Therapeutic Potential of Traditional Oriental Medicines in Targeting Tau Pathology: Insights from Cell-free and Cell-based Screening.

BACKGROUND: Traditional Oriental Medicines (TOMs) formulated using a variety of medicinal plants have a low risk of side effects. In previous studies, five TOMs, namely Dangguijakyaksan, Hwanglyeonhaedoktang, Ukgansan, Palmijihwanghwan, and Jowiseungchungtang have been commonly used to treat patients with Alzheimer's disease. However, only a few studies have investigated the effects of these five TOMs on tau pathology. OBJECTIVE: This study aimed to examine the effect of five TOMs on various tau pathologies, including post-translational modifications, aggregation and deposition, tau-induced neurotoxicity, and tau-induced neuroinflammation. METHODS: Immunocytochemistry was used to investigate the hyperphosphorylation of tau induced by okadaic acid. In addition, the thioflavin T assay was used to assess the effects of the TOMs on the inhibition of tau K18 aggregation and the dissociation of tau K18 aggregates. Moreover, a water-soluble tetrazolium-1 assay and a quantitative reverse transcription polymerase chain reaction were used to evaluate the effects of the TOMs on tau-induced neurotoxicity and inflammatory cytokines in HT22 and BV2 cells, respectively. RESULTS: The five TOMs investigated in this study significantly reduced okadaic acid-induced tau hyperphosphorylation. Hwanglyeonhaedoktang inhibited the aggregation of tau and promoted the dissociation of tau aggregates. Dangguijakyaksan and Hwanglyeonhaedoktang attenuated tau-induced neurotoxicity in HT22 cells. In addition, Dangguijakyaksan, Hwanglyeonhaedoktang, Ukgansan, and Palmijihwanghwan reduced tauinduced pro-inflammatory cytokine levels in BV2 cells. CONCLUSION: Our results suggest that five TOMs are potential therapeutic candidates for tau pathology. In particular, Hwanglyeonhaedoktang showed the greatest efficacy among the five TOMs in cell-free and cell-based screening approaches. These findings suggest that Hwanglyeonhaedoktang is suitable for treating AD patients with tau pathology.

Korean red ginseng polysaccharide as a potential therapeutic agent targeting tau pathology in Alzheimer's disease.

Tau is a microtubule-associated protein that plays a critical role in the stabilization and modulation of neuronal axons. Tau pathology is stronger associated with cognitive decline in patients with Alzheimer's disease (AD) than amyloid beta (Aß) pathology. Hence, tau targeting is a promising approach for the treatment of AD. Previous studies have demonstrated that the non-saponin fraction with rich polysaccharide (NFP) from Korean red ginseng (KRG) can modulate tau aggregation and exert a therapeutic effect on AD. Therefore, we investigated the efficacy of NFP isolated from KRG on tau pathology in experimental models of AD. Our results showed that NFP from KRG ameliorated deposition and hyperphosphorylation of tau in the brain of 3xTg mice. Moreover, NFP from KRG modulated the aggregation and dissociation of tau K18 in vitro. We demonstrated the alleviatory effects of NFP from KRG on hyperphosphorylated tau and tau kinase in okadaic acid-treated HT22 cells. Furthermore, NFP from KRG mitigated Aß deposition, neurodegeneration, and neuroinflammation in 3xTg mice. We revealed the neuroprotective effects of NFP from KRG on tau-induced neuronal loss in HT22 cells. Our results indicate that NFP extracted from KRG is a novel therapeutic agent for the treatment of AD associated with tau pathology.

Extract of Aster koraiensis Nakai Leaf Ameliorates Memory Dysfunction via Anti-inflammatory Action.

Aster koraiensis Nakai (AK) leaf reportedly ameliorates health problems, such as diabetes. However, the effects of AK on cognitive dysfunction or memory impairment remain unclear. This study investigated whether AK leaf extract could attenuate cognitive impairment. We found that AK extract reduced the production of nitric oxide (NO), tumour necrosis factor (TNF)-α, phosphorylated-tau (p-tau), and the expression of inflammatory proteins in lipopolysaccharide- or amyloid-ß-treated cells. AK extract exhibited inhibitory activity of control specific binding on N-methyl-D-aspartate (NMDA) receptors. Scopolamine-induced AD models were used chronically in rats and acutely in mice. Relative to negative controls (NC), hippocampal choline acetyltransferase (ChAT) and B-cell lymphoma 2 (Bcl2) activity was increased in rats chronically treated with scopolamine and fed an AK extract-containing diet. In the Y-maze test, spontaneous alterations were increased in the AK extract-fed groups compared to NC. Rats administered AK extract showed increased escape latency in the passive avoidance test. In the hippocampus of rats fed a high-AK extract diet (AKH), the expression of neuroactive ligand-receptor interaction-related genes, including Npy2r, Htr2c, and Rxfp1, was significantly altered. In the Morris water maze assay of mice acutely treated with scopolamine, the swimming times in the target quadrant of AK extract-treated groups increased significantly to the levels of the Donepezil and normal groups. We used Tg6799 Aß-overexpressing 5XFAD transgenic mice to investigate Aß accumulation in animals. In the AD model using 5XFAD, the administration of AK extract decreased amyloid-ß (Aß) accumulation and increased the number of NeuN antibody-reactive cells in the subiculum relative to the control group. In conclusion, AK extract ameliorated memory dysfunction by modulating ChAT activity and Bcl2-related anti-apoptotic pathways, affecting the expression of neuroactive ligand-receptor interaction-related genes and inhibiting Aß accumulation. Therefore, AK extract could be a functional material improving cognition and memory.

Effects of Perilla frutescens var. acuta in amyloid ß toxicity and Alzheimer's disease-like pathology in 5XFAD mice.

Although accumulation of amyloid ß (Aß) plaque is a major hallmark of Alzheimer's disease (AD), various pathologies have been suggested therapeutic targets. Therefore, therapies-targeting multiple pathologies would be required for effective managements of AD. Accordingly, natural products, which has multiple active ingredients, have been receiving a lot of attention. In this study, we tested whether standardized ethanol extract of leaves of Perilla frutescens var. acuta (L.) Britt. (Lamiaceae) (ELPF) could modulate various pathologies in AD using 5XFAD mice. ELPF blocked Aß aggregation and disassembled pre-formed Aß aggregates. ELPF blocked Aß aggregates-induced LTP impairment and ELPF-disassembled Aß aggregates failed to impair hippocampal LTP. Systemic administration of ELPF blocked Aß aggregates-induced memory impairment in a passive avoidance test. ELPF-disassembled Aß aggregates failed to impair passive avoidance memory. Prolonged administration of ELPF ameliorated memory impairments in 5XFAD mice. In the hippocampus of 5XFAD mice, ELPF administration significantly reduced Aß deposits and neuroinflammation. These results demonstrate that ELPF could be a promising therapeutic candidate for AD.

Therapeutic effects of non-saponin fraction with rich polysaccharide from Korean red ginseng on aging and Alzheimer's disease.

Biological aging provokes morbidity and several functional declines, causing older adults more susceptible to a variety of diseases than younger adults. In particular, aging is a major risk factor contributing to non-communicable diseases, such as neurodegenerative disorders. Alzheimer's disease (AD) is an aging-related neurodegenerative disease that is characterized by cognitive deficits and the formation of amyloid plaques formed by the accumulation of amyloid-ß (Aß) peptides. Non-saponin fraction with rich polysaccharide (NFP) from red ginseng, the largest fraction of the components of red ginseng, perform many biological activities. However, it has not been clarified whether the NFP from Korean red ginseng (KRG) has beneficial effects in the aging and AD. First, proteomics analysis was performed in aged brain to identify the effect of NFP on protein changes, and we confirmed that NFP induced changes in proteins related to the neuroprotective- and neurogenic-effects. Next, we investigated (1) the effects of NFP on AD pathologies, such as Aß deposition, neuroinflammation, neurodegeneration, mitochondrial dysfunction, and impaired adult hippocampal neurogenesis (AHN), in 5XFAD transgenic mouse model of AD using immunostaining; (2) the effect of NFP on Aß-mediated mitochondrial respiration deficiency in HT22 mouse hippocampal neuronal cells (HT22) using Seahorse XFp analysis; (3) the effect of NFP on cell proliferation using WST-1 analysis; and (4) the effect of NFP on Aß-induced cognitive dysfunction in 5XFAD mouse model of AD using Y-maze test. Histological analysis indicated that NFP significantly alleviated the accumulation of Aß, neuroinflammation, neuronal loss, and mitochondrial dysfunction in the subiculum of 5XFAD mouse model of AD. In addition, NFP treatment ameliorated mitochondrial deficits in Aß-treated HT22 cells. Moreover, NFP treatment significantly increased the AHN and neuritogenesis of neural stem cells in both healthy and AD brains. Furthermore, NFP significantly increased cell proliferation in the HT22 cells. Finally, NFP administration significantly enhanced and restored the cognitive function of healthy and AD mice, respectively. Taken together, NFP treatment demonstrated changes in proteins involved in central nervous system organization/maintenance in aged brain and ameliorates AD pathology. Collectively, our findings suggest that NFP from KRG could be a potential therapeutic candidate for aging and AD treatments.

Red Ginseng Inhibits Tau Aggregation and Promotes Tau Dissociation In Vitro.

Tau, a microtubule-associated protein expressed in mature neurons, interacts with tubulin to promote the assembly and stabilization of microtubules. However, abnormally hyperphosphorylated tau dissociates from microtubules and self-aggregates. Tau aggregates, including paired helical filaments and neurofibrillary tangles, promote neuronal dysfunction and death and are the defining neuropathological feature of tauopathies. Therefore, suppressing tau aggregation or stimulating the dissociation of tau aggregates has been proposed as an effective strategy for treating neurodegenerative diseases associated with tau pathology such as Alzheimer's disease (AD) and frontotemporal dementia. Interestingly, ginsenosides extracted from Panax ginseng reduced the hippocampal and cortical expression of phosphorylated tau in a rat model of AD. However, no studies have been conducted into the effect of red ginseng (RG) and its components on tau pathology. Here, we evaluated the effect of Korean red ginseng extract (KRGE) and its components on the aggregation and disassociation of tau. Using the thioflavin T assay, we monitored the change in fluorescence produced by the aggregation or disassociation of tau K18, an aggregation-prone fragment of tau441 containing the microtubule-binding domain. Our analysis revealed that KRGE not only inhibited tau aggregation but also promoted the dissociation of tau aggregates. In addition, the KRGE fractions, such as saponin, nonsaponin, and nonsaponin fraction with rich polysaccharide, also inhibited tau aggregation and promoted the dissociation of tau aggregates. Our observations suggest that RG could be a potential therapeutic agent for the treatment of neurodegenerative diseases associated with tauopathy.

Fat-1 expression enhance hippocampal memory in scopolamine-induced amnesia.

Omega-3 polyunsaturated fatty acids (PUFA) are critical for optimal brain health and are involved in psychiatric and neurological ailments. Here, we report the effects of higher endogenous omega-3 PUFA on memory impairment in the hippocampus by studying mice with transgenic expression of the fat-1 gene that converts omega-6 to omega-3 PUFA. We performed Y-maze and passive avoidance tests to evaluate the memory function of fat-1 mice treated with scopolamine. Fat-1 mice showed induced alternation in the Y-maze test and increased latency in the passive avoidance test. The effects of scopolamine on hippocampal neurogenesis were confirmed by increases in the number of Ki-67- and DCX-positive cells in the fat-1 mice. Western blotting revealed increased brain-derived neurotrophic factor (BDNF) and phosphorylated cAMP response element-binding protein levels, and lower scopolamine-induced apoptosis based on the cleaved-caspase 3 protein level in fat-1 mice. These findings suggest that higher endogenous omega-3 PUFA prevented granular cell loss, increased BDNF signaling, and decreased apoptosis signaling in scopolamine-treated fat-1 mice. These processes may underlie granular cell survival and suggest potential therapeutic targets for memory impairment.

Traditional Oriental Medicines and Alzheimer's Disease.

Alzheimer's disease (AD), which is the most major cause of dementia, is a progressive neurodegenerative disease that affects cognitive functions. Even though the prevalence of AD is continuously increasing, few drugs including cholinesterase inhibitors and N-methyl D-aspartate-receptor antagonists were approved to treat AD. Because the clinical trials of AD drugs with single targets, such as ß-amyloid and tau, have failed, the development of multi-target drugs that ameliorate many of the symptoms of AD is needed. Thus, recent studies have investigated the effects and underlying mechanisms of herbal formulae consisting of various herb combinations used to treat AD. This review discusses the results of clinical and nonclinical studies of the therapeutic efficacy in AD and underlying mechanisms of the herbal formulae of traditional Oriental medicines and bioactive compounds of medicinal plants.

The fruit of Crataegus pinnatifida ameliorates memory deficits in ß-amyloid protein-induced Alzheimer's disease mouse model.

ETHNOPHARMACOLOGICAL RELEVANCE: The fruit of Crataegus pinnatifida is a traditional medicine widely used as digestive drug in East Asia. Although Chinese herbal medicine used it for mental health, scientific evidence does not exist, yet. AIMS OF STUDY: The aim of this study is to show that the ethanol extract of the fruit of Crataegus pinnatifida (CPE) has neuroprotective effect on Alzheimer' disease model mice. MATERIALS AND METHODS: Intracerebroventricular injection of Aß was used to induce Alzheimer's disease-like pathology. Passive avoidance and Y-maze tasks were used to examine the effect of CPE on memory impairments by Aß. Immunohistochemistry was used to examine the effect of CPE on glial activation. ThT assay was used to observe the effect of CPE on Aß aggregation. MTT and LDH release assays were utilized to examine effects of CPE on Aß-induced cytotoxicity. RESULTS: CPE prevented memory deficit in Aß-induced memory impairment model. Moreover, CPE prevented glial activation in the hippocampus of Aß-injected model. In in vitro test, CPE inhibited Aß fibril formation in a concentration-dependent manner. CPE also caused disaggregation of Aß fibrils. Along with this, CPE blocked neuronal cell death induced by Aß. CONCLUSIONS: Collectively, these experimental findings demonstrated that CPE could be a candidate for development of AD therapy.

Red Ginseng Attenuates Aß-Induced Mitochondrial Dysfunction and Aß-mediated Pathology in an Animal Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aß) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aß-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aß-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aß accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aß-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aß deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.

Jowiseungchungtang Inhibits Amyloid-ß Aggregation and Amyloid-ß-Mediated Pathology in 5XFAD Mice.

Alzheimer's disease (AD) is a neurodegenerative disease, which is accompanied by memory loss and cognitive dysfunction. Although a number of trials to treat AD are in progress, there are no drugs available that inhibit the progression of AD. As the aggregation of amyloid-ß (Aß) peptides in the brain is considered to be the major pathology of AD, inhibition of Aß aggregation could be an effective strategy for AD treatment. Jowiseungchungtang (JWS) is a traditional oriental herbal formulation that has been shown to improve cognitive function in patients or animal models with dementia. However, there are no reports examining the effects of JWS on Aß aggregation. Thus, we investigated whether JWS could protect against both Aß aggregates and Aß-mediated pathology such as neuroinflammation, neurodegeneration, and impaired adult neurogenesis in 5 five familial Alzheimer's disease mutations (5XFAD) mice, an animal model for AD. In an in vitro thioflavin T assay, JWS showed a remarkable anti-Aß aggregation effect. Histochemical analysis indicated that JWS had inhibitory effects on Aß aggregation, Aß-induced pathologies, and improved adult hippocampal neurogenesis in vivo. Taken together, these results suggest the therapeutic possibility of JWS for AD targeting Aß aggregation, Aß-mediated neurodegeneration, and impaired adult hippocampal neurogenesis.

Uncaria rhynchophylla ameliorates amyloid beta deposition and amyloid beta-mediated pathology in 5XFAD mice.

One of the pathological hallmarks of Alzheimer's disease (AD) is the abnormal aggregation of amyloid beta (Aß) peptides. Uncaria rhynchophylla (UR), one of the Uncaria species, has long been used to treat neurodegenerative disease. In particular, it has been reported that UR inhibits aggregation of Aß in vitro. However, little is known about the histological effects of UR treatment on Aß pathology in AD animal models. In the present study, we investigated the effect of UR on Aß aggregation, Aß-mediated pathologies and adult hippocampal neurogenesis in the brain of 5XFAD mice. First, using the thioflavin T assay and amyloid staining, we demonstrated that UR treatment effectively inhibited Aß aggregation and accumulation in the cortex and subiculum. Second, immunofluorescence staining showed that administration of UR attenuated gliosis and neurodegeneration in the subiculum and cortex. Third, UR treatment ameliorated impaired adult hippocampal neurogenesis. The present results indicate that UR significantly alleviates Aß deposition and Aß-mediated neuropathology in the brain in 5XFAD mice, suggesting the potency of UR as a preventive and therapeutic agent for AD.

Coptidis Rhizoma Prevents Heat Stress-Induced Brain Damage and Cognitive Impairment in Mice.

Heat stress conditions lead to neuroinflammation, neuronal death, and memory loss in animals. Coptidis Rhizoma (CR) exhibits potent fever-reducing effects and has been used as an important traditional medicinal herb for treating fever. However, to date, the effects of antipyretic CR on heat-induced brain damages have not been investigated. In this study, CR significantly reduced the elevation of ear and rectal temperatures after exposure to heat in mice. Additionally, CR attenuated hyperthermia-induced stress responses, such as release of cortisol into the blood, and upregulation of heat shock protein and c-Fos in the hypothalamus and hippocampus of mice. The administration of CR inhibited gliosis and neuronal loss induced by thermal stress in the hippocampal CA3 region. Treatment with CR also reduced the heat stress-induced expression of nuclear factor kappa ß, tumor necrosis factor-α, and interleukin-1ß (IL-1ß) in the hippocampus. Moreover, CR significantly decreased proinflammatory mediators such as IL-9 and IL-13 in the heat-stressed hypothalamus. Furthermore, CR attenuated cognitive dysfunction triggered by thermal stress. These results indicate that CR protects the brain against heat stress-mediated brain damage via amelioration of hyperthermia and neuroinflammation in mice, suggesting that fever-reducing CR can attenuate thermal stress-induced neuropathology.

Platycodon grandiflorus Root Extract Improves Learning and Memory by Enhancing Synaptogenesis in Mice Hippocampus.

Platycodon grandiflorus (Jacq.) A.DC. (PG) has long been used as an ingredient of foods and is known to have beneficial effects on cognitive functions as well. The present study examined the effect of each PG extract (PGE) from root, aerial part, and seeds on cognitive functions in mice. Changes in spatial learning and memory using a Y-maze test, and markers of adult hippocampal neurogenesis and synaptogenesis were examined. Moreover, changes in neuritogenesis and activation of the ERK1/2 pathway were investigated. Results indicated that mice administered PGE (root) showed increased spontaneous alternation in the Y-maze test and synaptogenesis in the hippocampus. In addition, PGE (root) and platycodin D, the major bioactive compound from the PG root, significantly stimulated neuritic outgrowth by phosphorylation of the ERK1/2 signaling pathway in vitro. These results indicate that the PGE (root), containing platycodin D, enhances cognitive function through synaptogenesis via activation of the ERK1/2 signaling pathway.

Mulberry fruit ameliorates Parkinson's-disease-related pathology by reducing α-synuclein and ubiquitin levels in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid model.

Mulberry fruit, which has been long used in traditional oriental medicine, was reported to ameliorate motor dysfunction and dopaminergic neuronal degeneration via antioxidant and antiapoptotic effects in an animal model of Parkinson's disease (PD). More than 95% of PD patients exhibit nonmotor problems such as olfactory dysfunction and gastrointestinal constipation, which are generally considered to be early symptoms of PD. However, few studies have actually examined potential drugs to treat early PD symptoms. The present study examined the protective effects of mulberry fruit extract (ME) against neurotoxicity in a 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine/probenecid (MPTP/p) model of early PD. MPTP/p model was developed by systemic administration with MPTP (25 mg/kg) and probenecid (250 mg/kg) over 5 weeks. The behavioral studies showed that treatment of mice with ME significantly improved PD-related nonmotor symptoms as well as motor impairment, demonstrated by utilizing the olfactory, pole, rotarod and open field tests. In addition, immunohistochemical analysis indicated that ME exhibits the protective effects against dopaminergic neuronal damage induced by MPTP/p in the substantia nigra and striatum. Moreover, by using Western blot analysis, we found that treatment with ME inhibited the up-regulation of α-synuclein and ubiquitin, well known as composition of Lewy bodies in the substantia nigra and striatum of the MPTP/p mice. Taken together, these data suggest that ME may have therapeutic potential for preventing PD.

Memory-enhancing effects of Cuscuta japonica Choisy via enhancement of adult hippocampal neurogenesis in mice.

It is generally accepted that functional and structural changes within the hippocampus are involved in learning and memory and that adult neurogenesis in this region may modulate cognition. The extract of Cuscuta japonica Choisy (CJ) is a well-known traditional Chinese herbal medicine that has been used since ancient times as a rejuvenation remedy. The systemic effects of this herb are widely known and can be applied for the treatment of a number of physiological diseases, but there is a lack of evidence describing its effects on brain function. Thus, the present study investigated whether CJ would enhance memory function and/or increase hippocampal neurogenesis using mice orally administered with CJ water extract or vehicle for 21days. Performance on the novel object recognition and passive avoidance tests revealed that treatment with CJ dose-dependently improved the cognitive function of mice. Additionally, CJ increased the Ki-67-positive proliferating cells and the number of doublecortin-stained neuroblasts in the dentate gyrus (DG) of the hippocampus, and double labeling with 5-bromo-2-deoxyuridine and neuronal specific nuclear protein showed that CJ increased the number of mature neurons in the DG. Finally, CJ resulted in the upregulated expression of neurogenic differentiation factor, which is essential for the maturation and differentiation of granule cells in the hippocampus. Taken together, the present findings indicate that CJ stimulated neuronal cell proliferation, differentiation, and maturation, which are all processes associated with neurogenesis. Additionally, these findings suggest that CJ may improve learning and memory via the enhancement of adult hippocampal neurogenesis.

An Optimized Combination of Ginger and Peony Root Effectively Inhibits Amyloid-ß Accumulation and Amyloid-ß-Mediated Pathology in AßPP/PS1 Double-Transgenic Mice.

The progressive aggregation of amyloid-ß protein (Aß) into senile plaques is a major pathological factor of Alzheimer's disease (AD) and is believed to result in memory impairment. We aimed to investigate the effect of an optimized combination of ginger and peony root (OCGP), a standardized herbal mixture of ginger and peony root, on Aß accumulation and memory impairment in amyloid-ß protein precursor (AßPP)/presenilin 1 (PS1) double-transgenic mice. In an in vitro thioflavin T fluorescence assay, 100 µg/ml OCGP inhibited Aß accumulation to the same extent as did 10 µM curcumin. Furthermore, AßPP/PS1 double-transgenic mice treated with OCGP (50 or 100 mg/kg/day given orally for 14 weeks) exhibited reduced Aß plaque accumulation in the hippocampus and lower levels of glial fibrillary acid protein and cyclooxygease-2 expression compared with vehicle-treated controls. These results suggest that OCGP may prevent memory impairment in AD by inhibiting Aß accumulation and inflammation in the brain.

Ginger improves cognitive function via NGF-induced ERK/CREB activation in the hippocampus of the mouse.

Ginger (the rhizome of Zingiber officinale Roscoe) has been used worldwide for many centuries in cooking and for treatment of several diseases. The main pharmacological properties of ginger include anti-inflammatory, antihyperglycemic, antiarthritic, antiemetic and neuroprotective actions. Recent studies demonstrated that ginger significantly enhances cognitive function in various cognitive disorders as well as in healthy brain. However, the biochemical mechanisms underlying the ginger-mediated enhancement of cognition have not yet been studied in normal or diseased brain. In the present study, we assessed the memory-enhancing effects of dried ginger extract (GE) in a model of scopolamine-induced memory deficits and in normal animals by performing a novel object recognition test. We found that GE administration significantly improved the ability of mice to recognize novel objects, indicating improvements in learning and memory. Furthermore, to elucidate the mechanisms of GE-mediated cognitive enhancement, we focused on nerve growth factor (NGF)-induced signaling pathways. NGF enzyme-linked immunosorbent assay analysis revealed that GE administration led to elevated NGF levels in both the mouse hippocampus and rat glioma C6 cells. GE administration also resulted in phosphorylation of extracellular-signal-regulated kinase (ERK) and cyclic AMP response element-binding protein (CREB), as revealed by Western blotting analysis. Neutralization of NGF with a specific NGF antibody inhibited GE-triggered activation of ERK and CREB in the hippocampus. Also, GE treatment significantly increased pre- and postsynaptic markers, synaptophysin and PSD-95, which are related to synapse formation in the brain. These data suggest that GE has a synaptogenic effect via NGF-induced ERK/CREB activation, resulting in memory enhancement.

6-Shogaol, an active constituent of ginger, attenuates neuroinflammation and cognitive deficits in animal models of dementia.

Recently, increased attention has been directed towards medicinal extracts as potential new drug candidates for dementia. Ginger has long been used as an important ingredient in cooking and traditional herbal medicine. In particular, ginger has been known to have disease-modifying effects in Alzheimer's disease (AD). However, there is no evidence of which constituents of ginger exhibit therapeutic effects against AD. A growing number of experimental studies suggest that 6-shogaol, a bioactive component of ginger, may play an important role as a memory-enhancing and anti-oxidant agent against neurological diseases. 6-Shogaol has also recently been shown to have anti-neuroinflammatory effects in lipopolysaccharide (LPS)-treated astrocytes and animal models of Parkinson's disease, LPS-induced inflammation and transient global ischemia. However, it is still unknown whether 6-shogaol has anti-inflammatory effects against oligomeric forms of the Aß (AßO) in animal brains. Furthermore, the effects of 6-shogaol against memory impairment in dementia models are also yet to be investigated. In this study, we found that administration of 6-shogaol significantly reduced microgliosis and astrogliosis in intrahippocampal AßO-injected mice, ameliorated AßO and scopolamine-induced memory impairment, and elevated NGF levels and pre- and post-synaptic marker in the hippocampus. All these results suggest that 6-shogaol may play a role in inhibiting glial cell activation and reducing memory impairment in animal models of dementia.

Gami-Chunghyuldan ameliorates memory impairment and neurodegeneration induced by intrahippocampal Aß 1-42 oligomer injection.

Soluble oligomeric forms of amyloid beta (AßO) are regarded as a main cause of synaptic and cognitive dysfunction in Alzheimer's disease (AD) and have been a primary target in the development of drug treatments for AD. The present study utilized a mouse model of AD induced by intrahippocampal injection of AßO (10 µM) to investigate the effects of Gami-Chunghyuldan (GCD), a standardized multi-herbal medicinal formula, on the presentation of memory deficits and neurohistological pathogenesis. GCD (10 and 50mg/kg/day, 5 days, p.o.) improved AßO-induced memory impairment as well as reduced neuronal cell death, astrogliosis, and microgliosis in the hippocampus. In addition, GCD prevented AßO-triggered synaptic disruption and cholinergic fiber loss. These results suggest that GCD may be useful in the prevention and treatment of AD.