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SA plant extracts and zebrafish larvae could hold key to better epilepsy medication

20 September 2024 | Story André Damons | Photo Supplied

zebrafish-blue-in-aquarium — Zebrafish blue in an aquarium.

A researcher from the University of the Free State (UFS) hopes to make living with epilepsy and other diseases of the central nervous system (CNS) easier by using South African plants extracts which may have anti-epileptic properties and testing them on zebrafish larvae.

Prof Anke Wilhelm, Associate Professor and Divisional Head of Organic Chemistry in the UFS Department of Chemistry, focuses her research on the isolation of active GABAergic compounds (substances that affect the brain’s GABA system, which helps control nervous system activity) by using a test that measures the movement of zebrafish larvae.

Even though obtaining regulatory approval for use as a treatment for epilepsy is a long and complex process, Prof Wilhelm hopes to contribute to the better pain management of people suffering from epilepsy and diseases of the CNS through an affordable alternative drug with less side effects.

The tests are done in a zebrafish bioassay (an analytical method to determine the potency of a substance by its effect on living animals) housed at the UFS’ Chemistry Department.

Why zebrafish larvae?

Prof Wilhelm, who is a National Research Foundation Y2-rated synthetic organic chemist, says zebrafish share about 70% of their genes with humans, and about 84% of human genes known to be associated with diseases have a counterpart in zebrafish. This makes them a valuable model for studying human biology and disease.

“Zebrafish are powerful tools for modelling a wide range of CNS diseases, contributing significantly to the understanding of disease mechanisms and the development of potential treatments,” she says. “Mood disorders, anxiety, insomnia, and attention deficit hyperactivity disorder (ADHD) are all diseases which may be studied through this bioassay.”

She explains that the zebrafish larvae are studied seven days after fertilisation in their bioassay. The larvae are incubated with the specific plant extract at a certain (non-toxic) concentration for three hours. Pentylenetetrazol (PTZ), a GABAA receptor antagonist that has been extensively used in rodent models for acute seizure and anxiety, is then administered to induce concentration-dependent seizures in the zebrafish larvae.

“GABA receptor antagonists are drugs that inhibit the action of gamma-aminobutyric acid, the chief inhibitory neurotransmitter in the mammalian central nervous system,” Prof Wilhelm says. “A specialised infrared camera is then used to track the movement of the larvae inside a chamber. The data is then converted into a graph which shows the movement of each larva over 30 minutes.

“If lowering of movement is observed at a specific concentration it means that the plant extract may have the potential to be used as an epileptic drug, since it has the ability to counteract the induced seizure in the larvae. This bioassay is extremely useful in drug discovery and toxicity screening of plant extracts.”

Zebrafish embryos, she says, develop quickly, with major organs forming within 36 hours of fertilisation. This rapid development allows researchers to observe the effects of experiments in a short period. The maintenance of a zebrafish model is less costly and labour-intensive than using a rodent model. “The use of zebrafish larvae allows for high-throughput screening due to their small size and transparency, which facilitates observation of CNS-related effects. Their genetic and physiological similarities to humans make them a valuable model for early-stage drug discovery.”

Potential uses

The next step in the research, according to Prof Wilhelm, is to identify a single compound from a natural source which may have potential anti-epileptic activity while causing less side effects than current drugs on the market. Researchers would then investigate the possibility of synthesising such a compound on a large scale, to eliminate the use of a natural resource and promote sustainability.

“Many plant extracts which I have screened show a synergistic effect in the zebrafish bioassay, meaning that the extract or the combination of compounds shows potential, but the isolated compounds are inactive. Even if a plant extract shows promise in preclinical and early clinical studies, obtaining regulatory approval for use as a treatment for epilepsy is a long and complex process.

“This includes demonstrating consistent efficacy, safety, and quality in large-scale clinical trials. One of the major challenges in using plant extracts is the lack of standardisation. The concentration of active compounds in plant extracts can vary depending on factors like the plant's growing conditions, harvest time, and extraction methods. This variability makes it difficult to ensure consistent efficacy and safety, therefore this is a time-consuming process.”

Green chemistry

After being approached by Dr Glen Taylor, Senior Director of the UFS Directorate Research Development (DRD), in 2017, regarding funding for Noldus Daniovision equipment, Prof Wilhelm received training from Prof Matthias Hamburger of the University of Basel in Switzerland on how to use such equipment. The larval zebrafish locomotive bioassay was established at the UFS Chemistry Department during 2017 and 2018 and now provides a third-stream income for the department, in conjunction with the Department of Genetics, where the adult zebrafish are housed.

Prof Wilhelm’s other research interests include green chemistry, food sustainability, and recycling. She is looking into green extraction techniques using non-conventional extraction methods to recover valuable bioactive compounds from agricultural and food residues. “Techniques like ultrasound, microwave-assisted extraction, and the use of deep eutectic solvents are becoming popular for their efficiency and alignment with circular economy principles.”

The Noldus Daniovision equipment used by Prof Anke Wilhelm.

News Archive

Higher than expected prevalence of dementia in South African urban black population

2010-09-22

Prof. Malan Heyns and Mr Rikus van der Poel

Pilot research done by University of the Free State (UFS) indicates that the prevalence of dementia, of which Alzheimer’s disease is only one of the causes, is considerably higher than initially estimated. Clinical tests are now underway to confirm these preliminary findings.

To date it has been incorrectly assumed that dementia is less prevalent among urban black communities. This assumption is strongly disputed by the findings of the current study, which indicates a preliminary prevalence rate of approximately 6% for adults aged 65 years and older in this population group. Previous estimates for Southern Africa have been set at around 2,1%.

The research by the Unit for Professional Training and Services in the Behavioural Sciences (UNIBS) at the UFS and Alzheimer’s South Africa is part of the International 10/66 Dementia Research Group’s (10/66 DRG) initiative to establish the prevalence of dementia worldwide.

Mr Rikus van der Poel, coordinator of the local study, and Prof. Malan Heyns, Principal Investigator, say worldwide 66% of people with dementia live in low and middle income countries. It is expected that it will rise to more than 70% by 2040, and the socio-economic impact of dementia will increase accordingly within this period. 21 September marks World Alzheimer’s Day, and this year the focus is on the global economic impact of dementia. Currently, the world wide cost of dementia exceeds 1% of the total global GDP. If the global cost associated with dementia care was a company, it would be larger than Exxon-Mobil or Wal-Mart.

The researchers also say that of great concern is the fact that South Africa’s public healthcare system is essentially geared toward addressing primary healthcare needs, such as HIV/Aids and tuberculosis. The adult prevalence rate of HIV was 18,1% in 2007. According to UNAIDS figures more than 5,7 million people in South Africa are living with HIV/Aids, with an estimated annual mortality of 300 000. In many instances the deceased are young parents, with the result that the burden of childcare falls back on the elderly, and in many cases elderly grandparents suffering from dementia are left without children to take care of them. “These are but a few reasons that highlight the need for advocacy and awareness regarding dementia and care giving in a growing and increasingly urbanized population,” they say.

Low and middle income countries often lack epidemiological data to provide representative estimates of the regional prevalence of dementia. In general, epidemiological studies are challenging and expensive, especially in multi-cultural environments where the application of research protocols relies heavily on accurate language translations and successfully negotiated community access. Despite these challenges, the local researchers are keen to support advocacy and have joined the international effort to establish the prevalence of dementia through the 10/66 DRG.

The 10/66 DRG is a collective of researchers carrying out population-based research into dementia, non-communicable diseases and ageing in low and middle income countries. 10/66 refers to the two-thirds (66%) of people with dementia living in low and middle income countries, and the 10% or less of population-based research that has been carried out in those regions.

Since its inception in 1998, the 10/66 DRG has conducted population based surveys in 14 catchment areas in ten low and middle income countries, with a specific focus on the prevalence and impact of dementia. South Africa is one of seven LAMICs (low and medium income countries) where new studies have been conducted recently, the others being Puerto Rico, Peru, Mexico, Argentina, China and India.

Mr Van der Poel says participating researchers endeavour to conduct cross-sectional, comprehensive, one-phase surveys of all residents aged 65 and older within a geographically defined area. All centres share the same core minimum dataset with cross-culturally validated assessments (dementia diagnosis and subtypes, mental disorders, physical health, anthropometry, demographics, extensive non-communicable risk factor questionnaires, disability/functioning, health service utilization and caregiver strain).

The local pilot study, funded by Alzheimer’s South Africa, was rolled out through an existing community partnership, the Mangaung University of the Free State Community Partnership Programme (MUCPP).

According to Mr Van der Poel and Prof. Heyns, valuable insights have been gained into the myriad factors at play in establishing an epidemiological research project. The local community has responded positively and the pilot phase in and of itself has managed to promote awareness of the condition. The study has also managed to identify traditional and culture-specific views of dementia and dementia care. In addition, existing community-based networks are being strengthened, since part of the protocol will include the training and development of family caregivers within the local community in Mangaung.

“Like most developing economies, the South African population will experience continued urbanization during the next two decades, along with increased life expectancy. Community-based and residential care facilities for dementia are few and far between and government spending will in all probability continue to address the high demands associated with primary healthcare needs. These are only some of the reasons why epidemiological and related research is an important tool for assisting lobbyists, advocates and policymakers in promoting better care for those affected by dementia.”

Media Release
Issued by: Mangaliso Radebe
Assistant Director: Media Liaison
Tel: 051 401 2828
Cell: 078 460 3320
E-mail: radebemt@ufs.ac.za
21 September 2010

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