Curcumin is a constituent (up to ∼5%) of the traditional medicine known as turmeric. Interest in the therapeutic use of turmeric and the relative ease of isolation of curcuminoids has led to their extensive investigation. Curcumin has recently been classified as both a PAINS (pan-assay interference compounds) and an IMPS (invalid metabolic panaceas) candidate. The likely false activity of curcumin in vitro and in vivo has resulted in >120 clinical trials of curcuminoids against several diseases. No double-blinded, placebo controlled clinical trial of curcumin has been successful. This manuscript reviews the essential medicinal chemistry of curcumin and provides evidence that curcumin is an unstable, reactive, nonbioavailable compound and, therefore, a highly improbable lead. On the basis of this in-depth evaluation, potential new directions for research on curcuminoids are discussed.

The Essential Medicinal Chemistry of Curcumin

Alzheimer's disease (AD) is a devastating neurodegenerative disorder without a cure. Most AD cases are sporadic where age represents the greatest risk factor. Lack of understanding of the disease mechanism hinders the development of efficacious therapeutic approaches. The loss of synapses in the affected brain regions correlates best with cognitive impairment in AD patients and has been considered as the early mechanism that precedes neuronal loss. Oxidative stress has been recognized as a contributing factor in aging and in the progression of multiple neurodegenerative diseases including AD. Increased production of reactive oxygen species (ROS) associated with age- and disease-dependent loss of mitochondrial function, altered metal homeostasis, and reduced antioxidant defense directly affect synaptic activity and neurotransmission in neurons leading to cognitive dysfunction. In addition, molecular targets affected by ROS include nuclear and mitochondrial DNA, lipids, proteins, calcium homeostasis, mitochondrial dynamics and function, cellular architecture, receptor trafficking and endocytosis, and energy homeostasis. Abnormal cellular metabolism in turn could affect the production and accumulation of amyloid-β (Aβ) and hyperphosphorylated Tau protein, which independently could exacerbate mitochondrial dysfunction and ROS production, thereby contributing to a vicious cycle. While mounting evidence implicates ROS in the AD etiology, clinical trials with antioxidant therapies have not produced consistent results. In this review, we will discuss the role of oxidative stress in synaptic dysfunction in AD, innovative therapeutic strategies evolved based on a better understanding of the complexity of molecular mechanisms of AD, and the dual role ROS play in health and disease.

Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease

Therapeutics of Alzheimer's disease: Past, present and future.

There is substantial interest in the role of plant secondary metabolites as protective dietary agents. In particular, the involvement of flavonoids and related compounds has become a major topic in human nutrition research. Evidence from epidemiological and human intervention studies is emerging regarding the protective effects of various (poly)phenol-rich foods against several chronic diseases, including neurodegeneration, cancer and cardiovascular diseases. In recent years, the use of HPLC-MS for the analysis of flavonoids and related compounds in foods and biological samples has significantly enhanced our understanding of (poly)phenol bioavailability. These advancements have also led to improvements in the available food composition and metabolomic databases, and consequently in the development of biomarkers of (poly)phenol intake to use in epidemiological studies. Efforts to create adequate standardised materials and well-matched controls to use in randomised controlled trials have also improved the quality of the available data. In vitro investigations using physiologically achievable concentrations of (poly)phenol metabolites and catabolites with appropriate model test systems have provided new and interesting insights on potential mechanisms of actions. This article will summarise recent findings on the bioavailability and biological activity of (poly)phenols, focusing on the epidemiological and clinical evidence of beneficial effects of flavonoids and related compounds on urinary tract infections, cognitive function and age-related cognitive decline, cancer and cardiovascular disease.

https://afritradomedic.com/pdf/Rodriguez-Mateos14-Arch%20Tox%20-%20Review%20Polyphenols.pdf

Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: an update

The pathophysiologies of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and Alzheimer’s disease (AD), are far from being fully explained. Oxidative stress (OS) has been proposed as one factor that plays a potential role in the pathogenesis of neurodegenerative disorders. Clinical and preclinical studies indicate that neurodegenerative diseases are characterized by higher levels of OS biomarkers and by lower levels of antioxidant defense biomarkers in the brain and peripheral tissues. In this article, we review the current knowledge regarding the involvement of OS in neurodegenerative diseases, based on clinical trials and animal studies. In addition, we analyze the effects of the drug-induced modulation of oxidative balance, and we explore pharmacotherapeutic strategies for OS reduction.

/pdf/oxidative-stress-in-neurodegenerative-diseases-4msd3rys8x.pdf

Oxidative Stress in Neurodegenerative Diseases

Introduction: Curcumin is a polyphenolic compound derived from the plant Curcuma Long Lin that has been demonstrated to have antioxidant and anti-inflammatory effects as well as effects on reducing beta-amyloid aggregation. It reduces pathology in transgenic models of Alzheimer’s disease (AD) and is a promising candidate for treating human AD. The purpose of the current study is to generate tolerability and preliminary clinical and biomarker efficacy data on curcumin in persons with AD. Methods: We performed a 24-week randomized, double blind, placebo-controlled study of Curcumin C3 Complex ® with an open-label extension to 48 weeks. Thirty-six persons with mild-to-moderate AD were randomized to receive placebo, 2 grams/day, or 4 grams/day of oral curcumin for 24 weeks. For weeks 24 through 48, subjects that were receiving curcumin continued with the same dose, while subjects previously receiving placebo were randomized in a 1:1 ratio to 2 grams/day or 4 grams/day. The primary outcome measures were incidence of adverse events, changes in clinical laboratory tests and the Alzheimer’s Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) at 24 weeks in those completing the study. Secondary outcome measures included the Neuropsychiatric Inventory (NPI), the Alzheimer’s Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scale, levels of Ab1-40 and Ab142 in plasma and levels of Ab1-42, t-tau, p-tau181 and F2-isoprostanes in cerebrospinal fluid. Plasma levels of curcumin and its metabolites up to four hours after drug administration were also measured. Results: Mean age of completers (n = 30) was 73.5 years and mean Mini-Mental Status Examination (MMSE) score was 22.5. One subject withdrew in the placebo (8%, worsened memory) and 5/24 subjects withdrew in the curcumin group (21%, 3 due to gastrointestinal symptoms). Curcumin C3 Complex ® was associated with lowered hematocrit and increased glucose levels that were clinically insignificant. There were no differences between treatment groups in clinical or biomarker efficacy measures. The levels of native curcumin measured in plasma were low (7.32 ng/mL). Conclusions: Curcumin was generally well-tolerated although three subjects on curcumin withdrew due to gastrointestinal symptoms. We were unable to demonstrate clinical or biochemical evidence of efficacy of Curcumin C3 Complex ® in AD in this 24-week placebo-controlled trial although preliminary data suggest limited bioavailability of this compound. Trial registration: ClinicalTrials.gov Identifier: NCT00099710.

https://link.springer.com/content/pdf/10.1186%2Falzrt146.pdf

Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study.

Background: Curcumin is phenolic compound with anti-inflammatory and antioxidant properties that has been shown to have anti-amyloid activity in transgenic mice. The purpose of this study was to obtain tolerability and preliminary efficacy data of 2 gm/day and 4 gm/day of Curcumin C3 Complex in mild-to-moderate AD patients in a 24-week, randomized, double-blind study. Methods: Thirty-six patients were randomized to receive placebo, 2 gm, or 4 gm per day of curcumin in two divided doses. The MMSE, ADAS-Cog, NPI, and ADCS-ADL scales were performed at baseline and at 24 weeks’ time. Plasma and cerebrospinal fluid (CSF) samples were obtained at baseline and 24 weeks and Abeta40, Abeta42 measured in plasma and CSF and total tau and p-tau181 measured in CSF. Baseline and 24-week values were compared between groups using repeated measures ANOVA. Adverse events were recorded and the frequency of any adverse event at each visit compared between groups by chi-square. Results: Subjects’ age (mean 74 years), gender (62% female), baseline MMSE (mean 22.6), ADAS-Cog, NPI, and ADCS-ADL scores did not differ between treatment groups. 11 subjects on placebo, 9 on 2 grams and 10 on 4 grams of curcumin completed the study. In completer analyses, there were no differences or favorable trends between placebo and treatment groups on clinical measures. No difference in plasma or CSF biomarkers were found between groups except for a tendency (p 0.14) towards a lesser degree of increase in plasma Abeta42 in the combined group on 2 and 4 gm/day of curcumin. There were no differences between placebo and all treated patients’ change in laboratory values nor in the frequency of adverse events at any treatment visit. Conclusions: Orally administered Curcumin C3 Complex is safe in elderly persons treated for 24 weeks at doses up to 4 gm/day. Our data do not provide evidence for a large effect of curcumin on clinical and biochemical measures in mild-tomoderate AD patients at doses up to 4 gm/day. Limitations of this study include the small sample, short duration of treatment, and uncertain bioavailability of this curcumin formulation. Further analyses of clinical, pharmacokinetic, and biomarker data are pending.

P4-344: Oral curcumin for the treatment of mild-to-moderate Alzheimer's disease: Tolerability and clinical and biomarker efficacy results of a placebo-controlled 24-week study

Vladimir Badmaev

Papers

Oral curcumin for Alzheimer's disease: tolerability and efficacy in a 24-week randomized, double blind, placebo-controlled study.

P4-344: Oral curcumin for the treatment of mild-to-moderate Alzheimer's disease: Tolerability and clinical and biomarker efficacy results of a placebo-controlled 24-week study