Ginseng, a perennial plant belonging to the Panax genus of the Araliaceae family, has been used in China, Korea, and Japan as a traditional herbal medicine for thousands of years. Ginseng is recorded to have exhibited a wide variety of beneficial pharmacological effects and has become a popular and worldwide known health supplement and drug. The protective effects of ginseng on central nervous system are discussed in this review. Ginseng species and ginsenosides and their intestinal metabolism and bioavailability are concisely introduced. The molecular mechanisms of the effects of ginseng on central nervous system, mainly focused on the neuroprotection properties of ginseng, memory, and learning enhanced properties, and the effects on neurodegenerative disorders are presented. Thus, ginseng and its constituents are of potential merits in the treatment of cerebral disorders.

In an animal model of aluminum overload, (aluminium gluconate), the increases in tissue aluminium content were paralleled by elevations of tissue iron in the kidney, liver heart and spleen as well as in various brain regions, frontal, temporal and parietal cortex and hippocampus. Despite such increases in iron content there were no significant changes in the activities of a wide range of cytoprotective enzymes apart from an increase in superoxide dismutase in the frontal cortex of the aluminium loaded rats. Such increases in tissue iron content may be attributed to the stabilisation of IRP-2 by aluminium thereby promoting transferrin receptor synthesis while blocking ferritin synthesis. Using the radioactive tracer (26)Al less than 1% of the injected dose was recovered in isolated ferritin, supporting previous studies which also found little evidence for aluminium storage within ferritin. The increases in brain iron may well be contributory to neurodegeneration, although the pathogenesis by which iron exerts such an effect is unclear.

The toxicity of aluminum in plant and animal cell biology is well established, although poorly understood. Several recent studies have identified aluminum as a potential, although highly controversial, contributory factor in the pathology of Alzheimer disease, amyotrophic lateral sclerosis, and dialysis dementia. For example, aluminum has been found in high concentrations in senile plaques and neurofibrillary tangles, which occur in the brains of subjects with Alzheimer disease. However, a mechanism for the entry of aluminum (Al3+) into the cells of the central nervous system (CNS) has yet to be found. Here we describe a possible route of entry for aluminum into the cells of the CNS via the same high-affinity receptor-ligand system that has been postulated for iron (Fe3+) delivery to neurons and glial cells. These results suggest that aluminum is able to gain access to the central nervous system under normal physiological conditions. Furthermore, these data suggest that the interaction between transferrin and its receptor may function as a general metal ion regulatory system in the CNS, extending beyond its postulated role in iron regulation.

With continuing cooperation from 18 domestic and international brain banks over the last 36 years, we have analyzed the aluminum content of the temporal lobe neocortex of 511 high-quality human female brain samples from 16 diverse neurological and neurodegenerative disorders, including 2 groups of age-matched controls. Temporal lobes (Brodmann areas A20-A22) were selected for analysis because of their availability and their central role in massive information-processing operations including efferent-signal integration, cognition, and memory formation. We used the analytical technique of (i) Zeeman-type electrothermal atomic absorption spectrophotometry (ETAAS) combined with (ii) preliminary analysis from the advanced photon source (APS) hard X-ray beam (7 GeV) fluorescence raster-scanning (XRFR) spectroscopy device (undulator beam line 2-ID-E) at the Argonne National Laboratory, US Department of Energy, University of Chicago IL, USA. Neurological diseases examined were Alzheimer's disease (AD; N = 186), ataxia Friedreich's type (AFT; N = 6), amyotrophic lateral sclerosis (ALS; N = 16), autism spectrum disorder (ASD; N = 26), dialysis dementia syndrome (DDS; N = 27), Down's syndrome (DS; trisomy, 21; N = 24), Huntington's chorea (HC; N = 15),multiple infarct dementia (MID; N = 19), multiple sclerosis (MS; N = 23), Parkinson's disease (PD; N = 27), and prion disease (PrD; N = 11) that included bovine spongiform encephalopathy (BSE;"mad cow disease"), Creutzfeldt-Jakob disease (CJD) and Gerstmann-Straussler-Sheinker syndrome (GSS), progressive multifocal leukoencephalopathy (PML; N = 11), progressive supranuclear palsy (PSP; N = 24), schizophrenia (SCZ; N = 21), a young control group (YCG; N = 22; mean age, 10.2 ± 6.1 year), and an aged control group (ACG; N = 53; mean age, 71.4 ± 9.3 year). Using ETAAS, all measurements were performed in triplicate on each tissue sample. Among these 17 common neurological conditions, we found a statistically significant trend for aluminum to be increased only in AD, DS, and DDS compared to age- and gender-matched brains from the same anatomical region. This is the largest study of aluminum concentrationin the brains of human neurological and neurodegenerative disease ever undertaken. The results continue to suggest that aluminum's association with AD, DDS, and DS brain tissues may contribute to the neuropathology of those neurological diseases but appear not to be a significant factor in other common disorders of the human brain and/or CNS.

Grossamide, a representative lignanamide in hemp seed, has been reported to possess potential anti-inflammatory effects. However, the potential anti-neuroinflammatory effects and underlying mechanisms of action of grossamide are still unclear. Therefore, the present study investigated the possible effects and underlying mechanisms of grossamide against lipopolysaccharide (LPS)-induced inflammatory response in BV2 microglia cells. BV2 microglia cells were pre-treated with various concentrations of grossamide before being stimulated with LPS to induce inflammation. The levels of pro-inflammatory cytokines were determined using the enzyme-linked immunoassay (ELISA) and mRNA expression levels were measured by real-time PCR. The translocation of nuclear factor-kappa B (NF-κB) and contribution of TLR4-mediated NF-κB activation on inflammatory effects were evaluated by immunostaining and Western blot analysis. This study demonstrated that grossamide significantly inhibited the secretion of pro-inflammatory mediators such as interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α), and decreased the level of LPS-mediated IL-6 and TNF-α mRNA. In addition, it significantly reduced the phosphorylation levels of NF-κB subunit p65 in a concentration-dependent manner and suppressed translocation of NF-κB p65 into the nucleus. Furthermore, grossamide markedly attenuated the LPS-induced expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). Taken together, these data suggest that grossamide could be a potential therapeutic candidate for inhibiting neuroinflammation in neurodegenerative diseases.

Aquatherapy is used for rehabilitation and exercise; water provides a challenging, yet safe exercise environment for many special populations. We have reviewed the use of aquatherapy programs in four neurodegenerative disorders: Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. Results support the use of aquatherapy in Parkinson's disease and multiple sclerosis, however further evidence is required to make specific recommendations in all of the aforementioned disorders.

Avocados have a high content of phytochemicals especially antioxidants with potential neuroprotective effect. Aging is the major risk factor for neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. A large body of evidence indicates that oxidative stress is involved in the pathophysiology of these diseases. Oxidative stress can induce neuronal damages and modulate intracellular signaling, ultimately leading to neuronal death by apoptosis or necrosis. There is evidence for increased oxidative damage to macromolecules in amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and Alzheimer's disease. Thus, antioxidants have been used for their effectiveness in reducing these deleterious effects and neuronal death in many in vitro and in vivo studies. The critical review results indicate that compounds in avocado are unique antioxidants, preferentially suppressing radical generation, and thus may be promising as effective neuropreventive agents. The diverse array of bioactive nutrients present in avocado plays a pivotal role in the prevention and cure of various neurodegenerative diseases.

Cannabinoids and the endocannabinoid system have attracted considerable interest for therapeutic applications. Nevertheless, the mechanism of action of one of the main nonpsychoactive phytocannabinoids, cannabidiol (CBD), remains elusive despite potentially beneficial properties as an anti-convulsant and neuroprotectant. Here, we characterize the mechanisms by which CBD regulates Ca(2+) homeostasis and mediates neuroprotection in neuronal preparations. Imaging studies in hippocampal cultures using fura-2 AM suggested that CBD-mediated Ca(2+) regulation is bidirectional, depending on the excitability of cells. Under physiological K(+)/Ca(2+) levels, CBD caused a subtle rise in [Ca(2+)](i), whereas CBD reduced [Ca(2+)](i) and prevented Ca(2+) oscillations under high-excitability conditions (high K(+) or exposure to the K(+) channel antagonist 4AP). Regulation of [Ca(2+)](i) was not primarily mediated by interactions with ryanodine or IP(3) receptors of the endoplasmic reticulum. Instead, dual-calcium imaging experiments with a cytosolic (fura-2 AM) and a mitochondrial (Rhod-FF, AM) fluorophore implied that mitochondria act as sinks and sources for CBD's [Ca(2+)](i) regulation. Application of carbonylcyanide-p-trifluoromethoxyphenylhydrazone (FCCP) and the mitochondrial Na(+)/Ca(2+) exchange inhibitor, CGP 37157, but not the mitochondrial permeability transition pore inhibitor cyclosporin A, prevented subsequent CBD-induced Ca(2+) responses. In established human neuroblastoma cell lines (SH-SY5Y) treated with mitochondrial toxins, CBD (0.1 and 1 microm) was neuroprotective against the uncoupler FCCP (53% protection), and modestly protective against hydrogen peroxide- (16%) and oligomycin- (15%) mediated cell death, a pattern also confirmed in cultured hippocampal neurons. Thus, under pathological conditions involving mitochondrial dysfunction and Ca(2+) dysregulation, CBD may prove beneficial in preventing apoptotic signaling via a restoration of Ca(2+) homeostasis.

Neurodegenerative diseases represent, nowadays, one of the main causes of death in the industrialized country. They are characterized by a loss of neurons in particular regions of the nervous system. It is believed that this nerve cell loss underlies the subsequent decline in cognitive and motor function that patients experience in these diseases. A range of mutant genes and environmental toxins have been implicated in the cause of neurodegenerative disorders but the mechanism remains largely unknown. At present, inflammation, a common denominator among the diverse list of neurodegenerative diseases, has been implicated as a critical mechanism that is responsible for the progressive nature of neurodegeneration. Since, at present, there are few therapies for the wide range of neurodegenerative diseases, scientists are still in search of new therapeutic approaches to the problem. An early contribution of neuroprotective and antiinflammatory strategies for these disorders seems particularly desirable because isolated treatments cannot be effective. In this contest, marijuana derivatives have attracted special interest, although these compounds have always raised several practical and ethical problems for their potential abuse. Nevertheless, among Cannabis compounds, cannabidiol (CBD), which lacks any unwanted psychotropic effect, may represent a very promising agent with the highest prospect for therapeutic use.

Carnosic acid (CA; C20H28O4), a phenolic diterpene characterized as an ortho-dihydroquinone-type molecule, is a pro-electrophile agent that becomes an electrophile after reacting with free radicals. The electrophile generated from CA interacts with and activates the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, which is a major modulator of redox biology in mammalian cells. CA induces antioxidant and anti-inflammatory effects in several cell types, as observed in both in vitro and in vivo experimental models. In this context, CA has been viewed as a neuroprotective agent by activating signaling pathways associated with cell survival during stressful conditions. Indeed, CA exhibits the ability to promote mitochondrial protection in neural cells. Mitochondria are the main source of both ATP and reactive species in animal cells. Mitochondrial dysfunction plays a central role in the start and development of neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, among others. Therefore, the study of strategies aiming to reduce mitochondrial impairment in the case of neurodegeneration is of pharmacological interest. In the present review, it is described and discussed the effects of CA on brain mitochondria in experimental models of neural lesion. Based on the data discussed here, CA is a potential candidate to be listed as a neuroprotective agent by acting on the mitochondria of neural cells.

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded CAG repeat in exon 1 of thegene. HD usually manifests in mid-life with loss of GABAergic projection neurons from the striatum accompanied by progressive atrophy of the putamen followed by other brain regions, but linkages between the genetics and neurodegeneration are not understood. We measured metabolic perturbations in HD-human brain in a case-control study, identifying pervasive lowering of vitamin B5, the obligatory precursor of coenzyme A (CoA) that is essential for normal intermediary metabolism. Cerebral pantothenate deficiency is a newly-identified metabolic defect in human HD that could potentially: (i) impair neuronal CoA biosynthesis; (ii) stimulate polyol-pathway activity; (iii) impair glycolysis and tricarboxylic acid cycle activity; and (iv) modify brain-urea metabolism. Pantothenate deficiency could lead to neurodegeneration/dementia in HD that might be preventable by treatment with vitamin B5.

Coenzyme Q10 (CoQ10) is an essential cofactor of the electron transport gene as well as an important antioxidant, which is particularly effective within mitochondria. A number of prior studies have shown that it can exert efficacy in treating patients with known mitochondrial disorders. We investigated the potential usefulness of coenzyme Q10 in animal models of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). It has been demonstrated that CoQ10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in HD. It also protects against 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice. CoQ10 significantly extended survival in a transgenic mouse model of ALS. CoQ10 can significantly extend survival, delay motor deficits and delay weight loss and attenuate the development of striatal atrophy in a transgenic mouse model of HD. In this mouse model, it showed additive efficacy when combined with the N-methyl-D-aspartate (NMDA) receptor antagonist, remacemide. CoQ10 is presently being studied as a potential treatment for early PD as well as in combination with remacemide as a potential treatment for HD.

We compared the effects of acupuncture and electroacupuncture on cell proliferation and neuroblast differentiation using specific markers, Ki67 and doublecortin (DCX), in the subgranular zone of the dentate gyrus (SZDG) in 13-week old Wistar rats. Acupuncture and electroacupuncture were applied simultaneously in the acu-points, ST36 (Zusanli) and GV20 (Baihui), once a day for 3 weeks. Acupuncture and electroacupuncture at these acu-points significantly increased the number of Ki67-positive cells and DCX-immunoreactive neuroblasts compared to the control or sham acupuncture group. Electroacupuncture treatment significantly increased the number of well-developed (tertiary) dendrites in the SZDG compared to acupuncture treatment. These results suggest that both acupuncture and electroacupuncture increase neurogenesis in the normal, but that electroacupuncture has greater effects on neuroblast plasticity than acupuncture in the dentate gyrus.

We compared the effects of acupuncture and electroacupuncture on cell proliferation and neuroblast differentiation using specific markers, Ki67 and doublecortin (DCX), in the subgranular zone of the dentate gyrus (SZDG) in 13-week old Wistar rats. Acupuncture and electroacupuncture were applied simultaneously in the acu-points, ST36 (Zusanli) and GV20 (Baihui), once a day for 3 weeks. Acupuncture and electroacupuncture at these acu-points significantly increased the number of Ki67-positive cells and DCX-immunoreactive neuroblasts compared to the control or sham acupuncture group. Electroacupuncture treatment significantly increased the number of well-developed (tertiary) dendrites in the SZDG compared to acupuncture treatment. These results suggest that both acupuncture and electroacupuncture increase neurogenesis in the normal, but that electroacupuncture has greater effects on neuroblast plasticity than acupuncture in the dentate gyrus.

Substantial evidence indicates bioenergetic dysfunction and mitochondrial impairment contribute either directly and/or indirectly to the pathogenesis of numerous neurodegenerative disorders. Treatment paradigms aimed at ameliorating this cellular energy deficit and/or improving mitochondrial function in these neurodegenerative disorders may prove to be useful as a therapeutic intervention. Creatine is a molecule that is produced both endogenously, and acquired exogenously through diet, and is an extremely important molecule that participates in buffering intracellular energy stores. Once creatine is transported into cells, creatine kinase catalyzes the reversible transphosphorylation of creatine via ATP to enhance the phosphocreatine energy pool. Creatine kinase enzymes are located at strategic intracellular sites to couple areas of high energy expenditure to the efficient regeneration of ATP. Thus, the creatine kinase/phosphocreatine system plays an integral role in energy buffering and overall cellular bioenergetics. Originally, exogenous creatine supplementation was widely used only as an ergogenic aid to increase the phosphocreatine pool within muscle to bolster athletic performance. However, the potential therapeutic value of creatine supplementation has recently been investigated with respect to various neurodegenerative disorders that have been associated with bioenergetic deficits as playing a role in disease etiology and/or progression which include; Alzheimer's, Parkinson's, amyotrophic lateral sclerosis (ALS), and Huntington's disease. This review discusses the contribution of mitochondria and bioenergetics to the progression of these neurodegenerative diseases and investigates the potential neuroprotective value of creatine supplementation in each of these neurological diseases. In summary, current literature suggests that exogenous creatine supplementation is most efficacious as a treatment paradigm in Huntington's and Parkinson's disease but appears to be less effective for ALS and Alzheimer's disease.

Since its introduction in 1921, the ketogenic diet has been in continuous use for children with difficult-to-control epilepsy. After decades of relative disuse, it is now both extremely popular and well studied, with approximately two-thirds of children demonstrating significant seizure reduction after 6 months. It is being used for less intractable seizures in children as well as recently adults. Modifications that help improve tolerability include the medium chain triglyceride diet, modified Atkins diet, and low glycemic index treatment. Major side effects include acidosis, increased cholesterol, kidney stones, gastroesophageal reflux, and growth disturbance. However, these side effects are usually treatable and nowadays often even preventable. Future non-epilepsy indications such as Alzheimer disease, amyotrophic lateral sclerosis, autism, and brain tumors are under active investigation. This dietary treatment for epilepsy has undergone a rebirth. Its widespread use in Poland and Europe is a welcome additional treatment for those with drug-resistant epilepsy.

There is an exponential increase in dementia in old age at a global level because of increasing life expectancy. The prevalence of neurodegenerative diseases such as dementia and Alzheimer's disease (AD) will continue to rise steadily, and is expected to reach 42 million cases worldwide in 2020. Despite the advancement of medication, the management of these diseases remains largely ineffective. Therefore, it is vital to explore novel nature-based nutraceuticals to mitigate AD and other age-related neurodegenerative disorders. Mushrooms and their extracts appear to hold many health benefits, including immune-modulating effects. A number of edible mushrooms have been shown to contain rare and exotic compounds that exhibit positive effects on brain cells both in vitro and in vivo. In this review, we summarize the scientific information on edible and culinary mushrooms with regard to their antidementia/AD active compounds and/or pharmacological test results. The bioactive components in these mushrooms and the underlying mechanism of their activities are discussed. In short, these mushrooms may be regarded as functional foods for the mitigation of neurodegenerative diseases.

Autophagy is an intracellular bulk degradation process, induced under nutrient starvation. Failure of autophagy has been recognized as a contributor to aging and multiple age related neurodegenerative diseases. Improving autophagy is a beneficial anti-aging strategy, however very few physiological regulators have been identified. Here, we demonstrate that vitamin C is a nutritional stimulator of autophagy. Supplementation of fresh hepatocytes with vitamin C increased autophagic proteolysis significantly in the presence of amino acids in a dose- and time-dependent manner, although no effect was observed in the absence of amino acids. In addition, inhibitor studies with 3-methyladenine, chloroquine, leupeptin andβ-lactone confirmed that vitamin C is active through the lysosomal autophagy and not the proteasome pathway. Furthermore, the autophagy marker LC3 protein was significantly increased by vitamin C, suggesting its possible site of action is at the formation step. Both the reduced (ascorbic acid, AsA)and oxidized form (dehydroascorbic acid, DHA) of vitamin C exhibited equal enhancing effect, indicating that the effect does not depend on the anti-oxidation functionality of vitamin C. To understand the mechanism, we established that the effective dose (50 μM) was 15× lower than the intracellular content suggesting these would be only a minor influx from the extracellular pool. Moreover, transporter inhibitor studies in an AsA deficient ODS model rat revealed more accurately that the enhancing effect on autophagic proteolysis still existed, even though the intracellular influx of AsA wasblocked. Taken together, these results provide evidence that vitamin C can potentially act through extracellular signaling.

Hippocampal volume increase in response to aerobic exercise has been consistently observed in animal models. However, the evidence from human studies is equivocal. We undertook a systematic review to identify all controlled trials examining the effect of aerobic exercise on the hippocampal volumes in humans, and applied meta-analytic techniques to determine if aerobic exercise resulted in volumetric increases. We also sought to establish how volume changes differed in relation to unilateral measures of left/right hippocampal volume, and across the lifespan. A systematic search identified 4398 articles, of which 14 were eligible for inclusion in the primary analysis. A random-effects meta-analysis showed no significant effect of aerobic exercise on total hippocampal volume across the 737 participants. However, aerobic exercise had significant positive effects on left hippocampal volume in comparison to control conditions. Post-hoc analyses indicated effects were driven through exercise preventing the volumetric decreases which occur over time. These results provide meta-analytic evidence for exercise-induced volumetric retention in the left hippocampus. Aerobic exercise interventions may be useful for preventing age-related hippocampal deterioration and maintaining neuronal health.