Kahweol Induces Apoptosis in Hepatocellular Carcinoma Cells by Inhibiting the Src/mTOR/STAT3 Signaling Pathway.

Kahweol, a coffee-specific diterpene, induces apoptosis in human cancer cells, and some targets of kahweol-mediated apoptosis have been identified. However, the specific apoptotic effects and mechanism of action of kahweol in hepatocellular carcinoma (HCC) cells are unknown. This study was performed to investigate the molecular mechanism by which kahweol induces apoptosis in HCC cells. The Src pathway is associated with apoptosis in cancer. In this study, we found that kahweol induces apoptosis by inhibiting phosphorylation of Src, and also inhibiting p-mTOR and p-STAT3. Therefore, we suggest that kahweol is a potent inhibitor of HCC cell growth.

Prescription Opioid Use in Patients With and Without Systemic Lupus Erythematosus - Michigan Lupus Epidemiology and Surveillance Program, 2014-2015.

Rheumatic diseases are a leading cause of chronic, noncancer pain. Systemic lupus erythematosus (SLE) is a chronic autoimmune rheumatic disease characterized by periodic flares that can result in irreversible target organ damage, including end-stage renal disease. Both intermittent and chronic musculoskeletal pain, as well as fibromyalgia (considered a centralized pain disorder due to dysregulation of pain processing in the central nervous system), are common in SLE. Opioids are generally not indicated for long-term management of musculoskeletal pain or centralized pain (fibromyalgia) because of lack of efficacy, safety issues ranging from adverse medical effects to overdose, and risk for addiction (1,2). In this study of 462 patients with SLE from the population-based Michigan Lupus Epidemiology and Surveillance (MILES) Cohort and 192 frequency-matched persons without SLE, nearly one third (31%) of SLE patients were using prescription opioids during the study period (2014-2015), compared with 8% of persons without SLE (p<0.001). Among the SLE patients using opioids, 97 (68%) were using them for >1 year, and 31 (22%) were concomitantly on two or more opioid medications. Among SLE patients, those using the emergency department (ED) were approximately twice as likely to use prescription opioids (odds ratio [OR] = 2.1; 95% confidence interval [CI] = 1.3-3.6; p = 0.004). In SLE, the combined contributions of underlying disease and adverse effects of immunosuppressive and glucocorticoid therapies already put patients at higher risk for some known adverse effects attributed to long-term opioid use. Addressing the widespread and long-term use of opioid therapy in SLE will require strategies aimed at preventing opioid initiation, tapering and discontinuation of opioids among patients who are not achieving treatment goals of reduced pain and increased function, and consideration of nonopioid pain management strategies.

Prevalence and Factors Associated with De-escalation of Anti-TNFs in Older Adults with Rheumatoid Arthritis: A Medicare Claims-Based Observational Study.

OBJECTIVE: The aim was to evaluate prevalence and factors associated with anti-tumor necrosis factor (anti-TNF) de-escalation in older adults with rheumatoid arthritis (RA). METHODS: We identified adults ≥ 66 years of age with RA on anti-TNF therapy within 6 months after RA diagnosis with at least 6-7 months duration of use (proxy for stable use), using 20% Medicare data from 2008-2017. Patient demographic and clinical characteristics, including concomitant use of glucocorticoid (GC), were collected. Anti-TNF use was categorized as either de-escalation (identified by dosing interval increase, dose reduction, or cessation of use) or continuation. We used (1) an observational cohort design with Cox regression to assess patient characteristics associated with de-escalation and (2) a case-control design with propensity score-adjusted logistic regression to assess the association of de-escalation with different clinical conditions and concomitant medication use. RESULTS: We identified 5106 Medicare beneficiaries with RA on anti-TNF, 65.5% of whom had de-escalation. De-escalation was more likely with older age (hazard ratio [HR] 1.01, 95% confidence interval [CI] 1.01-1.02) or greater comorbidity (HR 1.07, 95% CI 1.05-1.09), but was less likely with low-income subsidy status (HR 0.85, 95% CI 0.78-0.92), adjusting for patient sex and race/ethnicity. Lower odds of de-escalation were associated with serious infection (odds ratio [OR] 0.79, 95% CI 0.66-0.94), new heart failure diagnosis (OR 0.70, 95% CI 0.52-0.95), and long-term GC use (OR 0.84, 95% CI 0.74-0.95), whereas higher odds were associated with concomitant methotrexate use (OR 1.16, 95% CI 1.03-1.31). CONCLUSIONS: Anti-TNFs are de-escalated in two-thirds of older adults with RA in usual care. Further study is needed on RA outcomes after anti-TNF de-escalation.

Deprescribing medications among patients with multiple prescribers: A socioecological model.

Deprescribing is the intentional dose reduction or discontinuation of a medication. The development of deprescribing interventions should take into consideration important organizational, interprofessional, and patient-specific barriers that can be further complicated by the presence of multiple prescribers involved in a patient's care. Patients who receive care from an increasing number of prescribers may experience disruptions in the timely transfer of relevant healthcare information, increasing the risk of exposure to drug-drug interactions and other medication-related problems. Furthermore, the fragmentation of healthcare information across health systems can contribute to the refilling of discontinued medications, reducing the effectiveness of deprescribing interventions. Thus, deprescribing interventions must carefully consider the unique characteristics of patients and their prescribers to ensure interventions are successfully implemented. In this special article, an international working group of physicians, pharmacists, nurses, epidemiologists, and researchers from the United States Deprescribing Research Network (USDeN) developed a socioecological model to understand how multiple prescribers may influence the implementation of a deprescribing intervention at the individual, interpersonal, organizational, and societal level. This manuscript also includes a description of the concept of multiple prescribers and outlines a research agenda for future investigations to consider. The information contained in this manuscript should be used as a framework for future deprescribing interventions to carefully consider how multiple prescribers can influence the successful implementation of the service and ensure the intervention is as effective as possible.

Frailty and Risk of Serious Infections in Patients With Rheumatoid Arthritis Treated With Biologic or Targeted-Synthetic Disease-Modifying Antirheumatic Drugs.

OBJECTIVE: It remains unknown whether frailty status portends an increased risk of adverse outcomes in patients with rheumatoid arthritis (RA) initiating biologic or targeted-synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The objective of our study was to evaluate the association between frailty and serious infections in a younger population of patients (<65 years old) with RA who initiated b/tsDMARDs. METHODS: Using MarketScan data, we identified new users of tumor necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs, or Janus kinase inhibitors (JAKi) between 2008 and 2019 among those with RA. Patients' baseline frailty risk score was calculated using a Claims-Based Frailty Index (≥0.2 defined as frail) 12 months prior to drug initiation. The primary outcome was time to serious infection; secondarily, we examined time-to-any infection and all-cause hospitalizations. We used Cox proportional hazards to estimate adjusted hazard ratios and 95% confidence intervals (95% CIs) and assessed the significance of interaction terms between frailty status and drug class. RESULTS: A total of 57,980 patients, mean (±SD) age 48.1 ± 10.1 were included; 48,139 (83%) started TNFi, 8,111 (14%) non-TNFi biologics, and 1,730 (3%) JAKi. Among these, 3,560 (6%) were categorized as frail. Frailty was associated with a 50% increased risk of serious infections (adjusted hazard ratio [95% CI] 1.5, 1.2-1.9) and 40% higher risk of inpatient admissions (1.4 [1.3-1.6]) compared with nonfrail patients among those who initiated TNFi. Frailty was also associated with a higher risk of any infection relative to nonfrail patients among those on TNFi (1.2 [1.1-1.3]) or non-TNFi (1.2 [1.0-1.4]) or JAKi (1.4 [1.0-2.0]). CONCLUSION: Frailty is an important predictor for the risk of adverse outcomes among patients with RA treated with biologic or targeted-synthetic DMARDs.

Initiation of Disease-Modifying Antirheumatic Drugs in Older Medicare Beneficiaries With New Diagnosis of Late-Onset Rheumatoid Arthritis.

OBJECTIVE: Older adults with rheumatoid arthritis (RA) account for up to one-third of the RA population and are less likely to receive optimal treatment. For the subgroup of older adults with late-onset RA (LORA), who experience more symptomatic and progressive disease, suboptimal treatment could be more consequential than the general population who age with RA. We evaluated use of disease-modifying antirheumatic drugs (DMARDs) in older adults with a new diagnosis of LORA. METHODS: In this retrospective observational study, we identified adults 66 years of age or older with a new diagnosis of LORA using Medicare data from 2008 to 2017. Information on baseline patient characteristics and DMARD initiation during the first 12 months after LORA diagnosis were collected. We also assessed concomitant use of glucocorticoids (GCs). RESULTS: We identified 33,373 older adults with new diagnosis of LORA. Average age at LORA diagnosis was 76.7 (SD 7.6); 75.4% were female, 76.9% were White, and 35.6% had low-income subsidy (LIS). Less than one-third were initiated on a DMARD (28.9%). In multivariable analyses, DMARD initiation was associated with younger age, fewer comorbidities, and absence of LIS status. Concomitant long-term (>3 months) GC use was higher among those on any DMARD (44.3%) compared with those without (15.2%). CONCLUSIONS: DMARD initiation after new diagnosis of LORA is low despite current clinical practice guidelines recommending early aggressive initiation of treatment. Long-term GC use is common among those on any DMARDs, raising concern for suboptimal DMARD use. Further studies are needed to understand drivers of DMARD use in older adults.

Provider Specialty and the Use of Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis Among Older Adults in the 2005-2016 National Ambulatory Medical Care Survey.

OBJECTIVE: We compared disease-modifying antirheumatic drug (DMARD) use for older adults with rheumatoid arthritis (RA)-related ambulatory visits from rheumatologists and primary care providers (PCPs). METHODS: In this study of national sample office visits, we characterized ambulatory visits by older adults 65 years of age or older seen by rheumatologists or PCPs for diagnosis of RA using the 2005-2016 National Ambulatory Medical Care Survey. We analyzed patterns and trends of DMARD use using descriptive statistics and multivariable analyses by provider specialty. RESULTS: We identified 518 observations representing 7,873,246 ambulatory RA visits by older adults over 12 years; 74% were with rheumatologists. Any DMARD use was recorded at 56% of rheumatologist and 30% of PCP visits. Among visits with any DMARD use, 20% of rheumatologist visits had two or more DMARDs compared with 6% of PCP visits. Over the 12-year study period, there was no statistical difference in trend of any or conventional synthetic DMARD use at visits by provider specialty, adjusted for patient characteristics, non-DMARD polypharmacy and multimorbidity. However, biologic DMARD use was more likely to incrementally increase with rheumatologist compared with PCP visits (P = 0.003). CONCLUSION: DMARD use for older adults with RA remains low from both rheumatologists and PCPs, including biologic DMARDs, even though American College of Rheumatology guidelines recommend earlier and more aggressive treatment of RA. With predicted shortages in the rheumatology workforce and maldistribution of rheumatology providers, PCPs may play an increasingly important role in caring for older adults with RA. Further research is needed to understand to optimize appropriate use of DMARDs in older patients with RA.

Optimizing Medication Use in Older Adults With Rheumatic Musculoskeletal Diseases: Deprescribing as an Approach When Less May Be More.

The world population is aging, and the rheumatology workforce must be prepared to care for medically complex older adults. We can learn from our colleagues and experts in geriatrics about how to best manage multimorbidity, polypharmacy, geriatric syndromes, and shifting priorities of older adults in the context of delivering care for rheumatic and musculoskeletal diseases (RMDs). Polypharmacy, a common occurrence in an aging population with multimorbidity, affects half of older adults with RMDs and is associated with increased risk of morbidity and mortality. In addition, potentially inappropriate medications that should be avoided under most circumstances is common in the RMD population. In recent years, deprescribing, known as the process of tapering, stopping, discontinuing, or withdrawing drugs, has been introduced as an approach to improve appropriate medication use among older adults and the outcomes that are important to them. As the rheumatology patient population ages globally, it is imperative to understand the burden of polypharmacy and the potential of deprescribing to improve medication use in older adults with RMDs. We encourage the rheumatology community to implement geriatric principles, when possible, as we move toward becoming an age-friendly health care specialty.

In Situ Supramolecular Gel Formed by Cyclohexane Diamine with Aldehyde Derivative.

Low-molecular-weight gels have great potential for use in a variety of fields, including petrochemicals, healthcare, and tissue engineering. These supramolecular gels are frequently metastable, implying that their properties are kinetically controlled to some extent. Here, we report on the in situ supramolecular gel formation by mixing 1,3-cyclohexane diamine (1) and isocyanate derivative (2) without any catalysis at room temperature in various organic solvents. A mixture of building blocks 1 and 2 in various organic solvents, dichloromethane, tetrahydrofuran, chloroform, toluene, and 1,4-dioxane, resulted in the stable formation of supramolecular gel at room temperature within 60-100 s. This gel formation was caused by the generation of urea moieties, which allows for the formation of intermolecular hydrogen-bonding interactions via reactions 1 and 2. In situ supramolecular gels demonstrated a typical entangled fiber structure with a width of 600 nm and a length of several hundred µm. In addition, the supramolecular gels were thermally reversible by heating and cooling. The viscoelastic properties of supramolecular gels in strain and frequency sweets were enhanced by increasing the concentration of a mixed 1 and 2. Furthermore, the supramolecular gels displayed a thixotropic effect, indicating a thermally reversible gel.

Incidence of and risk factors for colistin-associated nephrotoxicity in a large academic health system.

BACKGROUND: Colistin, originally abandoned due to high rates of nephrotoxicity, has been recently reintroduced due to activity against carbapenem-resistant Gram-negative organisms. Recent literature, largely obtained from outside the United States, suggests a lower rate of nephrotoxicity than historically reported. METHODS: A retrospective cohort of all patients who received colistin for ≥ 48 hours at the Detroit Medical Center over a 5-year period was performed to determine the rate of colistin-associated nephrotoxicity as defined by the RIFLE criteria. RESULTS: Fifty-four (43%) patients in the cohort developed nephrotoxicity. Patients who experienced nephrotoxicity after colistin administration were in the Risk (13%), Injury (17%), or Failure (13%) categories per RIFLE criteria. Patients who developed nephrotoxicity received significantly higher mean doses than those who did not (5.48 mg/kg per day vs 3.95 mg/kg per day; P < .001), and the toxicity occurred in a dose-dependent fashion. Independent predictors for nephrotoxicity were a colistin dose of ≥ 5.0 mg/kg per day of ideal body weight (odds ratio [OR], 23.41; 95% confidence interval [CI], 5.3-103.55), receipt of concomitant rifampin (OR, 3.81; 95% CI, 1.42-10.2), and coadministration of ≥ 3 concomitant nephrotoxins (OR, 6.80; 95% CI, 1.42-32.49). CONCLUSIONS: In this retrospective cohort, nephrotoxicity (as defined by RIFLE criteria) occurred among 43% of treated patients in a dose-dependent manner. Higher colistin doses, similar to those commonly used in the United States, led to a relatively high rate of nephrotoxicity. These data raise important questions regarding the safe use of colistin in the treatment of multidrug-resistant pathogens.

Medicare beneficiary panel characteristics associated with high Part D biologic disease-modifying anti-rheumatic drug prescribing for older adults among rheumatologists.

ABSTRACT: The aim of this study was to investigate beneficiary panel characteristics associated with rheumatologists' prescribing of biologic DMARDs (bDMARDs) for older adults.In this retrospective observational study, we used Medicare Public Use Files (PUFs) to identify rheumatologists who met criteria for high-prescribing, defined as bDMARD prescription constituting ≥20% of their DMARD claims for beneficiaries ≥65 years of age. We first used descriptive analysis then multivariable regression model to test the association of high prescribing of bDMARDs with rheumatologists' panel size and beneficiary characteristics. In particular, we quantified the proportion of panel beneficiaries ≥75 years of age to assess how caring for an older panel correlate with prescribing of bDMARDs.We identified 3197 unique rheumatologists, of whom 405 (13%) met criteria for high prescribing of bDMARDs for Medicare beneficiaries ≥65 years of age. The high-prescribers provided care to 12% of study older adults, and yet accounted for 21% of bDMARD prescriptions for them. High prescribing of bDMARDs was associated with smaller panel size, and their beneficiaries were more likely to be non-black, ≥75 years of age, non-dual eligible, have diagnosis of CHF, however, less likely to have CKD.Rheumatologists differ in their prescribing of bDMARDs for older adults, and those caring for more beneficiaries ≥75 years of age are more likely to be high-prescribers. Older adults are more prone to the side-effects of bDMARDs and further investigation is warranted to understand drivers of differential prescribing behaviors to optimize use of these high-risk and high-cost medications.

Access and Cost-Related Nonadherence to Prescription Medications Among Lupus Patients and Controls: The Michigan Lupus Epidemiology and Surveillance Program.

OBJECTIVE: Medication access and adherence are important determinants of health outcomes. We investigated factors associated with access and cost-related nonadherence to prescriptions in a population-based cohort of systemic lupus erythematosus (SLE) patients and controls. METHODS: Detailed sociodemographic and prescription data were collected by structured interview in 2014-2015 from participants in the Michigan Lupus Epidemiology and Surveillance (MILES) cohort. We compared access between cases and frequency-matched controls and examined associated factors in separate multivariable logistic regression models. RESULTS: A total of 654 participants (462 SLE patients, 192 controls) completed the baseline visit; 584 (89%) were female, 285 (44%) were Black, and the mean age was 53 years. SLE patients and controls reported similar frequencies of being unable to access prescribed medications (12.1% versus 9.4%, respectively; P was not significant). SLE patients were twice as likely as controls to report cost-related prescription nonadherence in the preceding 12 months to save money (21.7% versus 10.4%; P = 0.001) but were also more likely to ask their doctor for lower cost alternatives (23.8% versus 15.6%; P = 0.02). Disparities were found in association with income, race, and health insurance status, but the main findings persisted after adjusting for these and other variables in multivariable models. CONCLUSION: SLE patients were more likely than controls from the general population to report cost-related prescription nonadherence, including skipping doses, taking less medicine, and delaying filling prescriptions; yet, <1 in 4 patients asked providers for lower cost medications. Consideration of medication costs in patient decision-making could provide a meaningful avenue for improving access and adherence to medications.

Kahweol activates the Nrf2/HO-1 pathway by decreasing Keap1 expression independently of p62 and autophagy pathways.

Kahweol is a diterpene found in coffee beans and unfiltered coffee drinks. Several studies have demonstrated that kahweol induces the nuclear factor erythroid-2 related factor 2/ hemeoxygenase-1 (Nrf2/HO-1) pathway; however, the mechanisms involved are currently unknown. Kelch-like ECH-associated protein 1 (Keap1) is a major regulator of Nrf2 expression and is degraded mostly by autophagy. The p62 protein enhances binding to Keap1 and contributes to the activation of Nrf2. Here, we examined the role of Keap1 regulation in the effect of kahweol on the Nrf2/HO-1 pathway in hepatocytes. In AML12 cells and primary mouse hepatocytes, kahweol increased the levels of Nrf2 and HO-1 protein without increasing expression of the Nrf2 mRNA. In addition, kahweol reduced Keap1 protein levels significantly without decreasing Keap1 mRNA levels. Although regulation of the Keap1-Nrf2-pathway by p62-dependent autophagy is well known, we confirmed here that the reduction of Keap1 protein levels by kahweol does not involve p62-dependent autophagy degradation or ubiquitination. In conclusion, kahweol increases the expression of Nrf2 in hepatocytes by inhibiting translation of the Keap1 mRNA.

Src Inhibition Attenuates Liver Fibrosis by Preventing Hepatic Stellate Cell Activation and Decreasing Connetive Tissue Growth Factor.

The SRC kinase family comprises non-receptor tyrosine kinases that are ubiquitously expressed in all cell types. Although Src is reportedly activated in pulmonary and renal fibrosis, little is known regarding its role in liver fibrosis. This study investigated whether the inhibition of Src protects against liver fibrosis. The expression of Src was upregulated in thioacetamide (TAA)-induced fibrotic mouse liver and cirrhosis of patients, and phospho-Src was upregulated during activation of hepatic stellate cells (HSC). In addition, Src inhibition reduced the expression of α-smooth muscle actin (αSMA) in primary HSCs and suppressed transforming growth factor ß (TGF-ß)-induced expression of connective tissue growth factor (CTGF) in hepatocytes. Src inhibitor Saracatinib also attenuated TAA-induced expression of type I collagen, αSMA, and CTGF in mouse liver tissues. The antifibrotic effect of Src inhibitors was associated with the downregulation of smad3, but not of signal transducer and activator of transcription 3 (STAT3). In addition, Src inhibition increased autophagy flux and protected against liver fibrosis. These results suggest that Src plays an important role in liver fibrosis and that Src inhibitors could be treat liver fibrosis.

Opioid dispensation among systemic lupus erythematosus patients who persistently frequent the emergency department.

OBJECTIVE: To understand prevalence and factors associated with opioid dispensation among systemic lupus erythema-tosus (SLE) patients who persistently frequent the emergency department (ED) to improve quality of care. METHODS: In this retrospective observational cohort study, the authors identified SLE patients who persistently fre-quented the ED, defined as having three or more ED visits over 12 months, for at least 2 out of 4 years between 2013 and 2016. The authors collected patient-level variables including demographics and long-term opioid therapy (LTOT). Each encounter was categorized as: SLE-, infection-, pain-related, or "other." Additional encounter-level variables such as healthcare resource utilization and disposition were recorded. The authors used mixed effects multivariate logistic regression to analyze factors associated with (1) opioid administration in the ED and (2) opioid prescription upon dis-charge from the ED. RESULTS: Seventy-seven SLE patients having 1,143 encounters were identified as persistently frequent ED users. Opioids were administered in the ED for 38 percent of all encounters. Medicaid, LTOT, physician as the ED provider versus advanced-practice providers, more imaging tests, and rheumatology specialty consultation were associated with increased odds of opioid administration in the ED. Opioids were prescribed on discharge for 17 percent of encounters discharged from the ED. African American patients, those on Medicaid, and patients utilizing the ED for SLE-related activity/complications compared to "other" reasons were more likely to receive opioid prescription upon discharge from the ED than their respective counterparts. CONCLUSION: Opioids are commonly dispensed in the ED for SLE patients. This is true even for patients utilizing the ED for SLE-related disease activity/complications.

Persistently Frequent Emergency Department Utilization Among Persons With Systemic Lupus Erythematosus.

OBJECTIVE: In order to identify opportunities to improve outpatient care, we evaluated patients with systemic lupus erythematosus (SLE) who persistently frequent the emergency department (ED). METHODS: We conducted a retrospective study of patients with SLE who frequented the ED for ≥3 visits in a calendar year, from 2013 to 2016. Persistent users were those who met criteria for persistent use for at least 2 of the 4 years, and limited users for 1 of the 4 years. Each ED encounter was categorized as SLE-related, infection-related, pain-related, or other. We compared ED use between persistent and limited users, and analyzed factors associated with pain-related encounters among persistent users through multivariate logistic regression. RESULTS: We identified 77 participants who had 1,143 encounters as persistent users, and 52 participants who had 335 encounters as limited users. Persistent users accounted for 77% of ED use by patients with SLE who frequented the ED. Pain-related ED visits were more common among persistent users (32%) than limited users (18%). Among persistent users, most pain-related encounters were discharged from the ED (69%) or within 48 hours of admission (20%). Persistent users with pain-related encounters accounting for >10% of ED use were more likely to be obese, have fewer comorbid conditions, and be on long-term opioid therapy. CONCLUSION: Pain is a major cause of ED use. Patients with SLE who persistently utilize the ED for pain are likely to be noncritically ill, as evidenced by frequent discharges from the ED and short-stay admissions. Patients with SLE who persistently frequent the ED for pain represent a viable target for interventions to improve outpatient quality of care.

Clusterin Attenuates Hepatic Fibrosis by Inhibiting Hepatic Stellate Cell Activation and Downregulating the Smad3 Signaling Pathway.

Clusterin is a glycoprotein that is expressed in most human tissues and found in body fluids. In our previous studies we demonstrated that clusterin has a protective effect against hepatic lipid accumulation and renal fibrosis; however, the role of clusterin in hepatic fibrosis is unknown. Here, we examined whether clusterin had protective effects against hepatic fibrosis using in vitro and in vivo models. Clusterin was upregulated in the livers of human cirrhotic patients and in thioacetamide (TAA)-induced and bile duct ligation mouse models of liver fibrosis. Loss and overexpression of clusterin promoted and attenuated hepatic fibrosis after TAA injection, respectively. In addition, we found that clusterin attenuates hepatic fibrosis by inhibiting the activation of hepatic stellate cells and Smad3 signaling pathways. Thus, clusterin plays an important role in hepatic fibrosis.

Epicatechin Prevents Methamphetamine-Induced Neuronal Cell Death via Inhibition of ER Stress.

Methamphetamine (METH) acts strongly on the nervous system and damages neurons and is known to cause neurodegenerative diseases such as Alzheimer's and Parkinson's. Flavonoids, polyphenolic compounds present in green tea, red wine and several fruits exhibit antioxidant properties that protect neurons from oxidative damage and promote neuronal survival. Especially, epicatechin (EC) is a powerful flavonoid with antibacterial, antiviral, antitumor and antimutagenic effects as well as antioxidant effects. We therefore investigated whether EC could prevent METH-induced neurotoxicity using HT22 hippocampal neuronal cells. EC reduced METH-induced cell death of HT22 cells. In addition, we observed that EC abrogated the activation of ERK, p38 and inhibited the expression of CHOP and DR4. EC also reduced METH-induced ROS accumulation and MMP. These results suggest that EC may protect HT22 hippocampal neurons against METH-induced cell death by reducing ER stress and mitochondrial damage.