Publications by authors named "Amala Soumyanath"

26 Publications

  • Page 1 of 1

Effects of (Ashwagandha) on Stress and the Stress- Related Neuropsychiatric Disorders Anxiety, Depression, and Insomnia.

Curr Neuropharmacol 2021 ;19(9):1468-1495

BENFRA Botanical Dietary Supplements Research Center, Oregon Health and Science University, Portland, Oregon, United States.

Background: Withania somnifera (WS), also known as Ashwagandha, is commonly used in Ayurveda and other traditional medicine systems. WS has seen an increase in worldwide usage due to its reputation as an adaptogen. This popularity has elicited increased scientific study of its biological effects, including a potential application for neuropsychiatric and neurodegenerative disorders.

Objective: This review aims to provide a comprehensive summary of preclinical and clinical studies examining the neuropsychiatric effects of WS, specifically its application in stress, anxiety, depression, and insomnia.

Methods: Reports of human trials and animal studies of WS were collected primarily from the PubMed, Scopus, and Google Scholar databases.

Results: WS root and leaf extracts exhibited noteworthy anti-stress and anti-anxiety activity in animal and human studies. WS also improved symptoms of depression and insomnia, though fewer studies investigated these applications. WS may alleviate these conditions predominantly through modulation of the hypothalamic-pituitary-adrenal and sympathetic-adrenal-medullary axes, as well as through GABAergic and serotonergic pathways. While some studies link specific withanolide components to its neuropsychiatric benefits, there is evidence for the presence of additional, as yet unidentified, active compounds in WS.

Conclusion: While benefits were seen in the reviewed studies, significant variability in the WS extracts examined prevents a consensus on the optimum WS preparation or dosage for treating neuropsychiatric conditions. WS generally appears safe for human use; however, it will be important to investigate potential herb-drug interactions involving WS if used alongside pharmaceutical interventions. Further elucidation of active compounds of WS is also needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1570159X19666210712151556DOI Listing
January 2021

Caffeoylquinic acids: chemistry, biosynthesis, occurrence, analytical challenges, and bioactivity.

Plant J 2021 Sep 23;107(5):1299-1319. Epub 2021 Jul 23.

Department of Chemistry, Oregon State University, Corvallis, OR, USA.

Caffeoylquinic acids (CQAs) are specialized plant metabolites we encounter in our daily life. Humans consume CQAs in mg-to-gram quantities through dietary consumption of plant products. CQAs are considered beneficial for human health, mainly due to their anti-inflammatory and antioxidant properties. Recently, new biosynthetic pathways via a peroxidase-type p-coumaric acid 3-hydroxylase enzyme were discovered. More recently, a new GDSL lipase-like enzyme able to transform monoCQAs into diCQA was identified in Ipomoea batatas. CQAs were recently linked to memory improvement; they seem to be strong indirect antioxidants via Nrf2 activation. However, there is a prevalent confusion in the designation and nomenclature of different CQA isomers. Such inconsistencies are critical and complicate bioactivity assessment since different isomers differ in bioactivity and potency. A detailed explanation regarding the origin of such confusion is provided, and a recommendation to unify nomenclature is suggested. Furthermore, for studies on CQA bioactivity, plant-based laboratory animal diets contain CQAs, which makes it difficult to include proper control groups for comparison. Therefore, a synthetic diet free of CQAs is advised to avoid interferences since some CQAs may produce bioactivity even at nanomolar levels. Biotransformation of CQAs by gut microbiota, the discovery of new enzymatic biosynthetic and metabolic pathways, dietary assessment, and assessment of biological properties with potential for drug development are areas of active, ongoing research. This review is focused on the chemistry, biosynthesis, occurrence, analytical challenges, and bioactivity recently reported for mono-, di-, tri-, and tetraCQAs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/tpj.15390DOI Listing
September 2021

Prolonged Treatment with Centella asiatica Improves Memory, Reduces Amyloid-β Pathology, and Activates NRF2-Regulated Antioxidant Response Pathway in 5xFAD Mice.

J Alzheimers Dis 2021 ;81(4):1453-1468

Department of Neurology, Oregon Health & Science University, Portland, OR, USA.

Background: The medicinal herb Centella asiatica has been long been used for its neuroprotective and cognitive enhancing effects. We have previously shown that two weeks of treatment with a water extract of Centella asiatica (CAW) improves cognition and activates the endogenous antioxidant response pathway without altering amyloid-β (Aβ) plaque burden.

Objective: Here, we assess the effect of long-term treatment of CAW in the 5xFAD mouse model of Aβ accumulation.

Methods: Four-month-old 5xFAD mice were treated with CAW in their drinking water (2 g/L) for three months at which point they underwent cognitive testing as well as analysis of Aβ plaque levels and antioxidant and synaptic gene expression. In order to confirm the involvement of the antioxidant regulatory transcription factor NRF2 on the effects of CAW on synaptic plasticity, neurons isolated from 5xFAD mice were also treated with CAW and the targeted inhibitor ML385.

Results: Three months of treatment with CAW improved spatial and contextual memory as well as executive function in 5xFAD mice. This improvement was accompanied by increased antioxidant gene expression and a decrease in Aβ plaque burden relative to untreated 5xFAD animals. In isolated neurons, treatment with ML385 blocked the effects of CAW on dendritic arborization and synaptic gene expression.

Conclusion: These results suggest that prolonged CAW exposure could be beneficial in Alzheimer's disease and that these effects likely involve NRF2 activation. Moreover, these findings suggest that targeting NRF2 itself may be a relevant therapeutic strategy for improving synaptic plasticity and cognitive function in Alzheimer's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-210271DOI Listing
September 2021

Loss of NRF2 accelerates cognitive decline, exacerbates mitochondrial dysfunction, and is required for the cognitive enhancing effects of Centella asiatica during aging.

Neurobiol Aging 2021 04 25;100:48-58. Epub 2020 Dec 25.

Department of Neurology, Oregon Health & Science University, Portland, OR, USA. Electronic address:

The water extract of Centella asiatica (CAW) improves cognitive and mitochondrial function and activates the nuclear factor erythroid 2-related factor 2 (NRF2) regulated antioxidant response pathway in aged mice. Here we investigate whether NRF2 activation is required for the cognitive and mitochondrial effects of prolonged CAW exposure during aging. Five-month-old NRF2 knockout (NRF2KO) and wild-type mice were treated with CAW for 1, 7, or 13 months. Each cohort underwent cognitive testing and hippocampal mitochondrial analyses. Age-related cognitive decline was accelerated in NRF2KO mice and while CAW treatment improved cognitive performance in wild-type mice, it had no effect on NRF2KO animals. Hippocampal mitochondrial function also declined further with age in NRF2KO mice and greater hippocampal mitochondrial dysfunction was associated with poorer cognitive performance in both genotypes. Long-term CAW treatment did not affect mitochondrial endpoints in animals of either genotype. These data indicate that loss of NRF2 results in accelerated age-related cognitive decline and worsened mitochondrial deficits. NRF2 also appears to be required for the cognitive enhancing effects of CAW during aging.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2020.11.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920997PMC
April 2021

Caffeoylquinic Acids in Reverse Cognitive Deficits in Male 5XFAD Alzheimer's Disease Model Mice.

Nutrients 2020 Nov 13;12(11). Epub 2020 Nov 13.

Department of Neurology, School of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.

(CA) is an edible plant and a popular botanical dietary supplement. It is reputed, in Ayurveda, to mitigate age-related cognitive decline. There is a considerable body of preclinical literature supporting CA's ability to improve learning and memory. This study evaluated the contribution of CA's triterpenes (TT), widely considered its active compounds, and caffeoylquinic acids (CQA) to the cognitive effects of CA water extract (CAW) in 5XFAD mice, a model of Alzheimer's disease. 5XFAD mice were fed a control diet alone, or one containing 1% CAW or compound groups (TT, CQA, or TT + CQA) equivalent to their content in 1% CAW. Wild-type (WT) littermates received the control diet. Conditioned fear response (CFR) was evaluated after 4.5 weeks. Female 5XFAD controls showed no deficit in CFR compared to WT females, nor any effects from treatment. In males, CFR of 5XFAD controls was attenuated compared to WT littermates ( = 0.005). 5XFAD males receiving CQA or TT + CQA had significantly improved CFR ( < 0.05) compared to 5XFAD male controls. CFR did not differ between 5XFAD males receiving treatment diets and WT males. These data confirm a role for CQA in CAW's cognitive effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu12113488DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698091PMC
November 2020

Water Extract Shows Low Potential for Cytochrome P450-Mediated Drug Interactions.

Drug Metab Dispos 2020 10 24;48(10):1053-1063. Epub 2020 Jun 24.

Department of Neurology, Oregon Health and Science University, Portland, Oregon (K.M.W., J.F.Q., A.S.); Departments of Chemistry (A.A.M., C.S.M.) and Pharmaceutical Sciences (J.F.S.) and Linus Pauling Institute (A.A.M., J.F.S.), Oregon State University, Corvallis, Oregon; BioIVT, Durham, North Carolina (R.M.L., C.L.M., T.T.B.); and Department of Neurology, Veterans Affairs Portland Health Care System Center, Portland, Oregon (J.F.Q.)

(CA) shows considerable promise for development as a botanical drug for cognitive decline. Its primary bioactive components include triterpene glycosides asiaticoside and madecassoside and their corresponding aglycones asiatic acid and madecassic acid. Exploration of the bioactivity of CA's caffeoylquinic acids is ongoing. In this study, an aqueous extract of CA (CAW-R61J) was evaluated for drug interaction potential through inhibition or induction of P450 enzymes, as required by the US Food and Drug Administration. CAW-R61J was assessed for induction potential of CYP1A2, CYP2B6, and CYP3A4 using transporter-certified cryopreserved human hepatocytes in sandwich culture. Gene expression of these target P450s was quantified, and enzyme activities were determined to confirm gene expression results. No induction was observed up to 16.7 µg/ml CAW-R61J (equivalent to 1.1 µM asiaticoside, 0.8 µM madecassoside, 0.09 µM asiatic acid, and 0.12 µM madecassic acid). Reversible and time-dependent inhibitory effects of CAW-R61J on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 were evaluated using human liver microsomes. CAW-R61J showed weak reversible inhibition of most of the P450 forms tested, with the strongest being CYP2C9 (IC of 330 µg/ml). CAW-R61J (≤1000 µg/ml) was not a time-dependent inhibitor of any of these P450 enzymes. In summary, CAW-R61J had no, or only a weak impact, on P450 induction and inhibition in vitro. The clinical relevance of these results will depend on the in vivo concentration of CAW-R61J components achieved in humans. Plasma triterpene concentrations measured in our recent clinical studies suggest minimal risk of P450-mediated drug interactions by these components. SIGNIFICANCE STATEMENT: A preparation of is currently under clinical development for the prevention or treatment of cognitive decline. The US Food and Drug Administration required an evaluation of its potential for drug interactions mediated through drug-metabolizing enzymes. This in vitro study revealed minimal induction or inhibition of a range of P450 enzymes, including CYP3A4, by the extract, suggesting a low potential for drug interactions modulated by P450 metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1124/dmd.120.090860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543484PMC
October 2020

Integration of mass spectral fingerprinting analysis with precursor ion (MS1) quantification for the characterisation of botanical extracts: application to extracts of Centella asiatica (L.) Urban.

Phytochem Anal 2020 Nov 12;31(6):722-738. Epub 2020 Apr 12.

Department of Chemistry, Oregon State University, Corvallis, OR, USA.

Introduction: The phytochemical composition of plant material governs the bioactivity and potential health benefits as well as the outcomes and reproducibility of laboratory studies and clinical trials.

Objective: The objective of this work was to develop an efficient method for the in-depth characterisation of plant extracts and quantification of marker compounds that can be potentially used for subsequent product integrity studies. Centella asiatica (L.) Urb., an Ayurvedic herb with potential applications in enhancing mental health and cognitive function, was used as a case study.

Methods: A quadrupole time-of-flight analyser in conjunction with an optimised high-performance liquid chromatography (HPLC) separation was used for in-depth untargeted fingerprinting and post-acquisition precursor ion quantification to determine levels of distinct phytochemicals in various C. asiatica extracts.

Results: We demonstrate the utility of this workflow for the characterisation of extracts of C. asiatica. This integrated workflow allowed the identification or tentative identification of 117 compounds, chemically interconnected based on Tanimoto chemical similarity, and the accurate quantification of 24 phytochemicals commonly found in C. asiatica extracts.

Conclusion: We report a phytochemical analysis method combining liquid chromatography, high resolution mass spectral data acquisition, and post-acquisition interrogation that allows chemical fingerprints of botanicals to be obtained in conjunction with accurate quantification of distinct phytochemicals. The variability in the composition of specialised metabolites across different C. asiatica accessions was substantial, demonstrating that detailed characterisation of plant extracts is a prerequisite for reproducible use in laboratory studies, clinical trials and safe consumption. The methodological approach is generally applicable to other botanical products.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pca.2936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587007PMC
November 2020

Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice.

Antioxidants (Basel) 2019 Dec 8;8(12). Epub 2019 Dec 8.

Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.

(CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer's disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ - 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW's impact on amyloid-β plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/antiox8120630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943631PMC
December 2019

triterpenes for diabetic neuropathy: a randomized, double-blind, placebo-controlled, pilot clinical study.

Esper Dermatol 2018 Jun;20(2 Suppl 1):12-22

Department of Neurology, Oregon Health and Science University, Portland, OR, 97239, USA.

Background: Diabetic neuropathy (DN), a common complication of diabetes mellitus, results from hyperglycemia, poor microcirculation and attendant nerve damage. Currently available treatments relieve symptoms, but do not modify the neurodegeneration underlying DN. (CA) triterpenes improved microcirculation in earlier clinical studies, and showed neurotropic effects in preclinical models suggesting a potential disease modifying effect in DN. This 52-week, randomized, double-blind, placebo-controlled trial examined the effects of CAST, a standardized CA extract containing triterpenes, on neuropathy symptoms in Type II diabetic subjects.

Patients And Methods: The study enrolled patients with a history of Type II diabetes, with evidence of symptomatic symmetrical DN with total symptom score (TSS) ≥4, and stable HbA1c level <8. The primary outcome measure was TSS, which assessed intensity and frequency of parasthesia, numbness, pain and burning symptoms self-reported by patients. Secondary measures were nerve conduction, neurological impairment score, and quantitative sensory testing.

Results: Comparing CAST (n=21) and Placebo (n=22) groups, significant reductions from baseline for TSS (p<0.01) and paresthesia (p<0.01) were seen only in CAST treated groups. Numbness increased from baseline only in the Placebo group (p<0.05) and was significantly higher than for the CAST group (p<0.001). Burning sensation was reduced in both groups (p<0.01). Plasma triterpene levels in patients treated with CAST mirrored neurotropic concentrations .

Conclusions: CAST is a potential oral treatment for diabetic neuropathy, as it is well tolerated and effective in reducing the severity of DN symptoms in patients with Type II diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.23736/S1128-9155.18.00455-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510539PMC
June 2018

Centella asiatica attenuates hippocampal mitochondrial dysfunction and improves memory and executive function in β-amyloid overexpressing mice.

Mol Cell Neurosci 2018 12 22;93:1-9. Epub 2018 Sep 22.

Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.

Centella asiatica is a medicinal plant used to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates β-amyloid (Aβ)-induced spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its in vivo mechanism of improving Aβ-related cognitive impairment. This study investigates the effects of CAW on learning, memory and executive function as well as mitochondrial function and antioxidant response in the 5xFAD model of Aβ accumulation. Seven month old 5xFAD female mice were treated with CAW (2 mg/mL) in their drinking water for two weeks prior to behavioral testing. Learning, memory and executive function were assessed using the object location memory task (OLM), conditioned fear response (CFR) and odor discrimination reversal learning (ODRL) test. Mitochondrial function was profiled using the Seahorse XF platform in hippocampal mitochondria isolated from these animals and tissue was harvested for assessment of mitochondrial, antioxidant and synaptic proteins. CAW improved performance in all behavioral tests in the 5xFAD but had no effect on WT animals. Hippocampal mitochondrial function was improved and hippocampal and cortical expression of mitochondrial genes was increased in CAW-treated 5xFAD mice. Gene expression of the transcription factor NRF2, as well as its antioxidant target enzymes, was also increased with CAW treatment in both WT and 5xFAD mice. CAW treatment also decreased Aβ-plaque burden in the hippocampus of treated 5xFAD mice but had no effect on plaques in the cortex. These data show that CAW can improve many facets of Aβ-related cognitive impairment in 5xFAD mice. Oral treatment with CAW also attenuates hippocampal mitochondrial dysfunction in these animals. Because mitochondrial dysfunction and oxidative stress accompany cognitive impairment in many pathological conditions beyond Alzheimer's disease, this suggests potentially broad therapeutic utility of CAW.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mcn.2018.09.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242741PMC
December 2018

Centella asiatica increases hippocampal synaptic density and improves memory and executive function in aged mice.

Brain Behav 2018 07 19;8(7):e01024. Epub 2018 Jun 19.

Department of Neurology, Oregon Health and Science University, Portland, Oregon.

Introduction: Centella asiatica is a plant used for centuries to enhance memory. We have previously shown that a water extract of Centella asiatica (CAW) attenuates age-related spatial memory deficits in mice and improves neuronal health. Yet the effect of CAW on other cognitive domains remains unexplored as does its mechanism of improving age-related cognitive impairment. This study investigates the effects of CAW on a variety of cognitive tasks as well as on synaptic density and mitochondrial and antioxidant pathways.

Methods: Twenty-month-old CB6F1 mice were treated with CAW (2 mg/ml) in their drinking water for 2 weeks prior to behavioral testing. Learning, memory, and executive function were assessed using the novel object recognition task (NORT), object location memory task (OLM), and odor discrimination reversal learning (ODRL) test. Tissue was collected for Golgi analysis of spine density as well as assessment of mitochondrial, antioxidant, and synaptic proteins.

Results: CAW improved performance in all behavioral tests suggesting effects on hippocampal and cortical dependent memory as well as on prefrontal cortex mediated executive function. There was also an increase in synaptic density in the treated animals, which was accompanied by increased expression of the antioxidant response gene NRF2 as well as the mitochondrial marker porin.

Conclusions: These data show that CAW can increase synaptic density as well as antioxidant and mitochondrial proteins and improve multiple facets of age-related cognitive impairment. Because mitochondrial dysfunction and oxidative stress also accompany cognitive impairment in many pathological conditions this suggests a broad therapeutic utility of CAW.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/brb3.1024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043711PMC
July 2018

- Phytochemistry and mechanisms of neuroprotection and cognitive enhancement.

Phytochem Rev 2018 Feb 20;17(1):161-194. Epub 2017 Sep 20.

Department of Neurology, Oregon Health and Science University, Portland, Oregon 97239.

This review describes in detail the phytochemistry and neurological effects of the medicinal herb (L.) Urban. is a small perennial plant that grows in moist, tropical and sub-tropical regions throughout the world. Phytochemicals identified from to date include isoprenoids (sesquiterpenes, plant sterols, pentacyclic triterpenoids and saponins) and phenylpropanoid derivatives (eugenol derivatives, caffeoylquinic acids, and flavonoids). Contemporary methods for fingerprinting and characterization of compounds in extracts include liquid chromatography and/or ion mobility spectrometry in conjunction with high-resolution mass spectrometry. Multiple studies in rodent models, and a limited number of human studies support 's traditional reputation as a cognitive enhancer, as well as its anxiolytic and anticonvulsant effects. Neuroprotective effects of are seen in several models, for example against beta amyloid toxicity, and appear to be associated with increased mitochondrial activity, improved antioxidant status, and/or inhibition of the pro-inflammatory enzyme, phospholipase A2. Neurotropic effects of include increased dendritic arborization and synaptogenesis, and may be due to modulations of signal transduction pathways such as ERK1/2 and Akt. Many of these neurotropic and neuroprotective properties of have been associated with the triterpene compounds asiatic acid, asiaticoside and madecassoside. More recently, caffeoylquinic acids are emerging as a second important group of active compounds in , with the potential of enhancing the Nrf2-antioxidant response pathway. The absorption, distribution, metabolism and excretion of the triterpenes, caffeoylquinic acids and flavonoids found in have been studied in humans and animal models, and the compounds or their metabolites found in the brain. This review highlights the remarkable potential for extracts and derivatives to be used in the treatment of neurological conditions, and considers the further research needed to actualize this possibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11101-017-9528-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6857646PMC
February 2018

Analysis of Levodopa Content in Commercial Mucuna pruriens Products Using High-Performance Liquid Chromatography with Fluorescence Detection.

J Altern Complement Med 2018 Feb 18;24(2):182-186. Epub 2017 Sep 18.

1 Department of Neurology, Oregon Health and Science University , Portland, OR.

Objectives: Mucuna pruriens (MP) seeds contain levodopa (up to 2% by weight) and have been used in traditional Indian medicine to treat an illness named "Kampavata," now understood to be Parkinson's disease (PD). Studies have shown MP to be beneficial, and even superior, to levodopa alone in treating PD symptoms. Commercial products containing MP are readily available from online and retail sources to patients and physicians. Products often contain extracts of MP seeds, with significantly higher levodopa content than the seeds. However, MP products have limited regulatory controls with respect to quality and content of active ingredient. The aim of this study was to apply a quantitative method to determine levodopa content in readily available MP products that might be used by patients or in research studies.

Design: Levodopa present in six commercial MP products was quantified by solvent extraction followed by reversed-phase high-performance liquid chromatography (HPLC) coupled to fluorescence detection (FD). Certificates of analysis (COA) were obtained, from manufacturers of MP products, to assess the existence and implementation of specifications for levodopa content.

Results: HPLC-FD analysis revealed that the levodopa content of the six commercial MP products varied from 6% to 141% of individual label claims. No product contained levodopa within normal pharmacopeial limits of 90%-110% label claim. The maximum daily dose of levodopa delivered by the products varied from 14.4 to 720 mg/day. COAs were inconsistent in specifications for and verification of levodopa content.

Conclusions: The commercial products tested varied widely in levodopa content, sometimes deviating widely from the label claim. These deficiencies could impact efficacy and safety of MP products used by PD patients and compromise the results of scientific studies on MP products. The HPLC-FD method described in this study could be utilized by both manufacturers and scientific researchers to verify levodopa content of MP products.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/acm.2017.0054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5808387PMC
February 2018

Attenuates Mitochondrial Dysfunction and Oxidative Stress in A-Exposed Hippocampal Neurons.

Oxid Med Cell Longev 2017 13;2017:7023091. Epub 2017 Aug 13.

Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.

has been used for centuries to enhance memory. We have previously shown that a water extract of (CAW) protects against the deleterious effects of amyloid- (A) in neuroblastoma cells and attenuates A-induced cognitive deficits in mice. Yet, the neuroprotective mechanism of CAW has yet to be thoroughly explored in neurons from these animals. This study investigates the effects of CAW on neuronal metabolism and oxidative stress in isolated A-expressing neurons. Hippocampal neurons from amyloid precursor protein overexpressing Tg2576 mice and wild-type (WT) littermates were treated with CAW. In both genotypes, CAW increased the expression of antioxidant response genes which attenuated the A-induced elevations in reactive oxygen species (ROS) and lipid peroxidation in Tg2576 neurons. CAW also improved mitochondrial function in both genotypes and increased the expression of electron transport chain enzymes and mitochondrial labeling, suggesting an increase in mitochondrial content. These data show that CAW protects against mitochondrial dysfunction and oxidative stress in A-exposed hippocampal neurons which could contribute to the beneficial effects of the extract observed in vivo. Since CAW also improved mitochondrial function in the absence of A, these results suggest a broader utility for other conditions where neuronal mitochondrial dysfunction occurs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2017/7023091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572603PMC
May 2018

Centella asiatica attenuates Aβ-induced neurodegenerative spine loss and dendritic simplification.

Neurosci Lett 2017 04 6;646:24-29. Epub 2017 Mar 6.

Department of Neurology, Oregon Health and Science University, Portland, OR 97239, USA.

The medicinal plant Centella asiatica has long been used to improve memory and cognitive function. We have previously shown that a water extract from the plant (CAW) is neuroprotective against the deleterious cognitive effects of amyloid-β (Aβ) exposure in a mouse model of Alzheimer's disease, and improves learning and memory in healthy aged mice as well. This study explores the physiological underpinnings of those effects by examining how CAW, as well as chemical compounds found within the extract, modulate synaptic health in Aβ-exposed neurons. Hippocampal neurons from amyloid precursor protein over-expressing Tg2576 mice and their wild-type (WT) littermates were used to investigate the effect of CAW and various compounds found within the extract on Aβ-induced dendritic simplification and synaptic loss. CAW enhanced arborization and spine densities in WT neurons and prevented the diminished outgrowth of dendrites and loss of spines caused by Aβ exposure in Tg2576 neurons. Triterpene compounds present in CAW were found to similarly improve arborization although they did not affect spine density. In contrast caffeoylquinic acid (CQA) compounds from CAW were able to modulate both of these endpoints, although there was specificity as to which CQAs mediated which effect. These data suggest that CAW, and several of the compounds found therein, can improve dendritic arborization and synaptic differentiation in the context of Aβ exposure which may underlie the cognitive improvement observed in response to the extract in vivo. Additionally, since CAW, and its constituent compounds, also improved these endpoints in WT neurons, these results may point to a broader therapeutic utility of the extract beyond Alzheimer's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2017.02.072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533098PMC
April 2017

Centella asiatica modulates antioxidant and mitochondrial pathways and improves cognitive function in mice.

J Ethnopharmacol 2016 Mar 16;180:78-86. Epub 2016 Jan 16.

Department of Neurology, Oregon Health and Science University, Portland, OR 97239 USA.

Ethnopharmacological Relevance: This study investigates the cognitive enhancing effects of the plant Centella asiatica which is widely used Ayurvedic and traditional Chinese medicine.

Aim Of The Study: The goal of this study was to determine the effects of a water extract of the medicinal plant Centella asiatica (CAW) on cognitive ability as well as mitochondrial and antioxidant response pathways in vivo.

Materials And Methods: Old and young C57BL/6 mice were treated with CAW (2mg/mL) in their drinking water. Learning and memory was assessed using Morris Water Maze (MWM) and then tissue was collected and gene expression analyzed.

Results: CAW improved performance in the MWM in aged animals and had a modest effect on the performance of young animals. CAW also increased the expression of mitochondrial and antioxidant response genes in the brain and liver of both young and old animals. Expression of synaptic markers was also increased in the hippocampus and frontal cortex, but not in the cerebellum of CAW-treated animals.

Conclusions: These data indicate a cognitive enhancing effect of CAW in healthy mice. The gene expression changes caused by CAW suggest a possible effect on mitochondrial biogenesis, which in conjunction with activation of antioxidant response genes could contribute to cognitive improvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jep.2016.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764102PMC
March 2016

Curcumin Treatment Improves Motor Behavior in α-Synuclein Transgenic Mice.

PLoS One 2015 2;10(6):e0128510. Epub 2015 Jun 2.

Jungers Center for Neurosciences Research, Oregon Health & Science University, Portland, Oregon, United States of America; Department of Neurology, Oregon Health & Science University, Portland, Oregon, United States of America; Parkinson Center of Oregon, Oregon Health & Science University, Portland, Oregon, United States of America.

The curry spice curcumin plays a protective role in mouse models of neurodegenerative diseases, and can also directly modulate aggregation of α-synuclein protein in vitro, yet no studies have described the interaction of curcumin and α-synuclein in genetic synucleinopathy mouse models. Here we examined the effect of chronic and acute curcumin treatment in the Syn-GFP mouse line, which overexpresses wild-type human α-synuclein protein. We discovered that curcumin diet intervention significantly improved gait impairments and resulted in an increase in phosphorylated forms of α-synuclein at cortical presynaptic terminals. Acute curcumin treatment also caused an increase in phosphorylated α-synuclein in terminals, but had no direct effect on α-synuclein aggregation, as measured by in vivo multiphoton imaging and Proteinase-K digestion. Using LC-MS/MS, we detected ~5 ng/mL and ~12 ng/mL free curcumin in the plasma of chronic or acutely treated mice, with a glucuronidation rate of 94% and 97%, respectively. Despite the low plasma levels and extensive metabolism of curcumin, these results show that dietary curcumin intervention correlates with significant behavioral and molecular changes in a genetic synucleinopathy mouse model that mimics human disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0128510PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4452784PMC
April 2016

Centella asiatica Attenuates Amyloid-β-Induced Oxidative Stress and Mitochondrial Dysfunction.

J Alzheimers Dis 2015 ;45(3):933-46

Department of Neurology, Oregon Health and Science University, Portland, OR, USA.

Background: We previously showed that a water extract of the medicinal plant Centella asiatica (CAW) attenuates amyloid-β (Aβ)-induced cognitive deficits in vivo, and prevents Aβ-induced cytotoxicity in vitro. Yet the neuroprotective mechanism of CAW is unknown.

Objective: The goal of this study was to identify biochemical pathways altered by CAW using in vitro models of Aβ toxicity.

Methods: The effects of CAW on aberrations in antioxidant response, calcium homeostasis, and mitochondrial function induced by Aβ were evaluated in MC65 and SH-SY5Y neuroblastoma cells.

Results: CAW decreased intracellular reactive oxygen species and calcium levels elevated in response to Aβ, and induced the expression of antioxidant response genes in both cell lines. In SH-SY5Y cells, CAW increased basal and maximal oxygen consumption without altering spare capacity, and attenuated Aβ-induced decreases in mitochondrial respiration. CAW also prevented Aβ-induced decreases in ATP and induced the expression of mitochondrial genes and proteins in both cell types. Caffeoylquinic acids from CAW were shown to have a similar effect on antioxidant and mitochondrial gene expression in neuroblastoma cells. Primary rat hippocampal neurons treated with CAW also showed an increase in mitochondrial and antioxidant gene expression.

Conclusions: These data suggest an effect of CAW on mitochondrial biogenesis, which in conjunction with activation of antioxidant response genes and normalizing calcium homeostasis, likely contributes to its neuroprotective action against Aβ toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-142217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4412033PMC
January 2016

Caffeoylquinic acids in Centella asiatica protect against amyloid-β toxicity.

J Alzheimers Dis 2014 ;40(2):359-73

Department of Neurology, Oregon Health and Science University, Portland, OR, USA.

The accumulation of amyloid-β (Aβ) is a hallmark of Alzheimer's disease and is known to result in neurotoxicity both in vivo and in vitro. We previously demonstrated that treatment with the water extract of Centella asiatica (CAW) improves learning and memory deficits in Tg2576 mice, an animal model of Aβ accumulation. However the active compounds in CAW remain unknown. Here we used two in vitro models of Aβ toxicity to confirm this neuroprotective effect and identify several active constituents of the CAW extract. CAW reduced Aβ-induced cell death and attenuated Aβ-induced changes in tau expression and phosphorylation in both the MC65 and SH-SY5Y neuroblastoma cell lines. We confirmed and quantified the presence of several mono- and dicaffeoylquinic acids (CQAs) in CAW using chromatographic separation coupled to mass spectrometry and ultraviolet spectroscopy. Multiple dicaffeoylquinic acids showed efficacy in protecting MC65 cells against Aβ-induced cytotoxicity. Isochlorogenic acid A and 1,5-dicaffeoylquinic acid were found to be the most abundant CQAs in CAW, and the most active in protecting MC65 cells from Aβ-induced cell death. Both compounds showed neuroprotective activity in MC65 and SH-SY5Y cells at concentrations comparable to their levels in CAW. Each compound not only mitigated Aβ-induced cell death, but was able to attenuate Aβ-induced alterations in tau expression and phosphorylation in both cell lines, as seen with CAW. These data suggest that CQAs are active neuroprotective components in CAW, and therefore are important markers for future studies on CAW standardization, bioavailability, and dosing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JAD-131913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3973491PMC
January 2015

Centella asiatica Extract Improves Behavioral Deficits in a Mouse Model of Alzheimer's Disease: Investigation of a Possible Mechanism of Action.

Int J Alzheimers Dis 2012 15;2012:381974. Epub 2012 Feb 15.

Department of Neurology, Oregon Health & Science University, Portland, OR 97239, USA.

Centella asiatica (CA), commonly named gotu kola, is an Ayurvedic herb used to enhance memory and nerve function. To investigate the potential use of CA in Alzheimer's disease (AD), we examined the effects of a water extract of CA (GKW) in the Tg2576 mouse, a murine model of AD with high β-amyloid burden. Orally administered GKW attenuated β-amyloid-associated behavioral abnormalities in these mice. In vitro, GKW protected SH-SY5Y cells and MC65 human neuroblastoma cells from toxicity induced by exogenously added and endogenously generated β-amyloid, respectively. GKW prevented intracellular β-amyloid aggregate formation in MC65 cells. GKW did not show anticholinesterase activity or protect neurons from oxidative damage and glutamate toxicity, mechanisms of current AD therapies. GKW is rich in phenolic compounds and does not contain asiatic acid, a known CA neuroprotective triterpene. CA thus offers a unique therapeutic mechanism and novel active compounds of potential relevance to the treatment of AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2012/381974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296229PMC
August 2012

The effect of Echinacea purpurea, Astragalus membranaceus and Glycyrrhiza glabra on CD25 expression in humans: a pilot study.

Phytother Res 2007 Nov;21(11):1109-12

Helfgott Research Institute, National College of Natural Medicine, Portland, OR 97201, USA.

This phase 0, double-blind, repeated within subject, randomized pilot study examined CD25 expression on T cells after ingestion of three commonly used herbs: Echinacea purpurea, Astragalus membranaceus and Glycyrrhiza glabra, administered singly and in combination. CD25 expression on T cells was significantly increased for subjects ingesting Echinacea at 24 h with notable increases in activation from Astragalus and Glycyrrhiza. CD25 expression remains elevated with daily use of Echinacea for at least 7 days.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ptr.2207DOI Listing
November 2007

Amides from Piper nigrum L. with dissimilar effects on melanocyte proliferation in-vitro.

J Pharm Pharmacol 2007 Apr;59(4):529-36

Department of Pharmacy, King's College London, 150 Stamford Street, London SE1 9NN, UK.

Melanocyte proliferation stimulants are of interest as potential treatments for the depigmentary skin disorder, vitiligo. Piper nigrum L. (Piperaceae) fruit (black pepper) water extract and its main alkaloid, piperine (1), promote melanocyte proliferation in-vitro. A crude chloroform extract of P. nigrum containing piperine was more stimulatory than an equivalent concentration of the pure compound, suggesting the presence of other active components. Piperine (1), guineensine (2), pipericide (3), N-feruloyltyramine (4) and N-isobutyl-2E, 4E-dodecadienamide (5) were isolated from the chloroform extract. Their activity was compared with piperine and with commercial piperlongumine (6) and safrole (7), and synthetically prepared piperettine (8), piperlonguminine (9) and 1-(3, 4-methylenedioxyphenyl)-decane (10). Compounds 6-10 either occur in P. nigrum or are structurally related. Compounds 1, 2, 3, 8 and 9 stimulated melanocyte proliferation, whereas 4, 5, 6, 7 and 10 did not. Comparison of structures suggests that the methylenedioxyphenyl function is essential for melanocyte stimulatory activity. Only those compounds also possessing an amide group were active, although the amino component of the amide group and chain linking it to the methylenedioxyphenyl group can vary. P. nigrum, therefore, contains several amides with the ability to stimulate melanocyte proliferation. This finding supports the traditional use of P. nigrum extracts in vitiligo and provides new lead compounds for drug development for this disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1211/jpp.59.4.0007DOI Listing
April 2007

UV irradiation affects melanocyte stimulatory activity and protein binding of piperine.

Photochem Photobiol 2006 Nov-Dec;82(6):1541-8

Department of Pharmacy, King's College London, Franklin-Wilkins Building, 150 Stamford Street, London SE1 9NN, UK.

Piperine, the major alkaloid of black pepper (Piper nigrum L.; Piperaceae), stimulates melanocyte proliferation and dendrite formation in vitro. This property renders it a potential treatment for the skin depigmentation disorder vitiligo. However, piperine does not stimulate melanin synthesis in vitro, and treatments based on this compound may therefore be more effective with concomitant exposure of the skin to ultraviolet (UV) radiation or sunlight. The present study investigated the effect of UVA and simulated solar radiation (SSR) on the chemical stability of piperine, its melanocyte stimulatory effects and its ability to bind protein and DNA. Chromatographic and spectroscopic analysis confirmed the anticipated photoisomerization of irradiated piperine and showed the absence of any hydrolysis to piperinic acid. Isomerization resulted in the loss of ability to stimulate proliferation of a mouse melanocyte cell line, and to bind to human serum albumin. There was no evidence of DNA binding by piperine either before or after irradiation, showing the absence of photoadduct formation by either piperine or its geometric isomers. This is unlike the situation with psoralens, which form DNA adducts when administered with UVA in treating skin diseases. The present study suggests that exposure to bright sunlight should be avoided both during active application of piperine to the skin and in the storage of piperine products. If UVA radiation is used with piperine in the treatment of vitiligo, application of the compound and irradiation should be staggered to minimize photoisomerization. This approach is shown to effectively induce pigmentation in a sparsely pigmented mouse strain.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2007

The effect of Echinacea purpurea, Astragalus membranaceus and Glycyrrhiza glabra on CD69 expression and immune cell activation in humans.

Phytother Res 2006 Aug;20(8):687-95

Helfgott Research Institute, National College of Naturopathic Medicine, Portland, OR, USA.

The increasing use of medicinal herbs among the general public has piqued the need for scientific-based research to determine the mechanism of action of herbs administered orally in human subjects. The ability of three herbs, Echinacea purpurea, Astragalus membranaceus and Glycyrrhiza glabra, to activate immune cells in human subjects was assessed in this pilot study. The effect of these herbs when ingested for 7 days was measured both when administered singly, and in combination, using flow cytometry. The primary cell activation marker measured was CD69. The results demonstrate that Echinacea, Astragalus and Glycyrrhiza herbal tinctures stimulated immune cells as quantified by CD69 expression on CD4 and CD8 T cells. This activation took place within 24 h of ingestion, and continued for at least 7 days. In addition, these three herbs had an additive effect on CD69 expression when used in combination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ptr.1938DOI Listing
August 2006

alpha-Amylase inhibitory activity of some Malaysian plants used to treat diabetes; with particular reference to Phyllanthus amarus.

J Ethnopharmacol 2006 Oct 18;107(3):449-55. Epub 2006 Apr 18.

Pharmacognosy Research Laboratories, Pharmaceutical Sciences Research Division, King's College London, Franklin-Wilkins Building, 150, Stamford Street, London SE1 9NN, United Kingdom.

Extracts of six selected Malaysian plants with a reputation of usefulness in treating diabetes were examined for alpha-amylase inhibition using an in vitro model. Inhibitory activity studied by two different protocols (with and without pre-incubation) showed that Phyllanthus amarus hexane extract had alpha-amylase inhibitory properties. Hexane and dichloromethane extracts of Anacardium occidentale, Lagerstroemia speciosa, Averrhoa bilimbiPithecellobium jiringa and Parkia speciosa were not active when tested without pre-incubation. Extraction and fractionation of Phyllanthus amarus hexane extract led to the isolation of dotriacontanyl docosanoate, triacontanol and a mixture of oleanolic acid and ursolic acid. Dotriacontanyl docosanoate and the mixture of oleanolic acid and ursolic acid are reported from this plant species for the first time. All compounds were tested in the alpha-amylase inhibition assay and the results revealed that the oleanolic acid and ursolic acid (2:1) mixture was a potent alpha-amylase inhibitor with IC(50)=2.01 microg/ml (4.41 microM) and that it contributes significantly to the alpha-amylase inhibition activity of the extract. Three pure pentacyclic triterpenoids, oleanolic acid, ursolic acid and lupeol were shown to inhibit alpha-amylase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jep.2006.04.004DOI Listing
October 2006

Centella asiatica accelerates nerve regeneration upon oral administration and contains multiple active fractions increasing neurite elongation in-vitro.

J Pharm Pharmacol 2005 Sep;57(9):1221-9

Department of Neurology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland OR 97239, USA.

Axonal regeneration is important for functional recovery following nerve damage. Centella asiatica Urban herb, also known as Hydrocotyle asiatica L., has been used in Ayurvedic medicine for centuries as a nerve tonic. Here, we show that Centella asiatica ethanolic extract (100 microg mL-1) elicits a marked increase in neurite outgrowth in human SH-SY5Y cells in the presence of nerve growth factor (NGF). However, a water extract of Centella was ineffective at 100 microg mL-1. Sub-fractions of Centella ethanolic extract, obtained through silica-gel chromatography, were tested (100 microg mL-1) for neurite elongation in the presence of NGF. Greatest activity was found with a non-polar fraction (GKF4). Relatively polar fractions (GKF10 to GKF13) also showed activity, albeit less than GKF4. Thus, Centella contains more than one active component. Asiatic acid (AA), a triterpenoid compound found in Centella ethanolic extract and GKF4, showed marked activity at 1 microM (microg mL-1). AA was not present in GKF10 to GKF13, further indicating that other active components must be present. Neurite elongation by AA was completely blocked by the extracellular-signal-regulated kinase (ERK) pathway inhibitor PD 098059 (10 microM). Male Sprague-Dawley rats given Centella ethanolic extract in their drinking water (300-330 mg kg-1 daily) demonstrated more rapid functional recovery and increased axonal regeneration (larger calibre axons and greater numbers of myelinated axons) compared with controls, indicating that the axons grew at a faster rate. Taken together, our findings indicate that components in Centella ethanolic extract may be useful for accelerating repair of damaged neurons.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1211/jpp.57.9.0018DOI Listing
September 2005
-->