Neuroprotective Herbs and Active Constituents
Approaches to Preventing Degenerative Diseases
Considerable efforts have been made in recent decades to discover which substances can help prevent serious diseases and even limit the effects of the aging process. Foremost in this area has been research into the role of antioxidants, which come in numerous forms, such as vitamins, minerals, phenolic constituents, and sulfur compounds, from both foods and herbs. These substances may inhibit, among other things, development of cardiovascular diseases and cancer; the evidence for this effect is fairly strong. To get the benefits, the antioxidants must be ingested over a period of years in quantities sufficient to yield the desired effects. The quantities needed to attain measurable effects are often easily within reach through dietary habits. A number of common foods and beverages, such as broccoli, apples, blueberries, wine, and tea (to name but a few), have been identified as beneficial. Antioxidant properties of medicinal and beverage herbs and their active ingredients have been evaluated to determine how these might best fit into a healthful regimen. Several herbal teas appear of potential benefit, including the popular Rooibos tea of South Africa. Ordinary kitchen spices, including rosemary, basil, turmeric, and cumin, have been shown to have potent antioxidant action.
The effect of antioxidants is to control damage that is caused by oxidative compounds, mainly free radicals (also called reactive oxidative species, ROS). A free radical is a charged molecule that readily interacts with molecules it encounters to cause oxidation, which damages complex biological molecules: it alters the properties and functions of the affected molecules. Free radicals are produced naturally by metabolism, particularly from our utilization of oxygen (the primary "oxidizing" agent). To avoid damage by these processes, the body has a well adapted system of antioxidant molecules that neutralize the free radicals. A couple of well-known antioxidant systems are superoxide dysmutase (SOD) and glutathione. These antioxidant systems work well in the healthy, young body, but with aging they may become inadequate, and there can be genetic factors that lead to deficiencies of these systems. It is thought that there is then a degenerative effect: with less antioxidant protection, there is more damage; with more damage there is even less antioxidant protection.
Not all the protection comes from antioxidants produced in the body as its free radical "surveillance" system. A significant amount comes from dietary components that also serve as antioxidants. Diets vary considerably among individuals and population groups, and the antioxidant ingestion can have a very wide range. Fruits, vegetables, and certain beverages are particularly rich sources. It was recently reported that coffee is the primary source of antioxidants in the American diet, showing both its value and also the lack of antioxidant rich vegetables and fruits in eating habits common to this country (red wine and beer are also among the top ten sources of flavonoids in the U.S.). A major aspect of government sponsored and dietician inspired promotions for improving the American diet is to cajole people into consuming the recommended "five servings a day" of fruits and vegetables.
The initial discovery of the importance of dietary antioxidants is traced to population studies correlating dietary habits and incidence of serious diseases, such as cardiovascular diseases (the primary cause of premature death in the U.S. and most developed countries). Certain dietary components have been shown to reduce the incidence of these and other diseases, and one of the common features is the presence of antioxidants. However, that is not always the entire story. As an example, wine consumption has been shown to be associated with not only lowering cardiovascular disease but also with lengthening the life span (on average). This effect is observed for those who drink moderate amounts compared to those who avoid or minimize the beverage and those who drink to excess. One aspect of this effect comes from the antioxidant and circulation promoting action of anthocyanidins and other phenolic compounds that are found in grapes (more so in red or purple grapes); the same effect could be attained from drinking unfermented grape juice (and also from some other fruit juices), though there is little data for this effect since juice is consumed far less frequently than wine. One of the main active components of the grapes is resveratrol, which is included in dietary supplements, and is present in the Chinese herb huzhang (Polygonum cuspidatum), the main raw material for making the supplements. However, a possibly stronger health benefit comes from the alcohol itself, which is absent from plain grape juice and dietary supplements, but is present (and still effective) in beer and liquor. Thus, although the antioxidants are undoubtedly of benefit, they are not the whole story. Alcohol does not act as an antioxidant but has other effects, possibly related to the relaxing action that alcohol consumers notice. This situation is instructive in that avoidance of alcohol was often recommended by proponents of good health and this was largely on the basis of seeing the harm done by excessive alcohol consumption. However, viewing the negative effects of overdosing doesn't shed light on the possibility of beneficial effects from reasonable quantities. There is a somewhat similar situation in the case of coffee consumption; its antioxidants have a certain benefit, but there are also neuroprotective effects from caffeine (as will be mentioned below), which is not one of the antioxidants.
Following up on the study methods used to determine dietary components helpful in preventing cardiovascular diseases, a newer area of concern is the prevention of neurodegenerative diseases: conditions such as Parkinson's disease and Alzheimer's disease, as well as stroke (which is also in the category of cardiovascular disease). Antioxidants evidently play a role in protecting neurons; a few specific herbs and their active ingredients have been identified as particularly of value and will be discussed here. Antioxidants are not the only active compounds; substances that may stimulate or sedate the nervous system and those that reduce inflammation also help. The methods suggested to protect against brain damage may seem surprising; for example, laboratory results indicate the possibility of protection from stroke from consumption of caffeine plus alcohol (dubbed "caffeinol"). Although no one is recommending cigarette smoking, nicotine evidently protects against Parkinson's disease, based on studies of people's tobacco using habits.
Because clear evidence of protective effects in humans requires long-term administration of the substance and monitoring over a period of years to detect differences in incidence of neurodegenerative diseases, prospective clinical trials are lacking. The best evidence thus far is based on collecting data from large populations of people with or without a degenerative disease and comparing their history of using various substances. For many people, there are certain habits that are more-or-less consistent, such as drinking coffee or tea or alcoholic beverages, and eating certain types of foods (e.g., eating an apple a day); people that avoid certain foods and beverages are also well aware of their avoidance of them. Thus, some items can be relatively easily tracked. This data can then be used to seek correlations between ingestion of substances and incidence of degenerative diseases, suggesting either protective or harmful effects. The rest of the work is done in laboratory animals. By using appropriate models, one can detect certain protective effects or, at least, a potential for protective effects with short-term studies. Alternatively, one can look for regenerative effects; the regrowth of dendrites, for example, is both a useful repair mechanism for severe damage and a means of repairing minor damage that occurs at the beginning of a degenerative disease process, delaying onset of symptoms. Part of the problem with these laboratory studies, however, is that the monitoring involves only models of human conditions, which may or may not successfully match actual human conditions. The studies may be done with animals or with isolated brain tissues.
An example is a screening of herbs for ability to regenerate the neuronal network (1). Three active components of herbs were identified as potentially useful: panaxadiol (a group of ginsenosides) from ginseng, withanolides from ashwaganda (an Ayurvedic herb), and trigonelline from coffee beans. Ginseng and ashwaganda are logical choices for testing because these have been used for treatment and prevention of numerous diseases; coffee is an obvious choice because there is strong evidence from several population studies that it has potent neuroprotective effects. In the study, brain tissue taken from laboratory animals was atrophied by ί-amyloid, the substance that accumulates in the brains of Alzheimer's patients; then the herb extracts were added to see if dendrite formation could be detected. The compounds of interest were also tested in live mice that had an induced Alzheimer's-like disorder, using a memory test, suggesting that these natural substances were also useful in live animals.
The three test substances may be of value for humans. One of the difficulties in translating such studies to clinical use has to do with the duration of treatment. The laboratory study involves creating a disease condition immediately and testing the effects of applying the herb components for a very short time. By contrast, the patient with a diagnosis of Alzheimer's disease had a gradual process of brain damage developing for years and will be treated for months or years. The question arises: does the therapeutic effect indicated by the laboratory experiments produce results in the human where there are some similarities but a different process of disease development? If these substances have a benefit for humans that is reflected in the laboratory studies, then moderate doses consumed regularly over years might be able to prevent or at least slow development of the disease; they might even benefit those who already have a neurological disease.
The following are herbs that have multiple reports of potential benefits in neuroprotection and neurorepair. To help accurately present the type of research involved, for each one, at least two examples of recent medical journal abstracts (from 2001-2005) are included. The abstracts are found on the PubMed website (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi); statements of particular interest are in bold print, added for this report. The subjects to be covered are: coffee and tea; curry and curcumin; scute; salvia; ginseng; and others (with mention of licorice, forsythia, lonicera, fish oil, and the contribution of fitness).
Though many think of herbs as alternatives to coffee, this common beverage is also from an herb. There is clear evidence that Parkinson's disease occurs with much less frequency among regular coffee and tea drinkers than among those who avoid or minimize the beverage. An active constituent providing neuroprotection is the caffeine, though, as indicated above, trigonelline from coffee may also be effective.
From the Department of Neurology, Singapore General Hospital, Singapore (2):
INTRODUCTION: Few studies have examined the relationship of coffee and tea in Parkinson's disease (PD). The potential protective effect of coffee intake and risk of PD has not been studied in a Chinese population. There is a high prevalence of caffeine takers among Chinese in our population. OBJECTIVE: We undertook a case control study to examine the relationship between coffee and tea drinking, cigarette smoking, and other environmental factors and risk of PD among ethnic Chinese in our population. METHODS AND RESULTS: 300 PD and 500 population controls were initially screened. Two hundred case control pairs matched for age, gender, and race were finally included in the analysis. Univariate analysis revealed significant association of PD with coffee drinking (p<0.0005), tea drinking (p=0.019), alcohol drinking (p=0.001), cigarette smoking (p<0.0005), and exposure to heavy metals (p=0.006). Conditional logistic regression analysis demonstrated that amount of coffee drunk (OR 0.787, 95%CI 0.664-0.932, p=0.006), amount of tea drunk (OR 0.724, 95%CI 0.559-0.937, p=0.014), number of cigarettes smoked (OR 0.384, 95%CI 0.204-0.722, p=0.003), history of heavy metal and toxin exposure (OR 11.837, 95%CI 1.075-130.366, p=0.044), and heart disease (OR 5.518, 95%CI 1.377-22.116, p=0.016) to be significant factors associated with PD. One unit of coffee and tea (3 cups/day for 10 years) would lead to a 22% and 28% risk reduction of PD. One unit of cigarette smoke (3 packs/day for 10 years) reduced the risk of PD by 62%. CONCLUSIONS: We demonstrated a dose-dependent protective effect of PD in coffee and tea drinkers and smokers in an ethnic Chinese population. A history of exposure to heavy metals increased the risk of PD, supporting the multifactorial etiologies of the disease.
From the Department of Veterans Affairs, Honolulu, Hawaii, USA (3):
Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting 1-3% of individuals over the age of 65 years. While effective therapy exists for treating the bradykinesia, rigidity and tremor associated with the disease, the cause is unknown. There is no treatment available to prevent or slow the progressive neuronal loss in the substantia nigra and associated decreased levels of dopamine in the striatum that underlie the cardinal features of the disease. Both retrospective and prospective epidemiological studies have consistently demonstrated an inverse association between cigarette smoking and PD, leading to theories that smoking in general and nicotine in particular might be neuroprotective. Nicotine has been shown in animals to stimulate the release of dopamine in the striatum, and to preserve nigral neurons and striatal dopamine levels in laboratory animals with lesioned nigrostriatal pathways. Coffee and caffeine consumption have also been shown in epidemiological studies to be inversely related to PD risk. Caffeine is an adenosine A(2A) receptor antagonist that enhances locomotor activity in animal models of Parkinsonism. Theophylline, a related compound that has A(2A) receptor blocking properties, has been shown in one small trial to improve motor function in patients with PD. Recently, potent and highly selective A(2A) receptor antagonists have been developed that have demonstrated improvement in motor function in animal models of Parkinsonism. Exciting findings are emerging that demonstrate attenuation of dopaminergic neurotoxicity with caffeine and other adenosine receptor antagonists in mice given the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), suggesting that these compounds may be neuroprotective. Evidence for the neuroprotective potential of nicotine and caffeine is compelling, but further work is needed before testing these and related compounds in clinical trials for both individuals at high risk of developing PD and those with early, untreated disease.
From the Molecular Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital, Charlestown, Massachusetts, USA (4):
Recent epidemiological studies have established an association between the common consumption of coffee or other caffeinated beverages and a reduced risk of developing Parkinson's disease (PD). To explore the possibility that caffeine helps prevent the dopaminergic deficits characteristic of PD, we investigated the effects of caffeine and the adenosine receptor subtypes through which it may act in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model of PD. Caffeine, at doses comparable to those of typical human exposure, attenuated MPTP-induced loss of striatal dopamine and dopamine transporter binding sites. The effects of caffeine were mimicked by several A(2A) antagonists …and by genetic inactivation of the A(2A) receptor, but not by A(1) receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine, suggesting that caffeine attenuates MPTP toxicity by A(2A) receptor blockade. These data establish a potential neural basis for the inverse association of caffeine with the development of PD, and they enhance the potential of A(2A) antagonists as a novel treatment for this neurodegenerative disease.
The bright yellow color in curry powder is from the ground root of turmeric (a relative of ginger); its main active constituent, which is also bright yellow in color, is curcumin. Curcumin has been under investigation for numerous potential benefits, including antiviral, anticancer, and anti-inflammatory activity. The potential neuroprotective actions of this substance were discovered during a screening of its potential to protect against the adverse effects from high doses of alcohol, which revealed positive results (reported in 1999). Since then, studies have indicated potential benefits for Alzheimer's disease and Parkinson's disease, based on laboratory animal models; clinical work is now beginning (as relayed in the first abstract, below).
From the University of California, Los Angeles, Department of Neurology, Alzheimer's Disease Research Center, Los Angeles, CA USA (5):
There is substantial in-vitro data indicating that curcumin has antioxidant, anti-inflammatory, and anti-amyloid activity. In addition, studies in animal models of Alzheimer's disease (AD) indicate a direct effect of curcumin in decreasing the amyloid pathology of AD. As the widespread use of curcumin as a food additive and relatively small short-term studies in humans suggest safety, curcumin is a promising agent in the treatment and/or prevention of AD. Nonetheless, important information regarding curcumin bioavailability, safety and tolerability, particularly in an elderly population is lacking. We are therefore performing a study of curcumin in patients with AD to gather this information in addition to data on the effect of curcumin on biomarkers of AD pathology.
From the Veterans Administration Medical Center, North Hills, CA (6):
Both oxidative damage and inflammation are elevated in brains of Alzheimer's disease (AD) patients, but their pathogenic significance remains unclear. The reduced AD risk associated with high intake of both nonsteroidal anti-inflammatory drugs (NSAIDs) and antioxidants suggests causal roles, but clinical trials in AD patients have yielded only limited or negative results. To test the potential efficacy and mechanisms of candidate approaches, we have explored conventional and unconventional NSAIDs, antioxidants, and combined NSAID/antioxidants in cell culture and animal models for AD (including aging APPsw transgenic mice and soluble Abeta rodent infusion models). The conventional NSAID ibuprofen has the strongest epidemiological support. At sustainable doses designed to mimic protective consumption in the epidemiology, ibuprofen reduces amyloid accumulation but suppresses a surprisingly limited subset of inflammatory markers in APPsw transgenic mice. Both Ab production (APP, beta- and gamma-secretases) and post-production pathways (those affecting Abeta aggregation or clearance: e.g., IL-1 or alpha1ACT) are potentially involved in ibuprofen and other NSAID anti-AD activities. The post-production pathways are predictably shared with other seemingly protective NSAIDs, including naproxen, that do not lower Abeta42 in vitro. Using clinically feasible dosing, brain levels of NSAIDs appear too low to implicate a number of pharmacological dose targets that have been demonstrated in vitro. Ibuprofen did not suppress microglial markers related to phagocytosis. The putative anti-inflammatory omega-3 fatty acid DHA had a profound impact on pathogenesis but did not lower inflammation, while vitamin E was surprisingly ineffective in reducing oxidative damage or amyloid in the aged APPsw mouse. In contrast, the unconventional NSAID/antioxidant curcumin was effective, lowering oxidative damage, cognitive deficits, synaptic marker loss, and amyloid deposition. Curcumin proved to be immunomodulatory, simultaneously inhibiting cytokine and microglial activation indices related to neurotoxicity, but increasing an index of phagocytosis. Curcumin directly targeted Abeta and was also effective in other models, warranting further preclinical and clinical exploration.
From the Department of Biochemistry, University of Missouri, Columbia, Missouri, USA (7):
Increased oxidative stress has been regarded as an important underlying cause for neuronal damage induced by cerebral ischemia/reperfusion (I/R) injury. In recent years, there has been increasing interest in investigating polyphenols from botanical source for possible neuroprotective effects against neurodegenerative diseases. In this study, we investigated the mechanisms underlying the neuroprotective effects of curcumin, a potent polyphenol antioxidant enriched in tumeric. Global cerebral ischemia was induced in Mongolian gerbils by transient occlusion of the common carotid arteries. Histochemical analysis indicated extensive neuronal death together with increased reactive astrocytes and microglial cells in the hippocampal CA1 area at 4 days after I/R. These ischemic changes were preceded by a rapid increase in lipid peroxidation and followed by decrease in mitochondrial membrane potential, increased cytochrome c release, and subsequently caspase-3 activation and apoptosis. Administration of curcumin by i.p. injections (30 mg/kg body wt) or by supplementation to the AIN76 diet (2.0 g/kg diet) for 2 months significantly attenuated ischemia-induced neuronal death as well as glial activation. Curcumin administration also decreased lipid peroxidation, mitochondrial dysfunction, and the apoptotic indices. The biochemical changes resulting from curcumin also correlated well with its ability to ameliorate the changes in locomotor activity induced by I/R. Bioavailability study indicated a rapid increase in curcumin in plasma and brain within 1 hr after treatment. Together, these findings attribute the neuroprotective effect of curcumin against I/R-induced neuronal damage to its antioxidant capacity in reducing oxidative stress and the signaling cascade leading to apoptotic cell death.
The flavonoids of scute (huangqin; Scutellaria baicalensis) have been studied intensively because they show a potent and broad therapeutic benefit and no toxicity in moderately high clinical doses. Baicalin, baicalein, and wogonin have been isolated and evaluated for anti-inflammatory and neuroprotective actions. They have mainly been tested in models of brain damage associated with stroke. Flavonoids have a number of beneficial actions, which have been described, in part, in the ITM article Flavonoids for Health.
From the Department of Anatomy and Neurobiology, Research Institute of Natural Science, Gyeongsang National University College of Medicine, Kyungnam, Korea (8):
Wogonin (5,7-dihydroxy-8-methoxyflavone), a flavonoid originated from the root of a medicinal herb Scutellaria baicalensis Georgi, has been previously shown to have anti-inflammatory activities in various cell types including macrophages. In this work, we have found that wogonin is a potent neuroprotector from natural source. Wogonin inhibited inflammatory activation of cultured brain microglia by diminishing lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta, and nitric oxide (NO) production. Wogonin inhibited NO production by suppressing inducible NO synthase (iNOS) induction and NF-kappaB activation in microglia. Inhibition of inflammatory activation of microglia by wogonin led to the reduction in microglial cytotoxicity toward cocultured PC12 cells, supporting a neuroprotective role for wogonin in vitro. The neuroprotective effect of wogonin was further demonstrated in vivo using two experimental brain injury models; transient global ischemia by four-vessel occlusion and excitotoxic injury by systemic kainate injection. In both animal models, wogonin conferred neuroprotection by attenuating the death of hippocampal neurons, and the neuroprotective effect was associated with inhibition of the inflammatory activation of microglia. Hippocampal induction of inflammatory mediators such as iNOS and TNF-alpha was reduced by wogonin in the global ischemia model, and microglial activation was markedly down-regulated by wogonin in the kainate injection model as judged by microglia-specific isolectin B4 staining. Taken together, our results indicate that wogonin exerts its neuroprotective effect by inhibiting microglial activation, which is a critical component of pathogenic inflammatory responses in neurodegenerative diseases. The current study emphasizes the importance of medicinal herbs and their constituents as an invaluable source for the development of novel neuroprotective drugs.
From the Department of Pharmacology, College of Medicine, Dongguk University, Gyeongbuk, Korea (9):
The present study evaluated the effect of wogonin, a flavonoid originated from the root of Scutellaria baicalensis GEORGI, on focal ischemic brain injury in rats. Focal brain ischemia was induced by the permanent occlusion of middle cerebral artery (pMCAO) for 24 h with a silicone rubber cylinder inserted through the right internal carotid artery. We found that wogonin, intraperitoneally administered at a dosage of 20 mg/kg at 30 min before and 4 h after the surgery, reduced the pMCAO-induced infarct areas in the cerebral cortex as well as in the striatum. The total volume of infarction was significantly reduced by the treatment with wogonin. In addition, wogonin was found to significantly improve the pMCAO-induced behavioral deficits at 24 h after the surgery. Taken together, these results demonstrate that wogonin inhibits ischemic brain injury and improves behavioral dysfunction caused by pMCAO. These findings, along with previous reports demonstrating the neuroprotective effects of wogonin, provide strong pharmacological basis for the use of wogonin or Scutellaria baicalensis in the treatment of stroke.
From the Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou, China (10):
Baicalin is a flavonoid derivative from Scutellaria baicalensis Georgi with various pharmacological effects. Recently, the neuroprotective effect of baicalin was reported. To confirm this effect and explore the possible mechanism, we have investigated the protective effect of baicalin on ischaemiclike or excitotoxic injury and the activation of protein kinase C alpha (PKC(alpha)) in rat hippocampal slices. In-vitro ischaemic-like injury was induced by oxygen/glucose deprivation (OGD) and the excitotoxic injury by N-methyl-D-aspartate (NMDA). The viability and swelling of the slices were detected by triphenyltetrazolium chloride (TTC) staining and image analysis of light transmittance (LT), respectively. The translocation of PKC(alpha) was measured by immunoblotting. Baicalin was added during both injuries. Baicalin (0.1, 1, and 10 micromol L(-1)) concentration-dependently inhibited OGD-induced viability reduction and acute neuron swelling, and inhibited the increased portion of PKC(alpha) present in the membrane fraction over the total PKC(alpha). Baicalin ameliorated NMDA-induced viability reduction (not LT elevation) and inhibited the NMDA-increased membrane portion of PKC(alpha) at 1 micromol L(-1). We concluded that baicalin had a protective effect on ischaemic-like or excitotoxic injury in rat hippocampal slices, which might have been partly related to inhibition of PKC(alpha) translocation.
The benefits of salvia for promoting circulation and for alleviating fibrosis have been extensively described with research over several decades (see: Salvia and the history of microcirculation research). Continuing investigation suggests neuroprotective effects from the herb and its active components, which include tanshinones and salvianic acid. These compounds are being studied especially in relation to Parkinson's disease and stroke.
From the Department of Biology, Molecular Neuroscience Center and Biotechnology Research Institute, Hong Kong University of Science and Technology, Kowloon, China (11):
Tanshinones are the major lipid soluble pharmacological constituents of Danshen, the dried roots of Salvia miltiorrhiza Bunge (Labiatae), a well known traditional Chinese medicine used for the treatment of cerebrovascular diseases including stroke. Potential neuroprotective effects of tanshinones IIA (TsIIA) and IIB (TsIIB) were examined in adult mice subjected to transient focal cerebral ischemia caused by middle cerebral artery occlusion (MCAo). Our results revealed that TsIIA (16 mg/kg) readily penetrated the blood brain barrier reaching a peak concentration of 0.41 nmol/g brain wet weight 60 minutes after intraperitoneal injection and decreased slowly over several hours. Twenty-four hours after middle cerebral artery occlusion, brain infarct volume was reduced by 30% and 37% following treatment with TsIIA and TsIIB, respectively. The reduction in brain infarct volume was accompanied by a significant decrease in the observed neurological deficit. Tanshinones or other structurally related compounds may have potential for further development as neuroprotective drugs.
From the Institute of Biophysics, Chinese Academy of Sciences, Beijing, China (12):
1-methyl-4-phenylpyridinium ion (MPP(+)), an inhibitor of mitochondrial complex I, has been widely used as a neurotoxin because it elicits a severe Parkinson's disease-like syndrome with elevation of intracellular reactive oxygen species (ROS) level and apoptotic death. Salvianic acid A (SA), isolated from the Chinese herbal medicine Salvia miltiorrhiza, is capable of protecting diverse kinds of cells from damage caused by a variety of toxic stimuli. In the present study, we investigated the protective effects of SA on MPP(+)-induced cytotoxicity in human neuroblastoma SH-SY5Y cells, as well as the underlying mechanism. Treatment of SH-SY5Y cells with MPP(+) caused the loss of cell viability, and condensation and fragmentation of nuclei, which was associated with the elevation of ROS level, the increase in Bax/Bcl-2 ratio, and the activation of caspase-3. MPP(+) induced mitochondria dysfunction characterized by mitochondrial membrane potential loss and cytochrome c release. These phenotypes induced by MPP(+) were reversed by SA. Our results suggested that the protective effects of SA on MPP(+)-induced cytotoxicity may be ascribed to its antioxidative properties and anti-apoptotic activity via regulating the expression of Bcl-2 and Bax. These data indicated that SA might provide a useful therapeutic strategy for the treatment of progressive neurodegenerative disease such as Parkinson's disease.
Ginseng is one of the most widely used of all traditional Chinese herbs. It has been extensively evaluated, though problems with establishing an appropriate dosage have led to conflicting interpretations of the validity of claims made on the basis of such studies (see: The nature of ginseng). Laboratory investigations with isolated ginsenosides demonstrate its pharmacological potential, but successful human use may require ingestion of dosages higher than available in many of the most widely distributed ginseng products. For example, some products offer 40 mg or less of ginsenosides, but doses in the range of 60-240 mg per day may be essential to gaining reliable results. Neuroprotective effects are now being investigated (1).
From the Department of Physiology, Faculty of Medicine, University of Alberta, Edmonton, Alberta, Canada (13):
The ginsenosides have many pharmacological actions, including various actions on the nervous system. Our previous studies have demonstrated that two ginsenosides, Rb(1) and Rg(1) improve performance in a passive avoidance-learning paradigm and enhance cholinergic metabolism. The present study was designed to examine the cellular neurotrophic and neuroprotective actions of two pure ginsenosides in two model systems. PC12 cells were grown in the absence or presence of nerve growth factor (NGF) as a positive control, and different concentrations of Rb(1) or Rg(1). To assess neurotrophic properties, neurite outgrowth was quantified for representative fields of cells. After 8 days in culture, both ginsenosides enhanced neurite outgrowth in the presence of a sub-optimal dose of (2 ng/ml) NGF, but did not significantly stimulate neurite outgrowth in the absence of NGF. However, after 18 days in culture, both ginsenosides increased neurite outgrowth in the absence of NGF. SN-K-SH cells were grown in the absence or presence of MPTP or beta-amyloid to assess neuroprotection. Rb(1) and Rg(1) both reversed MPTP-induced cell death. beta-Amyloid-induced cell death was not reversed by either ginsenoside, but Rg(1) produced a modest enhancement of cell death in this model. These results suggest that these two ginsenosides have neurotrophic and selective neuroprotective actions that may contribute to the purported enhancement of cognitive function.
From the Department of Immunology, College of Pharmacy, Chung-Ang University, Seoul, Korea (14):
Ginsenosides, the active compounds inherent to most Ginseng species [e. g., Panax ginseng (Araliaceae)], have recently been the focus of increased attention, due to both their purported CNS, antineoplastic and immunomodulatory effects, and their ability to stimulate phagocytosis. In this study, we attempted to determine the effects of ginsenosides Rb1 and Rg1 in a rat model, with specific emphasis on nitric oxide and cytokines, which have been implicated in chronic brain inflammation. We discovered that Rb1 and Rg1 exert opposite effects in a dose-dependent manner (50-250 microg/mL). Whereas Rg1 stimulated nitric oxide and proinflammatory cytokines (IL-1beta, IL-6, and TNF-alpha), Rb1 exerted a significant inhibitory effect on this proinflammatory repertoire. In addition, the genetic expression of bcl-2 and bax, both of which have been implicated in apoptosis, was regulated by treatment with Rb1 and Rg1, at a concentration of 250 microg/mL. Moreover, when combined treatment with equal doses of Rb1 and Rg1 was given, Rb1 significantly counteracted the stimulatory effects of Rg1, as evidenced by an NO assay. This effect persisted stably for 72 h. In conclusion, neurodegenerative diseases such as Alzheimer's disease, which is caused primarily by cell death due to chronic inflammation and cell stress, might be controlled by proper doses of non-toxic, natural Rg1 and Rb1.
Aside from herbs, certain foods and supplements derived from them may provide protection, via anti-inflammatory, antioxidant, or other mechanisms. The role of inflammation and the possible use of natural anti-inflammatory agents is especially important as depicted in the following article:
From the Department of Pharmacology, University of Sassari Medical School, Sassari, Italy (15):
A sustained inflammatory reaction is present in acute (e.g. stroke) and chronic (e.g. Alzheimer's disease, Parkinson's disease and multiple sclerosis) neurodegenerative disorders. Inflammation, which is fostered by both residential glial cells and blood-circulating cells that infiltrate the diseased brain, probably starts as a time- and site-specific defense mechanism that could later evolve into a destructive and uncontrolled reaction. In this article, we review the crucial dichotomy of brain inflammation, where failure to resolve an acute beneficial response could lead to a vicious and anarchic state of chronic activation. The possible use of non-steroidal anti-inflammatory drugs for the management of neurodegenerative diseases is discussed in light of recent data demonstrating a neuroprotective role of local innate and adaptive immune responses. Novel therapeutic approaches must rely on potentiation of endogenous anti-inflammatory pathways, identification of early markers of neuronal deterioration and a combination treatment involving immune modulation and anti-inflammatory therapies.
One of the means of providing anti-inflammatory and immune modulating effects is through ingestion of fish, particularly the fish oil component, which may be used as a supplement to obtain sufficient quantities of the desired components, especially DHA (6). Among the anti-inflammation Chinese herbs are licorice, forsythia, and lonicera (16); the herbs described above, especially scute, provide anti-inflammatory effects.
Finally, it is important to mention the beneficial role of exercise. This subject was reviewed:
From the Beckman Institute, University of Illinois, 405 N. Mathews Ave, Urbana, IL, USA (17):
In this manuscript we provide a brief review of the recent literature that has examined the relationship among fitness training, cognition and brain. We began with a discussion of the non-human animal literature that has examined the relationship among these factors. Next we discuss recent epidemiological studies of the relationship between physical activity and fitness and cognition and age-related disease such as Alzheimer's dementia. We then discuss the results of randomized clinical trials of fitness training on human cognition. Finally, we conclude with a review of the nascent literature that has begun to employ neuroimaging techniques to examine fitness training effects on human brain. In general, the results are promising and suggest that fitness may serve a neuroprotective function for aging humans.
In sum, there is much work to do in this field before we can arrive at an ideal therapeutic approach to neuroprotection and neurorecovery. Only a few substances have been studied in depth, and much of the work is in the preliminary stages. Natural caffeine-containing beverages, such as coffee and tea, are already consumed by a large proportion of the population and appear quite helpful. In one evaluation, it was suggested that 3 cups per day is a quantity sufficient to obtain a measurable protective effect. Curry is used in some parts of the world routinely (e.g., India and Indonesia), but it might be of benefit to promote wider use; in addition, capsules containing 95% pure curcumin extracted from turmeric are readily available as a supplement. Ginseng, scute, and salvia are frequently used in the practice of traditional Chinese medicine. Ginseng has a long history of use, while salvia has become popular in recent decades; the evidence supportive of more widespread use of scute (not just for neuroprotection) is impressive. Other Chinese herbs, such as huzhang, licorice, lonicera, and forsythia are also receiving significant attention for treatment of several diseases. Fish consumption has been suggested as a healthful practice on the basis of reduction of cardiovascular disease incidence, and the oils are known to be important for reducing inflammation, with the component DHA (docosahexaenoic acid) being especially valuable for brain function. The herbs mentioned in this article have a reputation for safety, even though they haven't yet been adequately studied for use in protecting against neurological diseases. Certainly, under the guidance of a trained health professional, people should be able to begin a regimen of protective and restorative therapy now.