Curcumin, a compound found within the very popular cooking spice, turmeric, is a natural polyphenol that has been used for centuries in Ayurvedic and Chinese Traditional Medicine to help manage inflammation. Dr Ailsa McGregor, a Senior Lecturer in clinical pharmacology at the University of Otago, is investigating using curcumin on stroke patients who are not suitable for clot buster therapy but have inflammation in the brain. She mentions, “over the last 10 years, curcumin has transitioned from alternative to mainstream medicine and has been investigated as a potential therapy for cancer and other disorders with an inflammatory component, including diabetes and wound healing.” Dr McGregor continues to explain that, “administering curcumin before or immediately after stroke produces both anti-inflammatory and neuroprotective effects in experimental models, but it’s unclear whether this salvage of brain tissue translates to improvements in function and whether curcumins have a wider application as regenerative agents.”
Dr McGregor discusses her research in full below, and how curcumin could be used in the future in reducing inflammation post-stroke to promote functional recovery.
This research wouldn’t be possible without the generous support by the estate of Trevor Small.
What is your research about?
Dr Ailsa McGregor: This project will investigate whether delayed administration of a series of new and highly potent curcumin analogues can reduce brain inflammation and improve stroke-related neurological deficits in an experimental stroke model.
In clinical terms, this work will provide supporting evidence for the development of a pharmacological therapy which could be easily translated to the clinical setting. Designed to be administered in the days after stroke, this approach has implications for surviving stroke patients who arrive late to hospital and are not suitable for clot buster (thrombolytic) therapy.
What has led you to this?
Dr Ailsa McGregor: Brain injuries like stroke are associated with profound activation of inflammatory pathways. While inflammation is important in resolving injury, prolonged inflammation hampers repair and correlates with poor outcomes in stroke patients. We recently showed that reducing brain inflammation in the days after stroke upregulated markers of tissue repair and increased functional recovery in a clinically relevant mouse model of stroke. These results support our idea that counteracting this later phase of inflammation may be a more effective treatment approach.
Our lab group has a long-standing interest in using drug treatments to promote recovery post stroke. In recent years, increasing attention has focused on the use of natural products and their analogues in an attempt to identify new therapeutic options to treat stroke. The considerable excitement regarding the preclinical efficacy of curcumin, which is derived from the spice turmeric, has been largely driven by its lack of toxicity and low cost but its wider use has been restricted by solubility and poor absorption.
A series of curcumin analogues have been synthesised at the University of Otago to improve solubility and pharmacokinetic limitations. These second-generation curcumin analogues are more potent than any other curcumin derivatives synthesised by other research groups around the world. We have tested these analogues in vitro and they show anti-inflammatory effects and no toxicity. The next step is to optimise the dose and timeframe for administration in our stroke model.
What is involved in the study, how will you undertake it?
Dr Ailsa McGregor: The development of treatment strategies for stroke requires preclinical testing of therapeutic candidates in clinically valid animal models. The MacGreen mouse stroke model has become central to our work investigating of the role of inflammation in stroke pathogenesis and recovery. This unique stroke model is reliable, reproducible and recapitulates the key motor impairments observed in human stroke patients.
We have developed a screening platform for compounds with anti-inflammatory effects using organotypic brain slices from MacGreen mice subjected to experimental stroke. Our ex vivo model system retains more anatomical integrity than dissociated neuronal cultures and allows direct assessment of brain inflammation. We will first determine the dose of curcumin analogues required to produce anti-inflammatory effects in this ex vivo system. Once we have determined the optimal dose and timeframe for administration, we will investigate the analogues’ effects on functional recovery.
What will be the anticipated outcomes of the research?
Dr Ailsa McGregor: Stroke is the third leading cause of mortality and the leading cause of adult disability in New Zealand. Despite its prevalence and economic impact there are limited effective therapeutic options. Traditional research has focused on counteracting the very early pathways that lead to cell death, but these therapies don’t show beneficial effects in human stroke patients.
Investigating how these potent and highly sought-after curcumin analogues alter neuroinflammation in a unique stroke model will provide proof of principle for a new treatment strategy that may lead to identification of new and more realistic targets to treat a larger population of stroke patients.
How will this benefit people in the longer term? Why is it so important?
Dr Ailsa McGregor: It is estimated that from the late 2030s those aged 65 and over will represent 25% of the population of New Zealand and approximately 20% of this population will be affected by neurological disease (Statistics New Zealand; www.stats.govt.nz). Stroke is the leading cause of death in New Zealand, contributing to 9% of all deaths, and is a major cause of severe disability. To date, clinicians have remained helpless regarding the protection and recovery of brain tissue after stroke.
This project aims to use an established mouse model of stroke as a platform for investigating whether reducing inflammation post stroke can promote functional recovery. Identifying an intervention that increases recovery after stroke has the potential to reduce the number of patients who live with severe disabilities, and the costs of long-term healthcare. Designed to be administered days after stroke, this treatment would improve prospects for the large number of stroke patients with delayed hospital admission, particularly those of Maori and Pacific Island descent who suffer more severe strokes at a younger age and have poorer outcomes.
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