Self-Administered Acupressure for Probable Knee Osteoarthritis in Middle-Aged and Older Adults: A Randomized Clinical Trial.

Importance: The effects of self-administered acupressure (SAA) on knee osteoarthritis (OA) pain remain unclear. Objective: To evaluate the effectiveness of SAA taught via a short training course on reducing knee OA pain in middle-aged and older adults. Design, Setting, and Participants: This randomized clinical trial was conducted among community-dwelling individuals in Hong Kong who were aged 50 years or older with probable knee OA from September 2019 to May 2022. Interventions: The intervention included 2 training sessions for SAA with a brief knee health education (KHE) session, in which participants practiced acupressure twice daily for 12 weeks. The control group (KHE only) received only education about maintaining knee health on the same schedule and duration. Main Outcomes and Measures: The primary outcome was the numerical rating scale (NRS) pain score at 12 weeks. Other outcomes included Western Ontario and McMaster University Osteoarthritis Index, Short Form 6 Dimensions (SF-6D), Timed Up and Go, and Fast Gait Speed tests. Results: A total of 314 participants (mean [SD] age, 62.7 [4.5] years; 246 [78.3%] female; mean [SD] knee pain duration, 7.3 [7.6] years) were randomized into intervention and KHE-only groups (each 157). At week 12, compared with the KHE-only group, the intervention group had a significantly greater reduction in NRS pain score (mean difference [MD], -0.54 points; 95% CI, -0.97 to -0.10 points; P = .02) and higher enhancement in SF-6D utility score (MD, 0.03 points; 95% CI, 0.003 to 0.01 points; P = .03) but did not have significant differences in other outcome measures. The cost-effectiveness acceptability curve demonstrated a greater than 90% probability that the intervention is cost-effective at a willingness to pay threshold of 1 GDP per capita. Conclusions and Relevance: In this randomized clinical trial, SAA with a brief KHE program was efficacious and cost-effective in relieving knee pain and improving mobility in middle-aged and older adults with probable knee OA. Trial Registration: ClinicalTrials.gov Identifier: NCT04191837.

Acupuncture for primary insomnia: Effectiveness, safety, mechanisms and recommendations for clinical practice.

Primary insomnia (PI) is an increasing concern in modern society. Cognitive-behavioral therapy for insomnia is the first-line recommendation, yet limited availability and cost impede its widespread use. While hypnotics are frequently used, balancing their benefits against the risk of adverse events poses challenges. This review summarizes the clinical and preclinical evidence of acupuncture as a treatment for PI, discussing its potential mechanisms and role in reliving insomnia. Clinical trials show that acupuncture improves subjective sleep quality, fatigue, cognitive impairments, and emotional symptoms with minimal adverse events. It also positively impacts objective sleep processes, including prolonging total sleep time, improving sleep efficiency, reducing sleep onset latency and wake after sleep onset, and enhancing sleep architecture/structure, including increasing N3% and REM%, and decreasing N1%. However, methodological shortcomings in some trials diminish the overall quality of evidence. Animal studies suggest that acupuncture restores circadian rhythms in sleep-deprived rodents and improves their performance in behavioral tests, possibly mediated by various clinical variables and pathways. These may involve neurotransmitters, brain-derived neurotrophic factors, inflammatory cytokines, the hypothalamic-pituitary-adrenal axis, gut microbiota, and other cellular events. While the existing findings support acupuncture as a promising therapeutic strategy for PI, additional high-quality trials are required to validate its benefits.

Electromoxibustion for knee osteoarthritis in older adults: A pilot randomized controlled trial.

BACKGROUND: Electromoxibustion devices are commercially available and can be self-administered by patients. Nevertheless, little is known about the effectiveness and potential burn injury of these devices as this topic is under-investigated. OBJECTIVE: To assess the preliminary effects and safety of an electromoxibustion (EM) device for improving knee pain and joint functions in older adults with knee osteoarthritis (KOA). DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This was a pilot two-armed assessor-blinded randomized controlled trial to assess the effects of electromoxibustion (EM) on older adults with KOA. A total of 38 subjects aged 60 or above, with KOA for 3 months or above were recruited. Participants were randomized to the EM group or the knee health education group. The intervention group (n = 21) received 12 sessions of EM spanning across four weeks, while the control group (n = 17) received two sessions of knee health education. MAIN OUTCOME MEASURES: Primary outcome included the pain severity Numerical Rating Scale (NRS) at baseline and week 4. Secondary outcomes included the Western Ontario and McMaster University Osteoarthritis Index (WOMAC), Short-Form Six-Dimension (SF6D), Timed Up & Go Test (TUG) and Fast Speed Gait (FSG). RESULTS: Both groups showed a decreasing trend in knee pain intensity by NRS at post-intervention. There were also trends of improvement in the WOMAC score, TUG score, FGS test score and SF-6D score at week 4. Only a small between-group effect size (d = 0.13) was found, but medium between-group effects sizes were found in the WOMAC total score (d = 0.40) and WOMAC functional sub-score (d = 0.51). However, the differences were not statistically significant. CONCLUSION: This study suggested that EM may be beneficial for KOA in older adults, particularly in terms of improving knee function. Replication of similar studies in larger RCTs is warranted to confirm the effectiveness of EM on reducing pain and knee function of older adults with KOA. TRAIL REGISTRATION NUMBER: NCT04034394.

Traditional Chinese medicine (TCM) massage for the treatment of congenital muscular torticollis (CMT) in infants and children: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Congenital muscular torticollis (CMT) is a musculoskeletal condition occurring in infants and children. This systematic review is conducted to summarize the current evidence on the effects and safety of TCM massage therapy for the treatment of CMT in infants and children. METHODS: We searched for randomized controlled trials (RCTs) and quasi-RCTs on TCM massage for CMT in PubMed, Embase, CENTRAL, CINAHL, AMED, PsycINFO, Ovid MEDLINE, TCMLARS, ICTRP, CSTJ, CNKI, Wanfang Data, CBM, Taiwan Electronic Periodical Services, and the Index to Taiwan Periodical Literature System. Two reviewers conducted the data collection and analysis separately. Cochrane's collaboration tool was used to assess the risk of bias, and GRADEpro was used to assess the overall quality of the evidence. RevMan 5.3 software was used for data analysis with a random-effect model. RESULTS: A systematic review of six RCTs and one quasi-RCT was conducted with a meta-analysis of two of the RCTs. Pooled analysis showed that TCM massage has similar effects to those of stretching therapy on CMT symptoms in terms of effective rate (risk ratio: 1.00, 95% CI: 0.94-1.06; I2 = 0%; P = 0.99). CONCLUSION: Evidence suggests that TCM massage therapy is beneficial for treating CMT in infants and children. Further clinical trials with high-quality methodologies need to be conducted.

Application of Acupuncture to Attenuate Immune Responses and Oxidative Stress in Postoperative Cognitive Dysfunction: What Do We Know So Far?

Postoperative cognitive dysfunction (POCD) is a common sequela following surgery and hospitalization. The prevention and management of POCD are important during clinical practice. POCD more commonly affects elderly patients who have undergone major surgery and can result in major decline in quality of life for both patients and their families. Acupuncture has been suggested as an effective intervention for many neurological disorders. In recent years, there are increasing interest in the use of acupuncture to prevent and treat POCD. In this review, we summarized the clinical and preclinical evidence of acupuncture on POCD using a narrative approach and discussed the potential mechanisms involved. The experimental details and findings of studies were summarized in tables and analyzed. Most of the clinical studies suggested that acupuncture before surgery could reduce the incidence of POCD and reduce the levels of systematic inflammatory markers. However, their reliability is limited by methodological flaws. Animal studies showed that acupuncture reduced cognitive impairment and the associated pathology after various types of surgery. It is possible that acupuncture modulates inflammation, oxidative stress, synaptic changes, and other cellular events to mitigate POCD. In conclusion, acupuncture is a potential intervention for POCD. More clinical studies with good research design are required to confirm its effectiveness. At the same time, findings from animal studies will help reveal the protective mechanisms, in which systematic inflammation is likely to play a major role.

Silica nanoparticles induce neurodegeneration-like changes in behavior, neuropathology, and affect synapse through MAPK activation.

BACKGROUND: Silica nanoparticles (SiO2-NPs) are naturally enriched and broadly utilized in the manufacturing industry. While previous studies have demonstrated toxicity in neuronal cell lines after SiO2-NPs exposure, the role of SiO2-NPs in neurodegeneration is largely unknown. Here, we evaluated the effects of SiO2-NPs-exposure on behavior, neuropathology, and synapse in young adult mice and primary cortical neuron cultures. RESULTS: Male C57BL/6 N mice (3 months old) were exposed to either vehicle (sterile PBS) or fluorescein isothiocyanate (FITC)-tagged SiO2-NPs (NP) using intranasal instillation. Behavioral tests were performed after 1 and 2 months of exposure. We observed decreased social activity at both time points as well as anxiety and cognitive impairment after 2 months in the NP-exposed mice. NP deposition was primarily detected in the medial prefrontal cortex and the hippocampus. Neurodegeneration-like pathological changes, including reduced Nissl staining, increased tau phosphorylation, and neuroinflammation, were also present in the brains of NP-exposed mice. Furthermore, we observed NP-induced impairment in exocytosis along with decreased synapsin I and increased synaptophysin expression in the synaptosome fractions isolated from the frontal cortex as well as primary neuronal cultures. Extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were also activated in the frontal cortex of NP-exposed mice. Moreover, inhibition of ERK activation prevented NP-mediated changes in exocytosis in cultured neurons, highlighting a key role in the changes induced by NP exposure. CONCLUSIONS: Intranasal instillation of SiO2-NPs results in mood dysfunction and cognitive impairment in young adult mice and causes neurodegeneration-like pathology and synaptic changes via ERK activation.

The Protective Effects of Icariin against the Homocysteine-Induced Neurotoxicity in the Primary Embryonic Cultures of Rat Cortical Neurons.

Icariin, an ingredient in the medicinal herb Epimedium brevicornum Maxim (EbM), has been considered as a potential therapeutic agent for neurodegenerative diseases such as Alzheimer's disease (AD). Hyperhomocysteinaemia is a risk factor for AD and other associated neurological diseases. In this study we aim to investigate whether icariin can reverse homocysteine (Hcy)-induced neurotoxicity in primary embryonic cultures of rat cortical neurons. Our findings demonstrated that icariin might be able restore the cytoskeleton network damaged by Hcy through the modulation of acetyl-α-tubulin, tyrosinated-α-tubulin, and phosphorylation of the tubulin-binding protein Tau. In addition, icariin downregulated p-extracellular signal-regulated kinase (ERK) which is a kinase targeting tau protein. Furthermore, icariin effectively restored the neuroprotective protein p-Akt that was downregulated by Hcy. We also applied RT² Profiler PCR Arrays focused on genes related to AD and neurotoxicity to examine genes differentially altered by Hcy or icariin. Among the altered genes from the arrays, ADAM9 was downregulated 15 folds in cells treated with Hcy, but markedly restored by icariin. ADAM family, encoded α-secreatase, plays a protective role in AD. Overall, our findings demonstrated that icariin exhibits a strong neuroprotective function and have potential for future development for drug treating neurological disorders, such as AD.

Mechanisms underlying the effect of acupuncture on cognitive improvement: a systematic review of animal studies.

Acupuncture has been reported to be beneficial in treating cognitive impairment in various pathological conditions. This review describes the effort to understand the signaling pathways that underlie the acupunctural therapeutic effect on cognitive function. We searched the literature in 12 electronic databases from their inception to November 2013, with full text available and language limited to English. Twenty-three studies were identified under the selection criteria. All recruited animal studies demonstrate a significant positive effect of acupuncture on cognitive impairment. Findings suggest acupuncture may improve cognitive function through modulation of signaling pathways involved in neuronal survival and function, specifically, through promoting cholinergic neural transmission, facilitating dopaminergic synaptic transmission, enhancing neurotrophin signaling, suppressing oxidative stress, attenuating apoptosis, regulating glycometabolic enzymes and reducing microglial activation. However, the quality of reviewed studies has room for improvement. Further high-quality animal studies with randomization, blinding and estimation of sample size are needed to strengthen the recognition of group differences.

From small to big molecules: how do we prevent and delay the progression of age-related neurodegeneration?

Age-related neurodegeneration in the brain and retina is complicated. It comprises a series of events encompassing different modes of degeneration in neurons, as well as inflammation mediated by glial cells. Systemic inflammation and risk factors can contribute to disease progression. Age-related conditions such as Alzheimer's disease (AD), Parkinson's disease (PD) and Age-related Macular Degeneration (AMD) affect patients for 5 to 20 years and are highly associated with risk factors such as hyperhomocysteinaemia, hypercholesterolaemia, hypertension, and symptoms of mood disorder. The long duration of the degeneration and the wide array of systemic factors provide the opportunity for nutraceutical intervention to prevent or delay disease progression. Small molecules such as phenolic compounds are candidates for neuroprotection because they have anti-oxidant activities and can modulate intracellular signaling pathways. Bigger entities such as oligosaccharides and polysaccharides have often been neglected because of their complex structure. However, certain big molecules can provide neuroprotective effects. They may also have a wide spectrum of action against risk factors. In this review we use an integrative approach to the potential uses of nutraceutical products to prevent age-related neurodegeneration. These include direct effects of phenolic compounds and polysaccharides on neurons to antagonize various neurodegenerative mechanisms in AD, PD and AMD, and indirect effects of these compounds on peripheral disease-related risk factors.

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

Alzheimer's 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.

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 Alzheime's 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.

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 Alzheimer's diseases (AD) and Parkinson's 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.

Polysaccharides from wolfberry antagonizes glutamate excitotoxicity in rat cortical neurons.

Glutamate excitotoxicity is involved in many neurodegenerative diseases including Alzheimer's disease (AD). Attenuation of glutamate toxicity is one of the therapeutic strategies for AD. Wolfberry (Lycium barbarum) is a common ingredient in oriental cuisines. A number of studies suggest that wolfberry has anti-aging properties. In recent years, there is a trend of using dried Wolfberry as food supplement and health product in UK and North America. Previously, we have demonstrated that a fraction of polysaccharide from Wolfberry (LBA) provided remarkable neuroprotective effects against beta-amyloid peptide-induced cytotoxicity in primary cultures of rat cortical neurons. To investigate whether LBA can protect neurons from other pathological factors such as glutamate found in Alzheimer brain, we examined whether it can prevent neurotoxicity elicited by glutamate in primary cultured neurons. The glutamate-induced cell death as detected by lactate dehydrogenase assay and caspase-3-like activity assay was significantly reduced by LBA at concentrations ranging from 10 to 500 microg/ml. Protective effects of LBA were comparable to memantine, a non-competitive NMDA receptor antagonist. LBA provided neuroprotection even 1 h after exposure to glutamate. In addition to glutamate, LBA attenuated N-methyl-D-aspartate (NMDA)-induced neuronal damage. To further explore whether LBA might function as antioxidant, we used hydrogen peroxide (H(2)O(2)) as oxidative stress inducer in this study. LBA could not attenuate the toxicity of H(2)O(2). Furthermore, LBA did not attenuate glutamate-induced oxidation by using NBT assay. Western blot analysis indicated that glutamate-induced phosphorylation of c-jun N-terminal kinase (JNK) was reduced by treatment with LBA. Taken together, LBA exerted significant neuroprotective effects on cultured cortical neurons exposed to glutamate.

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.

Characterization of the effects of anti-aging medicine Fructus lycii on beta-amyloid peptide neurotoxicity.

Alzheimer's disease (AD) is an age-related neurodegenerative disease. There are increasing lines of evidence showing that the molecular signaling pathways in aged cells are altered so that cells are susceptible to injury. We and other laboratories have demonstrated the significant involvement of double-stranded RNA-dependent protein kinase (PKR) in beta-amyloid (A beta) peptide neurotoxicity and in AD. Fructus lycii (the fruit of Lycium barbarum) has long been used in oriental medicine as an anti-aging agent. Our previous studies demonstrated that the aqueous extract isolated from L. barbarum exhibited significant protection on cultured neurons against harmful chemical toxins such as A beta and dithiothreitol. We also showed that the polysaccharide-containing extract (LBP) from L. barbarum exhibited neuroprotective effects in the retina against ocular hypertension in a laser-induced glaucoma animal model. In this study, we aimed to investigate whether LBP can elicit neuroprotection to neurons stressed by A beta peptides. Furthermore, we planned to isolate and identify the neuroprotective agent from LBP using chromatographic methods. Our results showed that pretreatment of LBP effectively protected neurons against A beta-induced apoptosis by reducing the activity of both caspase-3 and -2, but not caspase-8 and -9. A new arabinogalactan-protein (LBP-III) was isolated from LBP and attenuated A beta peptide-activated caspase-3-like activity. LBP-III markedly reduced the phosphorylation of PKR triggered by A beta peptide. Since the phosphorylation state of PKR increased with age, reduction of its phosphorylation triggered by A beta peptide may implicate that LBP-III from Fructus lycii is a potential neuroprotective agent in AD. As herbal medicine has received increasing attention for the treatment of AD, our study will open a window for the development of a neuroprotective agent for anti-aging from Chinese medicine.

Characterizing the neuroprotective effects of alkaline extract of Lycium barbarum on beta-amyloid peptide neurotoxicity.

Lycium barbarum is an oriental medicinal herb that has long been used for its anti-aging and cell-protective properties. Previous studies have shown that aqueous extracts from L. barbarum exhibit neuroprotection via inhibiting pro-apoptotic signaling pathways. Other active components can also be accomplished by novel alkaline extraction method, which may give different profiles of water-soluble components. We hypothesize that another active component obtained by alkaline extraction method exerts different biological mechanisms to protect neurons. In this study, we aim to examine the neuroprotective effects from the alkaline extract of L. barbarum, namely LBB, to attenuate beta-amyloid (Abeta) peptide neurotoxicity. Primary cortical neurons were exposed to Abeta-peptides inducing apoptosis and neuronal cell death. Pretreatment of LBB significantly reduced the level of lactate dehydrogenase (LDH) release and the activity of caspase-3 triggered by Abeta. "Wash-out" procedures did not reduce its neuroprotective effects, suggesting that LBB may not bind directly to Abeta. We have further isolated three subfractions from LBB, namely LBB-0, LBB-I and LBB-II. LBB-I and LBB-II showed differential neuroprotective effects. Western blot analysis demonstrated that LBB-I and LBB-II markedly enhanced the phosphorylation of Akt. Taken together, our results suggested that the glycoconjugate isolated from novel alkaline extraction method can open up a new avenue for drug discovery in neurodegenerative diseases.

Cytoprotective effects of Lycium barbarum against reducing stress on endoplasmic reticulum.

Chinese medicinal herbs have been consumed for thousands of years for the purpose of healthy aging. Lycium barbarum is valued in Chinese culture for its benefits to anti-aging, vision, kidney and liver. Recent studies showed that extracts from L. barbarum possess biological activities including anti-aging, anti-tumor, immune-stimulatory and cytoprotection. Most of these studies emphasized that the protective function of L. barbarum is due to its anti-oxidative effects. We have previously demonstrated that extract from L. barbarum can protect neurons against beta-amyloid (Abeta) peptide-induced apoptosis. Since Abeta toxicity may be mediated via oxidative stress, it is still unclear whether the extract from L. barbarum is a simple anti-oxidant exhibiting cytoprotective effects. We hypothesized that extract from L. barbarum is not simply an anti-oxidant in order to function as a neuroprotective agent. The aim of this study is to investigate whether the extract from L. barbarum (LBG) protect neurons via mechanisms independent of anti-oxidative effects. Using a reducing agent, dithiothreitol (DTT), we found that LBG exhibits cytoprotective effects against reducing stress by lowering the DTT-induced LDH release and caspase-3 activity. DTT can trigger endoplasmic reticulum (ER) stress leading to PKR-like ER kinase (PERK) activation. We also showed that LBG attenuates DTT-induced PERK phosphorylation. The extract from L. barbarum is not simply an anti-oxidant; it can also exhibit cytoprotective effects against reducing stress by DTT.