curcumin and Cognitive-Dysfunction

Due to the global increase in lifespan, the proportion of people showing cognitive impairment is expected to grow exponentially. As target-specific drugs capable of tackling dementia are lagging behind, the focus of preclinical and clinical research has recently shifted towards natural products. Curcumin, one of the best investigated botanical constituents in the biomedical literature, has been receiving increased interest due to its unique molecular structure, which targets inflammatory and antioxidant pathways. These pathways have been shown to be critical for neurodegenerative disorders such as Alzheimer's disease and more in general for cognitive decline. Despite the substantial preclinical literature on the potential biomedical effects of curcumin, its relatively low bioavailability, poor water solubility and rapid metabolism/excretion have hampered clinical trials, resulting in mixed and inconclusive findings. In this review, we highlight current knowledge on the potential effects of this natural compound on cognition. Furthermore, we focus on new strategies to overcome current limitations in its use and improve its efficacy, with attention also on gender-driven differences.

Topics: Anti-Inflammatory Agents; Cognitive Dysfunction; Curcuma; Glucose; Homeostasis; Humans; Inflammation

The rate of cognitive decline in the elderly is highly variable. One potential factor contributing to accelerated cognitive decline is chronic systemic inflammation, because it has been linked to cognitive impairment and increased dementia risk. Certain lifestyle factors, such as excess body weight and sedentary behavior, can exacerbate a proinflammatory state in older adults, resulting in chronic low-grade inflammation. Supplementing the diet with curcumin, an anti-inflammatory polyphenolic compound from the curry spice turmeric, is a potential approach to prevent accelerated cognitive decline by counteracting chronic inflammatory processes. Although the anti-inflammatory effects of curcumin are well established, the potential cognitive benefits of curcumin were discovered more recently. Several animal and epidemiologic studies on the effect of curcumin supplementation on cognition showed promising results; however, randomized controlled trials in humans are limited. In this review, we identified 5 randomized controlled trials, of which only 2 observed a beneficial effect of curcumin supplementation on cognition by improving working memory. By critically examining the methodologies of those studies, we identified some limitations, one of which is that none of the studies explored the possibility that anti-inflammatory mechanisms were mediating cognitive benefits (i.e., no study tested participants with low-grade inflammation or measured inflammatory biomarkers). Other factors influencing the likelihood of conclusive outcomes include choice of study population (cognitively unimpaired compared with impaired), study duration, curcumin dose and its bioavailability, and neurocognitive test battery. On the basis of these findings, we offer recommendations for future studies to examine the potential cognitive benefits of curcumin in humans, which include evaluating its effects on cerebral endothelial vasodilator function and boosting its cognitive effects by combining it with long-chain omega-3 (n-3) fatty acids.

Topics: Animals; Anti-Inflammatory Agents; Cognition; Cognitive Dysfunction; Curcuma; Curcumin; Dementia; Dietary Supplements; Fatty Acids, Omega-3; Female; Humans; Inflammation; Male; Memory; Phytotherapy; Polyphenols

Processes such as aberrant redox signaling and chronic low-grade systemic inflammation have been reported to modulate age-associated pathologies such as cognitive impairment. Curcumin, the primary therapeutic component of the Indian spice, Turmeric (Curcuma longa), has long been known for its strong anti-inflammatory and antioxidant activity attributable to its unique molecular structure. Recently, an interest in this polyphenol as a cognitive therapeutic for the elderly has emerged. The purpose of this paper is to critically review preclinical and clinical studies that have evaluated the efficacy of curcumin in ameliorating and preventing age-associated cognitive decline and address the translational progress of preclinical to clinical efficacy. PubMed, semantic scholar, and Google scholar searches were used for preclinical studies; and clinicaltrials.gov , the Australian and New Zealand clinical trials registry, and PubMed search were used to select relevant completed clinical studies. Results from preclinical studies consistently demonstrate curcumin and its analogues to be efficacious for various aspects of cognitive impairment and processes that contribute to age-associated cognitive impairment. Results of published clinical studies, while mixed, continue to show promise for curcumin's use as a therapeutic for cognitive decline but overall remain inconclusive at this time. Both in vitro and in vivo studies have found that curcumin can significantly decrease oxidative stress, systemic inflammation, and obstruct pathways that activate transcription factors that augment these processes. Future clinical studies would benefit from including evaluation of peripheral and cerebrospinal fluid biomarkers of dementia and behavioral markers of cognitive decline, as well as targeting the appropriate population.

Topics: Aged; Aged, 80 and over; Aging; Animals; Animals, Genetically Modified; Australia; Cognitive Dysfunction; Cohort Studies; Curcumin; Female; Humans; Inflammation; Male; Middle Aged; Models, Animal; Narration; New Zealand; Oxidative Stress; Treatment Outcome

Cognitive impairment results from a complex interplay of many factors. The most important independent predictor of cognitive decline is age but other contributing factors include demographic, genetic, socio-economic, and environmental parameters, including nutrition. The number of persons with cognitive decline and dementia will increase in the next decades in parallel with aging of the world population. Effective pharmaceutical treatments for age-related cognitive decline are lacking, emphasizing the importance of prevention strategies. There is extensive evidence supporting a relationship between diet and cognitive functions. Thus, nutritional approaches to prevent or slow cognitive decline could have a remarkable public health impact. Several dietary components and supplements have been examined in relation to their association with the development of cognitive decline. A number of studies have examined the role of dietary patterns on late-life cognition, with accumulating evidence that combinations of foods and nutrients may act synergistically to provide stronger benefit than those conferred by individual dietary components. Higher adherence to the Mediterranean dietary pattern has been associated with decreased cognitive decline and incident AD. Another dietary pattern with neuroprotective actions is the Dietary Approach to Stop Hypertension (DASH). The combination of these two dietary patterns has been associated with slower rates of cognitive decline and significant reduction in incident AD. This review evaluates the evidence for the effects of some dietary components, supplements, and dietary patterns as neuroprotective, with potential to delay cognitive decline and the onset of dementia.

Topics: Antioxidants; Autophagy; Caffeine; Catechin; Central Nervous System Stimulants; Chocolate; Cognitive Dysfunction; Curcumin; Dementia; Diet; Fatty Acids, Omega-3; Garlic; Ginkgo biloba; Healthy Aging; Humans; Inflammation; Magnesium; Oxidative Stress; Phytoestrogens; Phytotherapy; Resveratrol; Tea; Vitamins

Mild cognitive impairment (MCI) refers to a state in which cognitive functions, such as memory, have diminished but daily activities are largely unhampered. MCI is often overlooked but carries the risk of leading to development of dementia later. Curcumin is the main component of the natural herbal medicine turmeric. Curcumin is widely used as a health food and is an antioxidant that has anti-inflammatory and anti-amyloid actions. The current trial was designed to determine the effects of curcumin on indicators of cognitive functioning.. The current trial will be a single-centre randomised placebo-controlled double-blind parallel group trial. The participants will be 60 members of the general public with potential MCI, based on dementia screening using the Japanese version of the Mini Mental State Examination (MMSE-J). The investigational health food used in this trial will be a recently developed preparation for highly absorbable oral curcumin. This trial will determine the effects of the highly absorbable oral curcumin (brand name: curcuRouge) on the indicators of cognitive functioning, including the scores obtained with the MMSE-J, which is an interview-based measure of cognitive functioning, and the blood biomarkers that have been reported to be associated with dementia.. Informed written consent will be obtained from all the participants. The Ethical Review Board of the National Hospital Organization Kyoto Medical Center approved the study protocol.. University Hospital Medical Information Network (UMIN000042471).

Topics: Antioxidants; Cognition; Cognitive Dysfunction; Curcumin; Dementia; Humans; Randomized Controlled Trials as Topic

Curcumin (a flavonoid isolated from turmeric) affects several processes involved in neurocognitive aging. We have previously reported that short term (4-weeks) administration of a highly bioavailable curcumin preparation (Longvida©) improved working memory and reduced fatigue and stress reactivity in a healthy older cohort. The present trial (ACTRN12616000484448) was a partial replication study, evaluating similar effects at 4 and 12-weeks Longvida© supplementation. A double-blind, placebo-controlled, parallel-groups trial was conducted. Eighty participants aged 50-80 years (mean = 68.1, SD = 6.34) were randomised to receive Longvida© (400 mg daily containing 80 mg curcumin) or a matching placebo. Assessment took place at baseline then following 4 and 12 weeks treatment. Outcome measures included cognitive performance, mood and biomarkers. Compared with placebo, curcumin was associated with several significant effects. These included better working memory performance at 12-weeks (Serial Threes, Serial Sevens and performance on a virtual Morris Water Maze), and lower fatigue scores on the Profile of Mood States (POMS) at both 4 and 12-weeks, and of tension, anger, confusion and total mood disturbance at 4-weeks only. The curcumin group had significantly elevated blood glucose. These results confirm that Longvida© improves aspects of mood and working memory in a healthy older cohort. The pattern of results is consistent with improvements in hippocampal function and may hold promise for alleviating cognitive decline in some populations.

Topics: Affect; Aged; Aged, 80 and over; Cognition; Cognitive Aging; Cognitive Dysfunction; Curcumin; Dietary Supplements; Double-Blind Method; Fatigue; Female; Healthy Aging; Humans; Male; Memory, Short-Term; Middle Aged; Treatment Outcome

Cognitive impairment, one of the most prevalent complications of trigeminal neuralgia, is troubling for patients and clinicians due to limited therapeutic options. Curcumin shows antinociception and neuroprotection pharmacologically, suggesting that it may have therapeutic effect on this complication. This study aimed to investigate whether curcumin alleviates orofacial allodynia and improves cognitive impairment by regulating hippocampal CA1 region synaptic plasticity in trigeminal neuralgia.. A mouse model of trigeminal neuralgia was established by partially transecting the infraorbital nerve (pT-ION). Curcumin was administered by gavage twice daily for 14 days. Nociceptive thresholds were measured using the von Frey and acetone test, and the cognitive functions were evaluated using the Morris water maze test. Dendritic spines and synaptic ultrastructures in the hippocampal CA1 area were observed by Golgi staining and transmission electron microscopy.. Curcumin intervention increased the mechanical and cold pain thresholds of models. It decreased the escape latency and distance to the platform and increased the number of platform crossings and dwell time in the target quadrant of models, and improved spatial learning and memory deficits. Furthermore, it partially restored the disorder of the density and proportion of dendritic spines and the abnormal density and structure of synapses in the hippocampal CA1 region of models.. Curcumin alleviates abnormal orofacial pain and cognitive impairment in pT-ION mice by a mechanism that may be related to the synaptic plasticity of hippocampal CA1, suggesting that curcumin is a potential strategy for repairing cognitive dysfunction under long-term neuropathic pain conditions.

Topics: Animals; Cognitive Dysfunction; Curcumin; Disease Models, Animal; Hippocampus; Hyperalgesia; Mice; Mice, Neurologic Mutants; Neuronal Plasticity; Trigeminal Neuralgia

Fucoxanthin is the most abundant marine carotenoid derived from brown seaweeds, possesses antioxidant, anti-inflammatory, and neuroprotective properties, and might be benefit for the treatment of neurological disorders. Post-operative cognitive dysfunction (POCD) is a neurological symptom with learning and memory impairments, mainly affecting the elderly after surgery. However, there is no effective treatments for this symptom.. In this study, we evaluated the neuroprotective effects of fucoxanthin against POCD in aged mice after surgery.. The animal model of POCD was established in 12 - 14 month aged mice with a laparotomy. Curcumin was used as a positive control. The beneficial effects of fucoxanthin on POCD was analyzed by behavioral tests. Pro-inflammatory cytokines were measured by Enzyme-linked Immunosorbent Assay (ELISA). And the expressions of key proteins in the Akt and ERK signaling pathways were analyzed by Western blotting analysis. The morphology of microglial cells and astrocytes was explored by immunohistochemical staining. The activity of antioxidant superoxide dismutase (SOD) and catalase (CAT) were measured by anti-oxidative enzyme activity assays.. Fucoxanthin at 100 - 200 mg/kg significantly attenuated cognitive dysfunction, with a similar potency as curcumin, in aged mice after surgery. In addition, fucoxanthin and curcumin significantly increased the expression of pAkt, prevented the activation of microglial cells and astrocytes, and inhibited the secretion of pro-inflammatory interleukin-1β (IL - 1β) and tumor necrosis factor-α (TNF-α). Furthermore, fucoxanthin and curcumin elevated the ERK pathway and potently increased the activity of antioxidant enzymes. Most importantly, U0126, an inhibitor of the ERK pathway, and wortmannin, an inhibitor of the Akt pathway, significantly abolished the cognitive-enhancing effects, as well as the inhibition of neuroinflammation and the reduction of oxidative stress, induced by fucoxanthin in aged mice after surgery.. Fucoxanthin might be developed as a functional food or drug for the treatment of POCD by inhibiting neuroinflammation and enhancing antioxidant capacity via the activation of the Akt and ERK signaling pathways.

Topics: Aged; Animals; Antioxidants; Carotenoids; Cognitive Dysfunction; Curcumin; Humans; MAP Kinase Signaling System; Mice; Neuroinflammatory Diseases; Proto-Oncogene Proteins c-akt

Stress is a condition affecting different body systems. Curcumin (CUR) is a natural compound that has various pharmacological benefits. However, its poor oral bioavailability limits its therapeutic value. This study aimed to formulating curcumin loaded chitosan nanoparticles (CS.CUR.NPs) and investigate its gastroprotective and neuroprotective effects in rats subjected to cold restraint stress (CRS), in reference to conventional oral CUR preparation, and explore its underlying mechanism. Treated groups received either CUR or CS.CUR.NPs (100 mg∕kg) orally for 14 days before exposure to CRS. CRS elicited marked behavioral changes and gastric ulcer accompanied by histopathological abnormalities of the brain and stomach along with elevation of pain score. CUR and CS.CUR.NPs improved stress-induced gastric ulcer, cognitive performance, and pain sensation. Mechanistically, CRS disrupts oxidative and inflammatory status of the brain as manifested by high malondialdehyde and IL-6 and low total antioxidant capacity and IL-10, along with high C-reactive protein level. CRS decreased nuclear factor erythroid 2-related factor2 (Nrf2) and increased nuclear factor-kappa B (NF-κB) expressions. Furthermore, brain levels of unphosphorylated signal transducer and activator of transcription3 (U-STAT3) and glial fibrillary acidic protein (GFAP) were upregulated with stress. CUR and CS.CUR.NPs provided beneficial effects against harmful consequences resulting from stress with superior beneficial effects reported with CS.CUR.NPs. In conclusion, these findings shed light on the neuroprotective effect of CUR and CS.CUR.NPs against stress-induced neurobehavioral and neurochemical deficits and protection against stress-associated gastric ulcer. Moreover, we explored a potential crosslink between neuroinflammation, U-STAT3, NF-κB, and GFAP in brain dysfunction resulted from CRS.

Topics: Animals; Behavior, Animal; Chitosan; Cognitive Dysfunction; Cold Temperature; Curcumin; Glial Fibrillary Acidic Protein; Inflammation; Nanoparticle Drug Delivery System; Neuroprotective Agents; Oxidation-Reduction; Pain; Rats; STAT3 Transcription Factor; Stomach; Stomach Ulcer; Stress, Physiological

We aimed to explore the molecular mechanisms of curcumin's protective action against heavy metal-related cognitive impairment (CI). In silico analysis, CTD, SwissADME, AutoDock Vina, Metascape, GeneMania, and MIENTURNET were key approaches. The server-predicted interactions (41.7%) and physical interactions (35.7%) were found to be the most important interactions in the gene network analysis. The most important pathways involved in curcumin's protective activity against heavy metals were categorized as "regulation of neuron apoptotic process" and "negative regulation of apoptotic signaling route". These pathways were also emphasized in the protein-protein interaction enrichment analysis. Curcumin was also well-positioned inside the CASP3 binding region. Three key miRNAs linked to CI, mixed heavy metals, and curcumin (hsa-miR-34a-5p, hsa-miR-24-3p, and hsa-miR-128-3p) were observed. These miRNAs were found to be related to the important pathways related to CI and involved in curcumin's protective activity against mixed heavy metals such as "apoptosis multiple species", "apoptosis", and "Alzheimer's disease". We also created and tested in silico sponges that inhibited these miRNAs. Curcumin's physicochemical characteristics and pharmacokinetics are consistent with its therapeutic benefits in CI, owing to its high gastrointestinal absorption and ability to cross the blood-brain barrier, and it is not a P-glycoprotein substrate. Our findings emphasize the protective effects of curcumin in CI caused by heavy metal mixtures and pave the way for molecular mechanisms involved in CI pathology.

Topics: Cognitive Dysfunction; Curcumin; Humans; Metals, Heavy; MicroRNAs; Signal Transduction

Doxorubicin (DOX) is known to cause cognitive impairments in patients submitted to long-term chemotherapy (deficits also known as chemobrain). Therefore, there is an urgent need for therapeutic strategies capable of returning cancer survivors back to their previous quality of life. The present study investigated whether resveratrol (RSV) or curcumin (CUR) administration could affect mnemonic function and brain morphological changes following DOX administration in rats. Male Wistar rats were divided into 4 groups: DOX group (2.5 mg/kg/week for 4 weeks, i.p., plus distilled water for 28 days, oral gavage - OG), DOX + RSV group (DOX, 2.5 mg/kg/week for 4 weeks, i.p., plus RSV, 10 mg/kg/day for 28 days, OG), DOX + CUR group (DOX, 2.5 mg/kg/week for 4 weeks, i.p., plus CUR, 100 mg/kg/day for 28 days, OG) and control (CTR) group (0.9% saline solution weekly for 4 weeks, i.p., plus distilled water for 28 days, OG). Behavioral analyses (open field - OF - and the novel object recognition test - NORT) were performed. Brains were collected and analyzed by hematoxylin-eosin and luxol fast blue staining techniques and by immunohistochemistry for GFAP (glial fibrillary acidic protein) expression in astrocytes and Iba1 (ionized calcium-binding adaptor molecule 1) expression in microglia. DOX-injected rats presented short-term and long-term memory impairments as seen in the NORT at 3 and 24 h after habituation and increased GFAP and Iba1 expression, respectively, in astrocytes and microglia of the frontal cortex, hypothalamus and hippocampus. Such cognitive deficits were prevented by CUR at both periods and by RSV at 24 h. DOX-induced astrogliosis and microgliosis were avoided by RSV and CUR. No signs of demyelination or neuronal loss were found in any group. Thus, CUR and RSV prevented memory loss, astrogliosis and microgliosis induced by DOX monotherapy.

Topics: Animals; Cognitive Dysfunction; Curcumin; Doxorubicin; Male; Quality of Life; Rats; Rats, Wistar; Resveratrol

Cognitive decline in dementia is associated with deficiency of the cholinergic system. In this study, five mono-carbonyl curcumin analogs were synthesized, and on the basis of their promising in vitro anticholinesterase activities, they were further investigated for in vivo neuroprotective and memory enhancing effects in scopolamine-induced amnesia using elevated plus maze (EPM) and novel object recognition (NOR) behavioral mice models. The effects of the synthesized compounds on the cholinergic system involvement in the brain hippocampus and their binding mode in the active site of cholinesterases were also determined. Compound

Topics: Amnesia; Animals; Catalytic Domain; Cholinergic Agents; Cholinesterase Inhibitors; Cholinesterases; Cognitive Dysfunction; Curcumin; Dementia; Hippocampus; Humans; Maze Learning; Memory; Mice; Molecular Docking Simulation; Neuroprotective Agents; Oxidative Stress; Scopolamine

To investigate whether curcumin promotes hippocampal neurogenesis in the cerebral ischemia (CI) mice via Wnt/β-catenin signaling pathway.. Male C57BL/6 mice were randomly divided into groups: sham operation group (Sham), cerebral ischemic group (CI), curcumin treatment group (50, 100 mg/kg/d, i.p.) and curcumin (100 mg/kg/d) + DKK1 (a blocker of Wnt receptor, 200 ng/d, icv) group. CI was induced by bilateral common carotid arteries occlusion (BCCAO) for 20 min. The Morris water maze test was conducted to detect spatial learning and memory. Immunofluorescence staining was used to examine the proliferation and differentiation of immature neurons in the hippocampal dentate gyrus. The proteins involved in neurogenesis and Wnt signaling pathway were examined using Western blot assay.. Curcumin significantly alleviated cognitive deficits induced by CI. Curcumin dose-dependently increased the proliferation of neural stem cells and promoted the differentiation and maturation of newly generated neural cells into neurons. Curcumin also increased the expression of proteins involved in neurogenesis (including Ngn2, Pax6 and NeuroD 1) and the Wnt/β-catenin signaling pathway. Moreover, the forenamed effects of curcumin were abolished by pretreatment with DKK1, a blocker of Wnt receptor.. Curcumin promotes hippocampal neurogenesis by activating Wnt/β-catenin signaling pathway to ameliorate cognitive deficits after acute CI.

Topics: Animals; beta Catenin; Brain; Brain Ischemia; Cell Differentiation; Cell Proliferation; Cerebral Infarction; China; Cognition Disorders; Cognitive Dysfunction; Curcumin; Dentate Gyrus; Hippocampus; Male; Memory; Mice; Mice, Inbred C57BL; Neural Stem Cells; Neurogenesis; Neurons; Wnt Signaling Pathway

Chronic cerebral hypoperfusion (CCH) is regarded as a high-risk factor for cognitive decline in vascular dementia (VaD). We have previously shown that diabetes mellitus (DM) synergistically promotes CCH-induced cognitive dysfunction via exacerbating neuroinflammation. Furthermore, curcumin has been shown to exhibit anti-inflammatory and neuroprotective activities. However, the effects of curcumin on CCH-induced cognitive impairments in DM have remained unknown.. Rats were fed with a high-fat diet (HFD) and injected with low-dose streptozotocin (STZ), followed by bilateral common carotid artery occlusion (BCCAO), to model DM and CCH in vivo. After BCCAO, curcumin (50 mg/kg) was administered intraperitoneally every two days for eight weeks to evaluate its therapeutic effects. Additionally, mouse BV2 microglial cells were exposed to hypoxia and high glucose to model CCH and DM pathologies in vitro.. Curcumin treatment significantly improved DM/CCH-induced cognitive deficits and attenuated neuronal cell death. Molecular analysis revealed that curcumin exerted protective effects via suppressing neuroinflammation induced by microglial activation, regulating the triggering receptor expressed on myeloid cells 2 (TREM2)/toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway, alleviating apoptosis, and reducing nod-like receptor protein 3 (NLRP3)-dependent pyroptosis.. Taken together, our findings suggest that curcumin represents a promising therapy for DM/CCH-induced cognitive impairments.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cells, Cultured; Cognitive Dysfunction; Curcumin; Diabetes Mellitus; Disease Models, Animal; Humans; Hypoxia, Brain; Male; Mice; Microglia; Neurogenic Inflammation; Pyroptosis; Rats; Rats, Sprague-Dawley

Oxidative stress has been shown to play an important role in the pathogenesis of multiple sclerosis (MS). Curcumin (CUR), an antioxidant compound, can be a potent treatment for neurodegenerative diseases, such as MS. CUR has poor bioavailability; therefore, it is used in nanoforms to increase its bioavailability. In the present study, the effects of CUR and conjugated linoleic acid-CUR (Lino-CUR) on spatial memory and oxidative stress in a putative animal model of MS were investigated. Forty-nine adult male Wistar rats (250 ± 50 g) were randomly divided into seven groups (n = 7): control, sham, ethidium bromide (EB), CUR (20 and 40 μg/kg) + EB, and Lino-CUR (20 and 40 μg/kg) + EB groups. Following MS induction, the groups were treated for 5 consecutive days. Finally, spatial memory and levels of oxidative stress parameters were assessed. Treatment with CUR and Lino-CUR at two doses significantly improved spatial memory and reduced oxidative stress parameters in the experimental models of MS. Furthermore, the effects of high dose (40 μg/kg) of Lino-CUR were more remarkable. These findings suggest that the microinjection of CUR in its synthetic form Lino-CUR significantly ameliorated spatial memory, through the reduction of oxidative stress markers in the brain of studied animals as a rat model of MS.

Topics: Animals; Cognitive Dysfunction; Curcumin; Demyelinating Diseases; Enzyme Inhibitors; Ethidium; Linoleic Acids, Conjugated; Male; Oxidative Stress; Rats; Rats, Wistar

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases leading to dementia. Despite research efforts, currently there are no effective pharmacotherapeutic options for the prevention and treatment of AD. Recently, numerous studies highlighted the beneficial effects of curcumin (CUR), a natural polyphenol, in the neuroprotection. Especially, its dual antioxidant and anti-inflammatory properties attracted the interest of researchers. In fact, besides its antioxidant and anti-inflammatory properties, this biomolecule is not degraded in the intestinal tract. Additionally, CUR is able to cross the blood-brain barrier and could therefore to be used to treat neurodegenerative pathologies associated with oxidative stress, inflammation and apoptosis. The present study aimed to assess the ability of CUR to induce neuronal protective and/or recovery effects on a rat model of neurotoxicity induced by aluminum chloride (AlCl

Topics: Acetylcholinesterase; Aluminum Chloride; Alzheimer Disease; Animals; Anxiety; Apoptosis; Body Weight; Cell Survival; Cognitive Dysfunction; Curcumin; Cytokines; Disease Models, Animal; Hippocampus; Inflammation; Inflammation Mediators; Male; Nerve Degeneration; Neuroprotective Agents; Neurotoxicity Syndromes; Organ Size; Oxidative Stress; Rats, Wistar

Cisplatin, a commonly used chemotherapy drug, can increase the survival rate of cancer patients. However, it often causes various side effects, including neuronal deficit-induced cognitive impairment. Considering that curcumin is effective in neuronal protection, the action of curcumin on cognitive improvement was evaluated in cisplatin-treated C57BL/6 mice in the present study. Our results first showed that curcumin restored impaired cognitive behaviors. Consistent with this, neurogenesis and synaptogenesis were improved by curcumin. In addition, cisplatin-induced dysfunction of apoptosis-related proteins was partly reversed by curcumin. Moreover, cisplatin-induced autophagy was enhanced by curcumin. Our results also indicated that cisplatin induced autophagy through the endoplasmic reticulum (ER) stress-mediated ATF4-Akt-mTOR signaling pathway. Curcumin activated AMPK-JNK signaling, which mediated both mTOR inhibition and Bcl-2 upregulation and in turn enhanced autophagy and suppressed apoptosis, respectively. In contrast, pretreatment with the autophagy inhibitor 3-methyladenine (3-MA) completely abolished the effects of curcumin on cognitive improvement and improved neurogenesis, synaptogenesis and autophagy. Our results show that cognitive improvement induced by curcumin during chemotherapy is mediated by the enhancement of hippocampal autophagy.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Autophagy; Cisplatin; Cognitive Dysfunction; Curcumin; Hippocampus; Male; Maze Learning; Mice; Mice, Inbred C57BL; Random Allocation

Accumulating studies have suggested that targeting transcription factor EB (TFEB), an essential regulator of autophagy-lysosomal pathway (ALP), is promising for the treatment of neurodegenerative disorders, including Alzheimer's disease (AD). However, potent and specific small molecule TFEB activators are not available at present. Previously, we identified a novel TFEB activator named curcumin analog C1 which directly binds to and activates TFEB. In this study, we systematically investigated the efficacy of curcumin analog C1 in three AD animal models that represent beta-amyloid precursor protein (APP) pathology (5xFAD mice), tauopathy (P301S mice) and the APP/Tau combined pathology (3xTg-AD mice). We found that C1 efficiently activated TFEB, enhanced autophagy and lysosomal activity, and reduced APP, APP C-terminal fragments (CTF-β/α), β-amyloid peptides and Tau aggregates in these models accompanied by improved synaptic and cognitive function. Knockdown of TFEB and inhibition of lysosomal activity significantly inhibited the effects of C1 on APP and Tau degradation in vitro. In summary, curcumin analog C1 is a potent TFEB activator with promise for the prevention or treatment of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Line, Tumor; Chromosome Pairing; Cognitive Dysfunction; Curcumin; Disease Models, Animal; Glycogen Synthase Kinase 3 beta; Lysosomes; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Motor Activity; Neurons; Phosphorylation; Proto-Oncogene Proteins c-akt; RNA, Small Interfering; tau Proteins

Type 2 diabetes mellitus (T2DM) is a metabolic disease associated with chronic low-grade inflammation that is mainly associated with lifestyles. Exercise and healthy diet are known to be beneficial for adults with T2DM in terms of maintaining blood glucose control and overall health. We investigated whether a combination of exercise and curcumin supplementation ameliorates diabetes-related cognitive distress by regulating inflammatory response and endoplasmic reticulum (ER) stress. This study was performed using male Otsuka Long-Evans Tokushima Fatty (OLETF) rats (a spontaneous diabetes Type 2 model) and Long-Evans Tokushima Otsuka (LETO) rats (LETO controls) by providing them with exercise alone or exercise and curcumin in combination. OLETF rats were fed either a diet of chow (as OLETF controls) or a diet of chow containing curcumin (5 g/kg diet) for five weeks. OLETF rats exercised with curcumin supplementation exhibited weight loss and improved glucose homeostasis and lipid profiles as compared with OLETF controls or exercised OLETF rats. Next, we examined cognitive functions using a Morris water maze test. Exercise plus curcumin improved escape latency and memory retention compared to OLETF controls. Furthermore, OLETF rats exercised and fed curcumin had lower IL6, TNFα, and IL10 levels (indicators of inflammatory response) and lower levels of ER stress markers (BiP and CHOP) in the intestine than OLETF controls. These observations suggest exercise plus curcumin may offer a means of treating diabetes-related cognitive dysfunction.

Topics: Animals; Cognition; Cognitive Dysfunction; Curcumin; Diabetes Mellitus, Experimental; Dietary Supplements; Endoplasmic Reticulum Stress; Glucose; Homeostasis; Lipid Metabolism; Male; Physical Conditioning, Animal; Phytotherapy; Rats, Inbred OLETF; Weight Loss

Our previous study has confirmed that a novel curcumin derivate nicotinate-curcumin (NC) can facilitate autophagic flux in THP-1 cells induced by oxidized low-density lipoprotein.. Given that autophagy plays critical roles in neurodegenerative diseases, the present study was carried out to investigate whether NC can improve cognitive function of rats with diabetes mellitus (DM) via restoring autophagic flux in CA1 hippocampus.. Our results showed that NC treatment improved cognitive deficit and attenuated neuronal loss as well as cellular ultrastructure impairment in the CA1 region of DM rats induced by streptozotocin. Moreover, NC lowered the expressions of the apoptosis-related proteins Bcl-2, Bax, Cyt-c, and cleaved Caspase-3. Notably, NC treatment reversed autophagic flux impairment as evidenced by the deceases in LC3-II and p62 protein levels, and autophagosome accumulation in the hippocampal CA1 region of DM rats. However, these protective effects of NC were abolished by cotreatment with 3-methyladenine (an autophagy inhibitor) and chloroquine (an autophagic flux inhibitor), respectively. Furthermore, NC treatment decreased the expressions of phosphorylated mammalian target of rapamycin (mTOR) and p70 ribosomal protein S6 kinase (p70S6k) proteins in the CA1 region of DM rats.. These results indicate that NC ameliorates DM-induced cognitive function impairment via restoring autophagic flux might by inhibiting mTOR/p70S6k activation in the CA1 region, and NC may be a promising agent for diabetic cognitive dysfunction prevention and treatment.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Autophagy; CA1 Region, Hippocampal; Cognitive Dysfunction; Curcumin; Diabetes Mellitus, Experimental; Drug Therapy, Combination; Male; Niacin; Rats; Rats, Sprague-Dawley; Vitamin B Complex

Rotenone, an environmental toxin, is used to induce neurodegeneration in both the cellular and animal model of Parkinson's disease. Demethoxycurcumin (DMC), derivative of curcumin has been reported to have antioxidant and anti-inflammatory characteristics in

Topics: Animals; Apoptosis; Behavior, Animal; Cognitive Dysfunction; Curcumin; Diarylheptanoids; Disease Models, Animal; Male; Neuroprotective Agents; Parkinson Disease; Random Allocation; Rats, Wistar; Rotenone

Topics: Cerebrovascular Circulation; Cognition; Cognitive Dysfunction; Curcumin; Fatty Acids, Omega-3; Humans

Peripheral blood-derived macrophages isolated from Alzheimer's disease (AD) patients have earlier been reported to demonstrate ineffective phagocytosis of amyloid-beta compared to the age-matched control subjects. However, the mechanisms causing unsuccessful phagocytosis remain unclear. Oxidative stress and the presence of ApoEε4 allele has been reported to play a major role in the pathogenesis of AD, but the contribution of oxidative stress and ApoEε4 in macrophage dysfunction leading to ineffective Aβ phagocytosis needs to be analyzed. Aβ phagocytosis assay has been performed using FITC-labeled Aβ and analyzed using flow cytometry and confocal imaging in patient samples and in THP-1 cells. Oxidative stress in patient-derived macrophages was analyzed by assessing the DNA damage using comet assay. ApoE polymorphism was analyzed using sequence-specific PCR and Hixson & Vernier Restriction isotyping protocol. In this study, we have analyzed the patterns of phagocytic inefficiency of macrophages in Indian population with a gradual decline in the phagocytic potential from mild cognitive impairment (MCI) to AD patients. Further, we have shown that the presence of ApoEε4 allele might also have a possible effect on the phagocytosis efficiency of the macrophages. Here, we demonstrate for the first time that oxidative stress could affect the amyloid-beta phagocytic potential of macrophages and hence by alleviating oxidative stress using curcumin, an anti-oxidant could enhance the amyloid-beta phagocytic efficacy of macrophages of patients with AD and MCI, although the responsiveness to curcumin might depends on the presence or absence of APOEε4 allele. Oxidative stress contributes significantly to decreased phagocytosis of Aβ by macrophages. Moreover, the phagocytic inefficiency of macrophages was correlated to the presence of ApoEε4 allele. This study also found that the Aβ-phagocytic potential of macrophage gets significantly enhanced in curcumin-treated patient-derived macrophages.

Topics: Aged; Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Case-Control Studies; Cell Differentiation; Cognitive Dysfunction; Curcumin; DNA Damage; Endocytosis; Fluorescence; Humans; Lysosomes; Macrophages; Monocytes; Oxidative Stress; Phagocytosis; Polymorphism, Genetic; THP-1 Cells

Topics: Administration, Oral; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cell Line; Cognitive Dysfunction; Copper; Curcumin; Disease Models, Animal; Drug Compounding; Humans; Hydrogen Peroxide; Male; Mice; Mice, Transgenic; Micelles; Nanostructures; Peptide Fragments

Intracellular inclusions of aggregated tau appear in neurons and glial cells in a range of neurodegenerative diseases known as tauopathies. Inhibition of pathological changes in tau is a therapeutic target for tauopathy. We recently synthesized a novel curcumin derivative, named Shiga-Y5, and showed that Shiga-Y5 inhibited cognitive impairment and amyloid deposition in a mouse model of Alzheimer's disease. Here we investigated whether Shiga-Y5 inhibited cognitive impairment and tau accumulation in a mouse model of tauopathy, rTg4510. The rTg4510 mouse is a bitransgenic mouse model that uses a system of responder and activator transgenes to express human four-repeat tau with the P301L mutation. This strain is obtained by crossing tetO-MAPT*P301L mouse line (on a FVB/NJ background) with CaMKII-tTA mouse line (on a C57BL/6J background). Male rTg4510 mice and wild-type mice were fed with a standard chow diet with or without Shiga-Y5 (500 ppm) for 4 months. Behavioral tests were conducted from 5.5 months of age, and the mice were sacrificed at 6 months of age. There were no significant changes in behavioral performance in rTg4510 mice fed with SY5-containing chow diet compared with rTg4510 mice fed with control chow diet. Histological and biochemical analyses also showed no significant alterations in tau accumulation by the treatment with SY5. One of noticeable finding in this study was that rTg4510 mice on a F1 female FVB/NJ x male C57BL/6J background showed more severe tau accumulation than rTg4510 mice on a F1 female C57BL/6J x male FVB/NJ background. Further studies to clarify the mechanisms underlying tau aggregation may help to develop therapeutic approaches aimed at preventing this pathological feature.

Topics: Animals; Breeding; Catechols; Cognitive Dysfunction; Curcumin; Disease Models, Animal; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Phenotype; tau Proteins; Tauopathies

Post-operative cognitive dysfunction (POCD) is associated with elderly patients undergoing surgery. However, pharmacological treatments for POCD are limited. In this study, we found that curcumin, an active compound derived from Curcuma longa, ameliorated the cognitive dysfunction following abdominal surgery in aged mice. Further, curcumin prevented surgery-induced anti-oxidant enzyme activity. Curcumin also increased brain-derived neurotrophic factor (BDNF)-positive area and expression of pAkt in the brain, suggesting that curcumin activated BDNF signaling in aged mice. Furthermore, curcumin neutralized cholinergic dysfunction involving choline acetyltransferase expression induced by surgery. These results strongly suggested that curcumin prevented cognitive impairments via multiple targets, possibly by increasing the activity of anti-oxidant enzymes, activation of BDNF signaling, and neutralization of cholinergic dysfunction, concurrently. Based on these novel findings, curcumin might be a potential agent in POCD prophylaxis and treatment.

Topics: Aging; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cognitive Dysfunction; Curcumin; Dose-Response Relationship, Drug; Male; Maze Learning; Mice; Mice, Inbred ICR; Postoperative Complications; Recognition, Psychology

Menopause occurs gradually and is characterized by increased susceptibility to developing mood disorders. Several studies have suggested treatments based on the antioxidant properties of vitamins and herbal compounds as an alternative to hormone replacement therapies, with few or none reporting toxicity. The present study was performed to explore the effects of curcumin oral supplementation on anxiety-like behavior and oxidative stress parameters in different central nervous system (CNS) areas of ovariectomized (OVX) rats. Female Wistar rats were randomly divided into either sham-operated or OVX groups. Sham-operated group (n=8) and an OVX group (n=11) were treated with vehicle, and the other two OVX groups received curcumin at 50 or 100mg/kg/day doses (n=8/group). Elevated plus maze (EPM) test was performed on the 28th day of treatment. On the 30th day, animals were killed and the dissected brain regions were removed and stored at-80°C until analysis. Ovariectomy induced deficit in the locomotor activity and increased anxiety-like behavior. Moreover, OVX rats showed increased lipid oxidized in the frontal cortex and striatum, increased hippocampal and striatal carbonylated protein level, and decreased striatal thiol content of non-protein fraction indicative of a glutathione (GSH) pool. Curcumin oral treatment for 30days reduced oxidative stress in the CNS areas as well as the behavior alterations resulting from ovariectomy. Curcumin supplementation attenuated most of these parameters to sham comparable values, suggesting that curcumin could have positive effects against anxiety-like disturbances and brain oxidative damage due to hormone deprivation.

Topics: Animals; Antioxidants; Anxiety; Behavior, Animal; Biomarkers; Cognitive Dysfunction; Corpus Striatum; Curcumin; Dietary Supplements; Female; Frontal Lobe; Hippocampus; Maze Learning; Mood Disorders; Neurons; Ovariectomy; Oxidative Stress; Postmenopause; Protein Carbonylation; Psychomotor Disorders; Random Allocation; Rats, Wistar

Due to the impermeability of the blood-brain barrier and the nonselective distribution of drugs in the brain, the therapeutic access to intractable neurological disorders is challenging. In this study, dual brain-targeting polymersomes (POs) functionalized by transferrin and Tet-1 peptide (Tf/Tet-1-POs) promoted the transportation of curcumin into the brain and provided neuroprotection. The modification of the ligands that bind to the surface of POs was revealed by X-ray photoelectron spectroscopy analysis. The cell uptake of a coculture model of mouse brain capillary endothelial cells with neurons showed that the Tf/Tet-1-POs had significant transportation properties and possessed affinity for neurons. The pharmacokinetic analysis showed that the blood-brain barrier permeability-surface efficiency of the Tf/Tet-1-POs was 0.28 mL/h/g and that the brain tissue uptake rate (% ID/g) was 0.08, which were significant compared with the controls (P<0.05). The curcumin-encapsulated Tf/Tet-1-POs provided neuroprotection and ameliorated cognitive dysfunction in intrahippocampal amyloid-β1-42-injected mice. These results suggest that the dual brain-targeting POs are more capable of drug delivery to the brain that can be exploited as a multiple noninvasive vehicle for targeting therapeutics.

Topics: Amyloid beta-Peptides; Animals; Biological Transport; Cell Line; Cognitive Dysfunction; Curcumin; Drug Delivery Systems; Hippocampus; Ligands; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C57BL; Mice, Nude; Neuroprotection; Peptide Fragments; Peptides; Photoelectron Spectroscopy; Polymers; Tissue Distribution; Transferrin