential oil also displayed its effect on anxiolytic and analgesic activities and prolonged sleeping in ICR mice . Furthermore, the study on healthy female subjects demonstrated that L. cubeba essential oil has a sedative effect by decreasing alpha and beta wave powers . In addition, L. cubeba essential oil can improve mood disorders and reduce confusion accompanied with decreased cortisol levels in the saliva of healthy subjects . These studies suggest that L. cubeba essential oil is effective on CNS functions, including anti-inflammatory, antioxidant, memory enhancement, and attention improvement. Therefore, L. cubeba essential oil may be hopeful for AD prevention.
Nardostachys jatamansi (N. jatamansi) belongs to the plant family of Caprifoliaceae. N. jatamansi is widely used in Asian countries as herbal medicine, and its protective effects against neurotoxicity, sleep deprivation, and inflammation have been well studied. N. jatamansi can improve memory performance in diazepam-induced amnesia mice. NJ can also increase the lifespan of drosophila and protect cells from Aβ-42 protein-induced neurotoxicity ,,. Besides, methanolic extract of N. jatamansi reverses the cognitive deficit caused by sleep deprivation . Studies on primary insomnia patients showed that NJ with milk can significantly improve the duration and disturbed sleep . N. jatamansi is known to benefit patients suffering from cognitive disturbances and depression with only one dose . Since sleep deprivation and depression are common symptoms of AD, N. jatamansi can become a possible therapeutic candidate for treating AD.
Convolvulus pluricaulis (C. pluricaulis) is commonly used for memory improvement in Ayurvedic Medhya Rasayana. Old mice (18–20 months) treated with C. pluricaulis extract showed significantly increased memory retention in elevated plus maze compared to the group treated with the marketed drug “piracetam” . The active compound of the C. pluricaulis extract, kaempferol, has anti-inflammatory activity and rejuvenates cerebral infarction in ischemic mice ,. C. pluricaulis extract reduced the anxiety-like and depression-like behavior of the CUMS rats in the open field and forced swimming tests and enhanced memory in contextual fear conditioning and novel object recognition test . It also enhances the long-term potentiation in the hippocampi of rats . C. pluricaulis can also improve survival latency, locomotor activity of human tau-expressing drosophila, by decreasing the tau protein levels, increasing antioxidant enzymes, and acetylcholine neurotransmitters . Administration of herbal mixture with C. pluricaulis as a primary ingredient for 6 weeks improved sleep and energy level in 91% of patients who were undergone treatment . C. pluricaulis extract can effectively enhance learning and memory in various animal models, including mice, rats, and drosophila, making it a promising candidate for treating early-stage AD symptoms.
Magnolia officinalis (MO) is a commonly used herb in Chinese, Japanese, and Korean medicine, added to food or applied to cosmetic products. The bark and flower of MO have been used widely in Chinese medicine for their low toxicity . Several studies have found that MO could improve cognitive deficit and synaptic dysfunction ,. MO treatment also exerts the anti-inflammation effect and helps the activation of phagocytosis of Aβ ,. MO as a dietary supplement for healthy adults reduces daily stress and weekly depression . Thus, MO can be a potential therapeutic target for AD.
Melissa officinalis (M. officinalis) is one of the oldest aromatic plants with an aroma of lemon, which is still used in treating dementia and amnesia . The extract of M. officinalis ameliorates the learning and memory deficits in scopolamine-injected rats by increasing the time spent in the target quadrant of the Morris water maze test . M. officinalis can improve long-term memory in the passive avoidance test along with decreased acetylcholinesterase enzyme activity and increased alterations in the Y-maze test of diabetic rats . In the carrageenan-induced paw edema model, the inflammation response was decreased significantly in rats treated with M. officinalis leaf extract compared with the drug “indomethacin” . Pilocarpine-induced neural death is rescued by the administration of M. officinalis leaf extract. It reduces inflammation by suppressing the proinflammatory cytokines and exhibiting antioxidative activity . The administration of M. officinalis extracts to patients with mild-moderate AD for 4 months significantly improved memory . In addition, M. officinalis extract is an excellent calming agent and is effective for patients disturbed with stress and agitation . Combining M. officinalis extract with other treatments would be a promising preventive approach for AD.
Withania somnifera (W. somnifera) has been used in ayurvedic medicine to enhance memory and cognitive functions. The leaf extract of W. somnifera improved the locomotor activity and memory in rats receiving low-fat or high-fat diets . Pretreatment with W. somnifera root extract enhanced thioacetamide-induced memory deficit and reduced inflammation in rats. Patients with mild-cognitive impairment receiving root extract of W. somnifera for 8 weeks showed a significant improvement in cognitive functions measured with Wechsler Memory Scale . Uptake of W. somnifera root extract for 90 days can improve sleep quality, attention, and memory performance, on the other hand, reducing stress levels in human subjects . The human trials treated with W. somnifera extract showed a significant memory improvement ,,, making it a promising candidate for AD prevention.
Nigella sativa (N. sativa), identified as black cumin or black seeds, is one of the most commonly used herbal medicinal plants which belong to the Ranunculaceae family. It grows annually in the Mediterranean region, Europe, and Asia ,. It is used for treating various diseases for its antibacterial, anticancer, antioxidative, antidiabetic, neuroprotective, gastroprotective, immunomodulatory, antihistaminic, and anti-inflammatory activities. In a placebo-controlled clinical trial, 40 healthy elderly volunteers were administered NS seed capsule twice a day for 9 weeks and showed improvement in cognition, memory, and attention . Another study reported similar results in 48 healthy adolescent males treated with N. sativa capsules once per day for 4 weeks showed mood stability and decreased anxiety . Thymoquinone bioactive constituent of N. sativa, elevated SOD, CAT levels and decreased caspase 3 level in amyloid beta-induced U87, a human astrocytoma cell line, thus protecting against oxidative stress and cellular death . Hydroalcoholic extract of N. sativa (100, 200, or 400 mg/kg) decreased TNF-alpha and NO expression levels and improved spatial memory performance and retention in LPS-treated rats . In a pentylenetetrazole-induced seizure rat model, 400 mg/kg treatment with N. sativa increased spatial memory and memory retention . Taken together, N. sativa may be a promising therapeutic candidate for AD prevention.
| Conclusion|| |
The excessive inflammatory response is an initiation factor of AD, which can induce later disease pathologies, including Aβ aggregation, NFTs, synaptic dysfunction, neuronal loss, and cognitive impairment. Unfortunately, the current AD treatments have limited success in preventing or curing the disease and caused many side effects. However, as studies reviewed in this paper, several Chinese herbal medicines may be promising in preventing AD. Many Chinese herbal extracts effectively decrease inflammation response, enhance memory performance, and prevent cognitive impairment in vitro, in vivo, and in human studies. Therefore, taking Chinese herbal medicines that are natural, affordable, and produce fewer side effects may become a promising therapeutic approach to preventing AD.
Financial support and sponsorship
This review article is supported by the Buddhist Tzu Chi Medical Foundation “TCMF-SP 108-04”.
Conflicts of interest
Prof. Ingrid Y. Liu, an editorial board member at Tzu Chi Med J, had no role in the peer review process of or decision to publish this article. The other authors declared no conflicts of interest in writing this paper.
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