Publications by authors named "Leah Mursaleen"

9 Publications

  • Page 1 of 1

Micellar Nanocarriers of Hydroxytyrosol Are Protective against Parkinson's Related Oxidative Stress in an In Vitro hCMEC/D3-SH-SY5Y Co-Culture System.

Antioxidants (Basel) 2021 May 31;10(6). Epub 2021 May 31.

Centre for Nutraceuticals, School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK.

Hydroxytyrosol (HT) is a natural phenolic antioxidant which has neuroprotective effects in models of Parkinson's disease (PD). Due to issues such as rapid metabolism, HT is unlikely to reach the brain at therapeutic concentrations required for a clinical effect. We have previously developed micellar nanocarriers from Pluronic F68 (P68) and dequalinium (DQA) which have suitable characteristics for brain delivery of antioxidants and iron chelators. The aim of this study was to utilise the P68 + DQA nanocarriers for HT alone, or in combination with the iron chelator deferoxamine (DFO), and assess their physical characteristics and ability to pass the blood-brain barrier and protect against rotenone in a cellular hCMEC/D3-SH-SY5Y co-culture system. Both HT and HT + DFO formulations were less than 170 nm in size and demonstrated high encapsulation efficiencies (up to 97%). P68 + DQA nanoformulation enhanced the mean blood-brain barrier (BBB) passage of HT by 50% ( < 0.0001, = 6). This resulted in increased protection against rotenone induced cytotoxicity and oxidative stress by up to 12% and 9%, respectively, compared to the corresponding free drug treatments ( < 0.01, = 6). This study demonstrates for the first time the incorporation of HT and HT + DFO into P68 + DQA nanocarriers and successful delivery of these nanocarriers across a BBB model to protect against PD-related oxidative stress. These nanocarriers warrant further investigation to evaluate whether this enhanced neuroprotection is exhibited in in vivo PD models.
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http://dx.doi.org/10.3390/antiox10060887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226543PMC
May 2021

Co-Administration of Iron and a Bioavailable Curcumin Supplement Increases Serum BDNF Levels in Healthy Adults.

Antioxidants (Basel) 2020 Jul 22;9(8). Epub 2020 Jul 22.

School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK.

Brain-derived neurotrophic factor (BDNF) is key for the maintenance of normal neuronal function and energy homeostasis and has been suggested to improve cognitive function, including learning and memory. Iron and the antioxidant curcumin have been shown to influence BDNF homeostasis. This 6-week, double blind, randomized, placebo-controlled study examined the effects of oral iron supplementation at low (18 mg) and high (65 mg) ferrous (FS) iron dosages, compared to a combination of these iron doses with a bioavailable formulated form of curcumin (HydroCurc; 500 mg) on BDNF levels in a healthy adult cohort of 155 male (26.42 years ± 0.55) and female (25.82 years ± 0.54) participants. Participants were randomly allocated to five different treatment groups: both iron and curcumin placebo (FS0+Plac), low dose iron and curcumin placebo (FS18+Plac), low dose iron and curcumin (FS18+Curc), high dose iron and curcumin placebo (FS65+Plac) and high dose iron and curcumin (FS65+Curc). Results showed a significant increase in BDNF over time (26%) in the FS18+Curc group ( = 0.024), and at end-point between FS18+Curc and FS18+Plac groups (35%, = 0.042), demonstrating for the first time that the combination with curcumin, rather than iron supplementation alone, results in increased serum BDNF. The addition of curcumin to iron supplementation may therefore provide a novel approach to further enhance the benefits associated with increased BDNF levels.
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http://dx.doi.org/10.3390/antiox9080645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463477PMC
July 2020

N-Acetylcysteine Nanocarriers Protect against Oxidative Stress in a Cellular Model of Parkinson's Disease.

Antioxidants (Basel) 2020 Jul 9;9(7). Epub 2020 Jul 9.

School of Life Sciences, University of Westminster, 115 New Cavendish Street, London W1W 6UW, UK.

Oxidative stress is a key mediator in the development and progression of Parkinson's disease (PD). The antioxidant n-acetylcysteine (NAC) has generated interest as a disease-modifying therapy for PD but is limited due to poor bioavailability, a short half-life, and limited access to the brain. The aim of this study was to formulate and utilise mitochondria-targeted nanocarriers for delivery of NAC alone and in combination with the iron chelator deferoxamine (DFO), and assess their ability to protect against oxidative stress in a cellular rotenone PD model. Pluronic F68 (P68) and dequalinium (DQA) nanocarriers were prepared by a modified thin-film hydration method. An MTT assay assessed cell viability and iron status was measured using a ferrozine assay and ferritin immunoassay. For oxidative stress, a modified cellular antioxidant activity assay and the thiobarbituric acid-reactive substances assay and mitochondrial hydroxyl assay were utilised. Overall, this study demonstrates, for the first time, successful formulation of NAC and NAC + DFO into P68 + DQA nanocarriers for neuronal delivery. The results indicate that NAC and NAC + DFO nanocarriers have the potential characteristics to access the brain and that 1000 μM P68 + DQA NAC exhibited the strongest ability to protect against reduced cell viability ( = 0.0001), increased iron ( = 0.0033) and oxidative stress ( ≤ 0.0003). These NAC nanocarriers therefore demonstrate significant potential to be transitioned for further preclinical testing for PD.
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http://dx.doi.org/10.3390/antiox9070600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402157PMC
July 2020

GDNF and Parkinson's Disease: Where Next? A Summary from a Recent Workshop.

J Parkinsons Dis 2020 ;10(3):875-891

The Cure Parkinson's Trust, London, UK.

The concept of repairing the brain with growth factors has been pursued for many years in a variety of neurodegenerative diseases including primarily Parkinson's disease (PD) using glial cell line-derived neurotrophic factor (GDNF). This neurotrophic factor was discovered in 1993 and shown to have selective effects on promoting survival and regeneration of certain populations of neurons including the dopaminergic nigrostriatal pathway. These observations led to a series of clinical trials in PD patients including using infusions or gene delivery of GDNF or the related growth factor, neurturin (NRTN). Initial studies, some of which were open label, suggested that this approach could be of value in PD when the agent was injected into the putamen rather than the cerebral ventricles. In subsequent double-blind, placebo-controlled trials, the most recent reporting in 2019, treatment with GDNF did not achieve its primary end point. As a result, there has been uncertainty as to whether GDNF (and by extrapolation, related GDNF family neurotrophic factors) has merit in the future treatment of PD. To critically appraise the existing work and its future, a special workshop was held to discuss and debate this issue. This paper is a summary of that meeting with recommendations on whether there is a future for this therapeutic approach and also what any future PD trial involving GDNF and other GDNF family neurotrophic factors should consider in its design.
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http://dx.doi.org/10.3233/JPD-202004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458523PMC
January 2020

Deferoxamine and Curcumin Loaded Nanocarriers Protect Against Rotenone-Induced Neurotoxicity.

J Parkinsons Dis 2020 ;10(1):99-111

School of Life Sciences, University of Westminster, London, UK.

Background: Reduced glutathione and excess free iron within dopaminergic, substantia nigra neurons in Parkinson's disease (PD) can drive accumulation of toxic hydroxyl radicals resulting in sustained oxidative stress and cellular damage. Factors such as brain penetrance and bioavailability have limited the advancement of potential antioxidant and iron chelator therapies for PD.

Objective: This study aimed to develop novel nanocarrier delivery systems for the antioxidant curcumin and/or iron chelator deferoxamine (DFO) to protect against rotenone-induced changes in cell viability and oxidative stress in SH-SY5Y cells.

Methods: Nanocarriers of curcumin and/or DFO were prepared using Pluronic F68 (P68) with or without dequilinium (DQA) by modified thin-film hydration. Cell viability was assessed using an MTT assay and oxidative stress was measured using thiobarbituric acid reactive substances and cellular antioxidant activity assays.

Results: All formulations demonstrated high encapsulation efficiency (65-96%) and nanocarrier size was <200 nm. 3-h pretreatment with P68 or P68+DQA nanocarriers containing various concentrations of curcumin and/or DFO significantly protected against rotenone-reduced cell viability. The addition of DFO to curcumin-loaded P68+DQA nanocarriers resulted in increased protection by at least 10%. All nanoformulations significantly protected against rotenone-induced lipid peroxidation (p < 0.0001). The addition of DQA, which targets mitochondria, resulted in up to 65% increase in cellular antioxidant activity. In nearly all preparations, the combination of 10 μM curcumin and 100 μM DFO had the most antioxidant activity.

Conclusion: This study demonstrates for the first time the formulation and delivery using P68 and P68+DQA curcumin and/or DFO nanocarriers to protect against oxidative stress induced by a rotenone PD model. This strategy to combine antioxidants with iron chelators may provide a novel approach to fully utilise their therapeutic benefit for PD.
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http://dx.doi.org/10.3233/JPD-191754DOI Listing
April 2021

The benefit of evolving multidisciplinary care in ALS: a diagnostic cohort survival comparison.

Amyotroph Lateral Scler Frontotemporal Degener 2017 11 18;18(7-8):569-575. Epub 2017 Jul 18.

a Department of Basic and Clinical Neuroscience , Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London , London , UK.

Background: Care for people with amyotrophic lateral sclerosis (ALS) has altered at King's College Hospital over the last 20 years. The clinic has been a multidisciplinary, specialist, tertiary referral centre since 1995 with a large team with integrated palliative and respiratory care since 2006. We hypothesised that these changes would improve survival.

Methods: In this retrospective observational study, patients diagnosed with El Escorial definite, probable and possible ALS between 1995-1998 and 2008-2011 were followed up. The primary outcome measure was a chi-square test for the proportion of each cohort surviving. Kaplan-Meier survival analysis and Cox multivariate regression were secondary analyses.

Results: There was low reporting of some interventions. Five hundred and forty-seven people were included. Survival between the cohorts was significantly different (p = 0.022) with a higher proportion surviving during 2008-2011. Survival time was 21.6 (95% CI 19.2-24.0) months in the 2008-2011 cohort compared to 19.2 years (15.6-21.6) in the 1995-1998 cohort (log rank p = 0.018). Four hundred and ninety-three cases were included in the Cox regression. Diagnostic cohort was a significant predictor variable (HR 0.79 (0.64-0.97) p = 0.023).

Conclusions: These results support the hypothesis that integrated specialist clinics with multidisciplinary input improve survival in ALS.
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http://dx.doi.org/10.1080/21678421.2017.1349151DOI Listing
November 2017

Attitudes Towards Data Collection, Ownership and Sharing Among Patients with Parkinson's Disease.

J Parkinsons Dis 2017 ;7(3):523-531

The Cure Parkinson's Trust, London, UK.

Background: The ownership and sharing of patient medical data is an increasingly contentious subject in medicine generally but also within the field of Parkinson's disease (PD). Despite being the providers of the medical data, patients are rarely consulted as to its usage.

Objective: The objective of this paper is to establish patient attitudes to ownership of their own medical data and the sharing thereof.

Methods: We report here the results of an online survey of people with Parkinson's. A total of 310 people took part in the 'sharing data' component of the survey, answering some or all of the questions for which they were eligible.

Results: Most respondents (208/306) were aged between 55 and 74 years. 55% of the sample were female and the mean number of years diagnosed was 7.1. Although 93% of respondents were willing to share data, only 41% were currently doing so and a further 8% did not know whether they were sharing any information in this way. There was a significant association between age and data sharing (p = 0.006). However, no clear relationship was found between data sharing and the number of years diagnosed, sex, medication class or health confidence. There was also no consensus among patients on ownership of, access to and usage of their research data.

Conclusion: The lack of consensus on data ownership and general absence of clear demographic predictors of data sharing implies impaired communication pathways. We suggest that strategies directed towards improved communication may help to clarify data ownership and promote data sharing.
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http://dx.doi.org/10.3233/JPD-161045DOI Listing
April 2018

Challenges of Improving Patient-Centred Care in Parkinson's Disease.

J Parkinsons Dis 2017 ;7(1):163-174

Parkinson's Movement, London, UK.

Background: Parkinson's disease is a neurodegenerative condition with a complex pattern of motor and non-motor symptoms. Of several clinical scales used to measure patient experience few are delivered by patients themselves.

Objective: The present study reports the results of an online survey to establish (a) factors that most influence QoL (quality of life) for people with Parkinson's and (b) areas where self-monitoring may help.

Methods: A 27 question online survey (using Survey Monkey) was developed by The Cure Parkinson's Trust, comprising four main sections (demographics, monitoring, symptoms and communication).

Results: 492 patients participated. 97% felt it 'very' or 'moderately' important to understand their own Parkinson's symptoms and recognise patterns in their condition (n = 420). Although, 87% (n = 467) were interested in recording information about their Parkinson's to monitor their well-being, only 49% of respondents were actually doing so. Slowness of movement (82% n = 432) and lack of energy (61% n = 432) were the most reported motor and non-motor symptoms, respectively. These symptoms were also commonly reported to impact QoL (n = 407). In monitoring these symptoms 75% (n = 409) thought it would help improve their understanding of their condition, 64% thought it would improve their wellbeing and ability to cope, 61% thought it would improve their treatment and 59% thought it would improve communication with their healthcare team.

Conclusion: Collectively, the data suggest that a measurement tool supporting a patient-centred care model would be a combination of objective and accurate measurement of the most bothersome symptoms for patients towards the end goal of improving patients' QoL.
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http://dx.doi.org/10.3233/JPD-160922DOI Listing
November 2017

Drugs of abuse and Parkinson's disease.

Prog Neuropsychopharmacol Biol Psychiatry 2016 Jan 27;64:209-17. Epub 2015 Mar 27.

The Cure Parkinson's Trust, 120 Baker Street, London W1U 6TU, United Kingdom; Parkinson's Movement, 120 Baker Street, London W1U 6TU, United Kingdom. Electronic address:

The term "drug of abuse" is highly contextual. What constitutes a drug of abuse for one population of patients does not for another. It is therefore important to examine the needs of the patient population to properly assess the status of drugs of abuse. The focus of this article is on the bidirectional relationship between patients and drug abuse. In this paper we will introduce the dopaminergic systems of the brain in Parkinson's and the influence of antiparkinsonian drugs upon them before discussing this synergy of condition and medication as fertile ground for drug abuse. We will then examine the relationship between drugs of abuse and Parkinson's, both beneficial and deleterious. In summary we will draw the different strands together and speculate on the future merit of current drugs of abuse as treatments for Parkinson's disease.
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http://dx.doi.org/10.1016/j.pnpbp.2015.03.013DOI Listing
January 2016
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