Ys Ho

Dietary oxyresveratrol prevents parkinsonian mimetic 6-hydroxydopamine neurotoxicity

Oxyresveratrol (OXY) is a polyhydroxylated stilbene existing in mulberry. Increasing lines of evidence have shown its neuroprotective effects against Alzheimer disease and stroke. However, little is known about its neuroprotective effect in Parkinson disease (PD). Owing to its antioxidant activity, blood-brain barrier permeativity, and water solubility, we hypothesized that OXY may exert neuroprotective effects against parkinsonian mimetic 6-hydroxydopamine (6-OHDA) neurotoxicity. Neuroblastoma SH-SY5Y cells have long been used as dopaminergic neurons in PD research. We found that both pretreatment and posttreatment with OXY on SH-SY5Y cells significantly reduced the release of lactate dehydrogenase, the activity of caspase-3, and the generation of intracellular reactive oxygen species triggered by 6-OHDA. Compared to resveratrol, OXY exhibited a wider effective dosage range. We proved that OXY could penetrate the cell membrane by HPLC analysis of cell extracts. These results suggest that OXY may act as an intracellular antioxidant to reduce oxidative stress induced by 6-OHDA. Western blot analysis demonstrated that OXY markedly attenuated 6-OHDA-induced phosphorylation of JNK and c-Jun. Furthermore, we proved that OXY increased the basal levels of SIRT1, which may disclose new pathways accounting for the neuroprotective effects of OXY. Taken together, our results suggest OXY, a dietary phenolic compound, as a potential nutritional candidate for protection against neurodegeneration in PD.

Anti-aging herbal medicine--how and why can they be used in aging-associated neurodegenerative diseases?

Aging is a universal biological process that leads to progressive and deleterious changes in organisms. From ancient time, mankind has already interested in preventing and keeping ourselves young. Anti-aging study is certainly not a new research area. Nowadays, the meaning of anti-aging has been changed from simply prolonging lifespan to increasing health span, which emphasizes more on the quality of life. This is the concept of healthy aging and prevention of pathological aging, which is associated with diseases. Keeping our brain functions as in young age is an important task for neuroscientists to prevent aging-associated neurological disorders, such as Alzheimers diseases (AD) and Parkinsons disease (PD). The causes of these diseases are not fully understood, but it is believed that these diseases are affected by multiple factors. Neurodegenerative diseases can be cross-linked with a number of aging-associated conditions. Based on this, a holistic approach in anti-aging research seems to be more reasonable. Herbal medicine has a long history in Asian countries. It is believed that many of the medicinal herbs have anti-aging properties. Recent studies have shown that some medicinal herbs are effective in intervention or prevention of aging-associated neurological disorders. In this review, we use wolfberry and ginseng as examples to elaborate the properties of anti-aging herbs. The characteristics of medicinal herbs, especially their applications in different disease stages (prevention and intervention) and multi-targets properties, allow them to be potential anti-aging intervention in prevention and treatment of the aging-associated neurological disorders.

Neuroprotective Effects of Polysaccharides from Wolfberry, the Fruits of Lycium barbarum, Against Homocysteine-induced Toxicity in Rat Cortical Neurons

Previous clinical and epidemiological studies have suggested that elevated plasma homocysteine (Hcy) levels increased the risk of Alzheimes disease (AD). Although the underlying mechanisms of its toxicity are elusive, it has been shown that Hcy damages neurons by inducing apoptosis, DNA fragmentation, and tau hyperphosphorylation. Wolfberry (Lycium barbarum) is a fruit that is known for its eye-protective and anti-aging properties in Asian countries. Previous studies from our laboratory have demonstrated that polysaccharides derived from wolfberry (LBA) have the ability to protect neurons from amyloid-beta (Abeta) peptide neurotoxicity. We hypothesize that the neuroprotective effects of wolfberry is not limited to Abeta and can also provide protection against other AD risk factors. In this study, we aim to elucidate the neuroprotective effects of wolfberry against Hcy-induced neuronal damage. Our data showed that LBA treatment significantly attenuated Hcy-induced neuronal cell death and apoptosis in primary cortical neurons as demonstrated by LDH and caspase-3 like activity assay. LBA also significantly reduced Hcy-induced tau phosphorylation at tau-1 (Ser198/199/202), pS396 (Ser396), and pS214 (Ser214) epitopes as well as cleavage of tau. At the same time, we also found that the phosphorylation level of p-GSK3beta (Ser9/Tyr 216) remained unchanged among different treatment groups at all detected time points. LBA treatment suppressed elevation of both p-ERK and p-JNK. In summary, our data demonstrated that LBA exerted neuroprotective effects on cortical neurons exposed to Hcy. Therefore, LBA has the potential to be a diseasemodifying agent for the prevention of AD.

Cigarette smoking accelerated brain aging and induced pre-Alzheimer-like neuropathology in rats.

Cigarette smoking has been proposed as a major risk factor for aging-related pathological changes and Alzheimers disease (AD). To date, little is known for how smoking can predispose our brains to dementia or cognitive impairment. This study aimed to investigate the cigarette smoke-induced pathological changes in brains. Male Sprague-Dawley (SD) rats were exposed to either sham air or 4% cigarette smoke 1 hour per day for 8 weeks in a ventilated smoking chamber to mimic the situation of chronic passive smoking. We found that the levels of oxidative stress were significantly increased in the hippocampus of the smoking group. Smoking also affected the synapse through reducing the expression of pre-synaptic proteins including synaptophysin and synapsin-1, while there were no changes in the expression of postsynaptic protein PSD95. Decreased levels of acetylated-tubulin and increased levels of phosphorylated-tau at 231, 205 and 404 epitopes were also observed in the hippocampus of the smoking rats. These results suggested that axonal transport machinery might be impaired, and the stability of cytoskeleton might be affected by smoking. Moreover, smoking affected amyloid precursor protein (APP) processing by increasing the production of sAPPβ and accumulation of β–amyloid peptide in the CA3 and dentate gyrus region. In summary, our data suggested that chronic cigarette smoking could induce synaptic changes and other neuropathological alterations. These changes might serve as evidence of early phases of neurodegeneration and may explain why smoking can predispose brains to AD and dementia.

Endoplasmic Reticulum Stress Induces Tau Pathology and Forms a Vicious Cycle: Implication in Alzheimer's Disease Pathogenesis

Accumulation of unfolded proteins can disturb the functions of the endoplasmic reticulum (ER), leading to ER-stress or unfolded protein response (UPR). Recent data have shown that activation of UPR can be found in postmortem brains of Alzheimers disease (AD) patients; and biological markers for activation of UPR are abundant in neurons with diffuse phosphorylated tau. Although these observations suggest a linkage between ER-stress and tau pathology, little is known of their relationship. In this study, we found that high levels of phosphorylated PKR-like ER-resident kinase (p-PERK) and phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) as markers for activation of UPR in the hippocampus of aged P301L mutant tau transgenic mice. The immunoreactivity of p-PERK was found to co-localize with that of phosphorylated tau. We then hypothesized that phosphorylation of tau could induce ER-stress and vice versa in promoting AD-like pathogenesis. By using the protein phosphatase 2A inhibitor okadaic acid (OA) as an inducer for phosphorylation of tau, we found that primary cultures of rat cortical neurons treated with OA triggered UPR as indicated by increased levels of p-PERK and p-eIF2α, splicing of mRNA for xbp-1 and elevated levels of mRNA for GADD153. On the other hand, thapsigargin as an ER-stress inducer stimulated phosphorylation of tau at Thr231, Ser262 and Ser396. Thapsigargin also induced activation of caspase-3 and cleavage of tau. These findings suggested that ER-stress and hyperphosphorylation of tau could be induced by each other to form a vicious cycle to propagate AD-like neurodegeneration.

Drug discovery from Chinese medicine against neurodegeneration in Alzheimer's and vascular dementia

Alzheimers disease and vascular dementia are two major diseases associated with dementia, which is common among the elderly. While the etiology of dementia is multi-factorial and complex, neurodegeneration may be the major cause of these two diseases. Effective drugs for treating dementia are still to be discovered. Current western pharmacological approaches against neurodegeneration in dementia develop symptom-relieving and disease-modifying drugs. Current integrative and holistic approaches of Chinese medicine to discovering drugs for neurodegeneration in dementia include (1) single molecules from the herbs, (2) standardized extracts from a single herb, and (3) herbal formula with definite composition. This article not only reviews the concept of dementia in western medicine and Chinese medicine but also evaluates the advantages and disadvantages of these approaches.

Cytokines: How important are they in mediating sickness?

Sickness refers to a set of coordinated physiological and behavioral changes in response to systemic inflammation. It is characterized by fever, malaise, social withdrawal, fatigue, and anorexia. While these responses collectively represent a protective mechanism against infection and injury, increasing lines of evidence indicate that over-exaggerated or persistent sickness can damage the brain, and could possibly raise the risk to developing delirium. Therefore, a clear understanding in sickness will be beneficial. It has long been believed that sickness results from increased systemic cytokines occurring during systemic inflammation. However, in recent years more and more conflicting data have suggested that development of sickness following peripheral immune challenge could be independent of cytokines. Hence, it is confusing as to whether cytokines really do act as primary mediators of sickness, or if they are secondary to alternative inducing factor(s). In this review, we will (1) introduce the relationships between systemic inflammation, cytokines, sickness, and delirium, and (2) attempt to interpret the recent controversies.

A pro-drug of the green tea polyphenol (−)-epigallocatechin-3-gallate (EGCG) prevents differentiated SH-SY5Y cells from toxicity induced by 6-hydroxydopamine

Regular consumption of green tea benefits people in prevention from cardiovascular disorders, obesity as well as neurodegenerative diseases. (-)-Epigallocatechin-3-gallate (EGCG) is regarded as the most biologically active catechin in green tea. However, the stability and bioavailability of EGCG are restricted. The purpose of the present study was to investigate whether a pro-drug, a fully acetylated EGCG (pEGCG), could be more effective in neuroprotection in Parkinsonism mimic cellular model. Retinoic acid (RA)-differentiated neuroblastoma SH-SY5Y cells were pre-treated with different concentrations of EGCG and pEGCG for 30 min and followed by incubation of 25 microM 6-hydroxydopamine (6-OHDA) for 24h. We found that a broad dosage range of pEGCG (from 0.1 to 10 microM) could significantly reduce lactate dehydrogenase release. Likewise, 10 microM of pEGCG was effective in reducing caspase-3 activity, while EGCG at all concentrations tested in the model failed to attenuate caspase-3 activity induced by 6-OHDA. Furthermore, Western-blot analysis showed that Akt could be one of the specific signaling pathways stimulated by pEGCG in neuroprotection. It was demonstrated that 25 microM of 6-OHDA significantly suppressed the phosphorylation level of Akt. Only pEGCG at 10 microM markedly increased its phosphorylation level compared to 6-OHDA alone. Taken together, as pEGCG has higher stability and bioavailability for further investigation, it could be a potential neuroprotective agent and our current findings may offer certain clues for optimizing its application in future.

Modulation of mitochondrial calcium as a pharmacological target for Alzheimer's disease

Perturbed neuronal calcium homeostasis is a prominent feature in Alzheimers disease (AD). Mitochondria accumulate calcium ions (Ca(2+)) for cellular bioenergetic metabolism and suppression of mitochondrial motility within the cell. Excessive Ca(2+) uptake into mitochondria often leads to mitochondrial membrane permeabilization and induction of apoptosis. Ca(2+) is an interesting second messenger which can initiate both cellular life and death pathways in mitochondria. This review critically discusses the potential of manipulating mitochondrial Ca(2+) concentrations as a novel therapeutic opportunity for treating AD. This review also highlights the neuroprotective role of a number of currently available agents that modulate different mitochondrial Ca(2+) transport pathways. It is reasoned that these mitochondrial Ca(2+) modulators are most effective in combination with agents that increase the Ca(2+) buffering capacity of mitochondria. Modulation of mitochondrial Ca(2+) handling is a potential pharmacological target for future development of AD treatments.

Sickness: From the focus on cytokines, prostaglandins, and complement factors to the perspectives of neurons

Systemic inflammation leads to a variety of physiological (e.g. fever) and behavioral (e.g. anorexia, immobility, social withdrawal, depressed mood, disturbed sleep) responses that are collectively known as sickness. While these phenomena have been studied for the past few decades, the neurobiological mechanisms by which sickness occurs remain unclear. In this review, we first revisit how the body senses and responds to infections and injuries by eliciting systemic inflammation. Next, we focus on how peripheral inflammatory molecules such as cytokines, prostaglandins, and activated complement factors communicate with the brain to trigger neuroinflammation and sickness. Since depression also involves inflammation, we further elaborate on the interrelationship between sickness and depression. Finally, we discuss how immune activation can modulate neurons in the brain, and suggest future perspectives to help unravel how changes in neuronal functions relate to sickness responses.