Parkinson’s research in Nigeria

# # # # In an effort to highlight under-represented populations within the Parkinson’s community world-wide, today we will look at some recent research that has been conducted in the central African republic of Nigeria. Nigeria is a nation of more than 200 million people. Despite a lower general life expectancy rate, the country does have a large Parkinson’s community. In an effort to help those individuals, local researchers are conducting studies – both preclinical and clinical.  In today’s post, we will review some of that research and discuss a clinical trial being conducted in Nigeria. # # # #

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Nigeria. Source: Britannica

Nigeria has been called the “Giant of Africa”, and for good reason.

Between 1990 and 2019, the population of Nigeria surged from 95 million to 201 million.

It currently sits around 220 million and it is on track to increase to over 400 million by 2050 (when it will overtake the USA as the world’s third most populated country). All of these people – who speak over 500 different languages/dialects – live in an area of 923,769 square kilometres (356,669 sq mi).

That is equivalent to the triangular area of land between Chicago, New York and Atlanta in the US:

Source: Quora

The country boasts the largest gross domestic product (GDP) in Africa, with a GDP of approximately $450 billion – making it the 29th largest economy in the world (Source). The sizeable GDP is mainly driven by finance, transport, infrastructure, tourism, and a large abundance of crude oil.

Source: Guardian

With such a large economy and significant resources at hand, improving health care has become a key goal for Nigeria. It currently spends only 3% of its GDP on health (compared to 16% in the US – Source). And this is unfortunately reflected in a high infant mortality rate (74/1000 live births), high maternal mortality rate (560/100 000 live births), and low life expectancy (<53 years – Source).

Interesting, but what does this have to do with Parkinson’s?

The country produces approximately 2300 medical doctors each year across 28 medical schools. And there are currently approximately 40 000 registered doctors.

Despite these numbers, in 2016, Nigeria had only 80 registered neurologists (Source). For a population of almost 200 million people, this meant that at the time there was one neurologist for every 2.5 million people (compare that to 1 per 39,059 in the UK and an average across Europe of 1 per 15,799 – source).

Given the limited number of neurologists, it is extremely encouraging to see impressive Parkinson’s-focused research coming out of Nigeria.

What do you mean?

Very recently, this research report was published:

Title: An assessment of the rescue action of resveratrol in parkin loss of function-induced oxidative stress in Drosophila melanogaster.
Authors: Adedara AO, Babalola AD, Stephano F, Awogbindin IO, Olopade JO, Rocha JBT, Whitworth AJ, Abolaji AO.
Journal: Sci Rep. 2022 Mar 10;12(1):3922.
PMID: 35273283               (This report is OPEN ACCESS if you would like to read it)

In this study, the investigators from the University of Ibadan (and collaborators) wanted to assess the potential of resveratrol in a genetic model of Parkinson’s.

What is resveratrol?

Resveratrol is a stilbenoid.

Stilbenoids are a large class of compounds that share the basic chemical structure of C₆-C₂-C_6:

Resveratrol. Source: Wikipedia

Stilbenoids are phytoalexins (think: plant antibiotics) produced naturally by numerous plants. They are small compounds that become active when the plant is under attack by pathogens, such as bacteria or fungi. Thus, their function is generally considered to part of an anti-microbial/anti-bacterial plant defence system for plants.

The most well-known stilbenoid is resveratrol as it grabbed the attention of the research community back in 1997, when a group of scientists found that it could inhibit tumour growth in particular animal models of cancer:

Title: Cancer chemopreventive activity of resveratrol, a natural product derived from grapes
Authors: Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM.
Journal: Science. 1997 Jan 10;275(5297):218-20.
PMID: 8985016

In this study, the investigators found the resveratrol – which usually acts like an antioxidant – has anti-mutagenic properties (meaning it reduces the chances of a genetic mutation occurring). It also mediated anti-inflammatory effects and inhibited the development of cancerous growths in mammary glands and skin cancer models. The researcher concluded that resveratrol warrants further investigation “as a potential cancer chemopreventive agent in humans”.

And these results were quickly replicated by other independent research groups (Click here, here and here to read more about this).

Then in 2006, a research article was published in the prestigious journal Nature suggesting that resveratrol improved the health and survival of mice on a high-calorie diet:

Title: Resveratrol improves health and survival of mice on a high-calorie diet.
Authors: Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA.
Journal: Nature. 2006 Nov 16;444(7117):337-42.
PMID: 17086191                (This article is OPEN ACCESS if you would like to read it)

In this study, the investigators placed middle-aged (one-year-old) mice on either a standard diet or a high-calorie diet (with 60% of calories coming from fat). The mice were maintained on this diet for the remainder of their lives. Some of the high-calorie diet mice were also placed on resveratrol (20mg/kg per day). After 6 months of this treatment, the researchers found that resveratrol increased survival of the mice and insulin sensitivity. Resveratrol treatment also improved mitochondria activity and motor performance in the mice – mitochondria being the power stations of cells (see this previous SoPD post to learn more about mitochondria).

Now, as you can imagine that report caused a quite a bit of excitement – suddenly there was the possibility that we could eat whatever we wanted and this amazing little molecule would save us from any negative consequences.

And then the news got even better!

Fruit are a particularly good source of resveratrol, especially the skins of grapes, blueberries, raspberries, mulberries and lingonberries. So everyone should just eat more fruit!

One issue with fruit as a source of resveratrol, however, is that tests in rodents have shown that less than 5% of the fruit-based dose of resveratrol was found to be passed from the gut through to the blood system (Source).

This has lead to the extremely popular idea of taking resveratrol in the form of wine, in the hope that it would have higher absorption (the difference between taking your medication in liquid (wine) versus pill (grape) form).

Source: Winebythebar

Red wines have the highest levels of Resveratrol in their skins (particularly Mabec, Petite Sirah, St. Laurent, and pinot noir), and folks fell in love with the idea that ageing and disease could potentially be cured by drinking lots of big Bordeaux wines (which contain approximately 3-6 mg of resveratrol per 750ml bottle).

Everyone thought it was party time. Source: Nature

Excellent! I’m off to the bottle shop!

Yeah, before you do that… there is one minor detail.

Unfortunately (and it truly pains me to rain on this parade) a study out of the University of Illinois suggested that resveratrol needs to be used at levels of at least 8mg/kg of body weight in mice. If translated to humans, this equates to a 150-pound (70kg) individual needing to consume about 550mg of resveratrol per day.

For those of you who struggled with Maths class, that’s approximately 266 bottles of red wine… per day!

And no, this should not be seen as a new challenge or goal.

Obviously consuming red wine is NOT the most efficient way of absorbing resveratrol. Grape juice is a much better (less exciting) option. It has much higher levels of resveratrol than wine (Click here to read more on this).

EDITOR’S NOTE HERE: The recommended daily dose of resveratrol should not exceed 250 mg per day over the long term (Source). Resveratrol might increase the risk of bleeding in people with bleeding disorders and should be used with caution if you are being treated with blood thinning medication (such as warfarin). PLEASE discuss any change in treatment regimes with your doctor before starting.

# RECAP #1:  Researchers in Nigeria have recently published a study looking at the effects of resveratrol in a genetic model of Parkinson’s. Resveratrol is a type of plant antibiotic, that has displayed remarkable properties in models of cancer and obesity. #

Has Resveratrol been investigated in models of Parkinson’s?

Yes, it has.

In fact, the Nigerian researchers who recently published the study above have previously published similar research investigating resveratrol in a model of PD:

Title: Resveratrol prolongs lifespan and improves 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced oxidative damage and behavioural deficits in Drosophila melanogaster.
Authors: Abolaji AO, Adedara AO, Adie MA, Vicente-Crespo M, Farombi EO.
Journal: Biochem Biophys Res Commun. 2018 Sep 5;503(2):1042-1048.
PMID: 29935183

In this older study, the researchers looked at the effect of resveratrol in a neurotoxic model of Parkinson’s. They exposed flies (Drosophila) to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (also known as MPTP). Their results showed that resveratrol increased lifespan of the flies exposed to the toxin in a dose-dependent manner. It also reduced the amount of cell death and behavioural deficits in these flies as well.

Source: Ecolab

Interesting. So in their more recent report, you said that they used a genetic model of Parkinson’s?

Yes. In research published this month, the researchers in Nigeria used flies that carry a genetic mutation in their Parkin gene.

What is the Parkin gene?

Sometimes referred to as PARK2, Parkin is a protein that is closely associated with Parkinson’s. Tiny genetic errors in the region of our DNA that provides the instructions for making Parkin protein were the second genetic risk factor to be connected with PD.

The structure of PARKIN. Source: Wikipedia

Genetic variations in Parkin are particularly associated with early onset Parkinson’s (which are cases diagnosed under the age of 40 years of age).

Biologically speaking, what does Parkin do?

Parkin is an enzyme – that is a protein that interacts with other proteins and acts as a catalyst. Specifically, Parkin functions as an E3 ubiquitin ligase.

What is an E3 ubiquitin ligase?

A ligase is an enzyme that initiates the joining of two molecules. It forms a new chemical bond between them. Inside of cells, Parkin interacts with lots of proteins and has a role in many different functions. It has been studied extensively in terms of its relationship with mitochondria, where is plays a key role in the disposal/recycling of old/damaged mitochondria.

So what happens to flies with Parkin genetic mutations?

At 21 days of age, flies with Parkin mutants have a 75% decrease in survival rate when compared with unaffected/wild-type flies (referred to as w¹¹¹⁸ in the image below).

Source: PMC

The researchers found that resveratrol treatment significantly increased the survival of the Parkin mutant flies (see blue, magenta and grey lines in the graph above).

The Parkin mutant flies also exhibit a significant reduction in their climbing rate (measured as negative geotaxis). The investigators found that resveratrol treatment significantly improved the locomotor function of the Parkin mutant flies:

Source: PMC

In addition, resveratrol reduced oxidative stress and inflammatory markers in Parkin mutant flies after 10 days of treatment. The researchers concluded their study by stating “that appropriate concentrations of resveratrol can reduce oxidative stress associated with parkin loss-of-function mutation and therefore might be harnessed for the management of Parkinson’s“.

Source: PMC

IMPORTANT TO NOTE: While they wrote “appropriate concentrations of resveratrol”, the dose of resveratrol used in this study was extremely high and would be difficult to achieve in humans.

Interesting. What other research have these scientists done?

This preclinical research we are reviewing in this post today has been conducted by a team of researchers (and collaborators) led by Dr Amos Abolaji:

You can find him on Twitter.

They have also recently been exploring the effects of other agents in fly models of Parkinson’s:

Title: Protective capacity of carotenoid trans-astaxanthin in rotenone-induced toxicity in Drosophila melanogaster.
Authors: Akinade TC, Babatunde OO, Adedara AO, Adeyemi OE, Otenaike TA, Ashaolu OP, Johnson TO, Terriente-Felix A, Whitworth AJ, Abolaji AO.
Journal: Sci Rep. 2022 Mar 17;12(1):4594.
PMID: 35301354                  (This report is OPEN ACCESS if you would like to read it)

In this recently published research, Dr Abolaji and colleagues were interested in the effect of trans-astaxanthin in models of Parkinson’s.

Source: Chemicalbook

Trans-astaxanthin is a keto-carotenoid and a precursor of vitamin A, that has various uses including dietary supplement and food dye. It belongs to a larger class of chemical compounds known as terpenes. Importantly, astaxanthin is a powerful antioxidant.

Trans-astaxanthin is a very lipophilic agent and has low oral bioavailability (distribution in the body), but it is known to cross the blood-brain-barrier (the protective membrane covering the brain) and has been shown to be neuroprotective in mouse models of PD (Click here to read an example of this research).

In this new study, the investigators assessed trans-astaxanthin in a neurotoxin model of Parkinson’s, which involved exposing flies to the chemical rotenone. As with the resveratrol experiments, they observed an increase in survival time in the flies exposed to rotenone and treated with trans-astaxanthin. The treatment also prevented locomotor issues and the build up of various inflammatory markers.

Source: PMC

Have they tested anything of local West African medicinal interest in their studies?

Yes, researchers in Nigeria have long been testing various molecules that have been extracted from local plants and produce to better understand their properties and potential utility.

For example, kolaviron is a biflavonoid that can be extracted from Garcinia kola seeds. Garcinia kola is a flowering plant found mostly in the tropical rain forest region of Central and West Africa, and the seeds have long been used by African folk healers for a variety of ailments.

Garcinia kola seeds. Source: News-medical

Kolaviron has been found to possess anti-oxidative and anti-inflammatory properties, which have been tested in PD models.

For example:

Title: Garcinia kola seed biflavonoid fraction (Kolaviron), increases longevity and attenuates rotenone-induced toxicity in Drosophila melanogaster.
Authors: Farombi EO, Abolaji AO, Farombi TH, Oropo AS, Owoje OA, Awunah MT.
Journal: Pestic Biochem Physiol. 2018 Feb;145:39-45.
PMID: 29482730

In this study, the researchers used rotenone-exposed flies and found that kolaviron promoted lifespan extension and protective properties (via anti-oxidant and anti-inflammatory mechanisms).

So, I hope you will agree that there is some very interesting preclinical Parkinson’s research coming out of Nigeria.

# # RECAP #2:  Resveratrol has been found to rescue both neurotoxic and genetic models of Parkinson’s. Additional molecules that have been tested, include trans-astaxanthin and kolaviron – both of which have strong anti-oxidant and anti-inflammatory properties. # #

Interesting. Is there much clinical research for Parkinson’s in Nigeria?

The correct answer here is: Not enough.

But there are a number of noteworthy projects that deserve discussion. One in particular is the Nigerian Parkinson’s Disease Registry. This is a national registry that was established in November 2016, with the goal of providing “a platform for development of multipronged evidence-based policies and initiatives to improve quality of care of Parkinson’s disease and research engagement in Nigeria“.

It should be noted that most Western countries do not have registries for PD, so this is an ambitious project.

In 2020, this report was published, describing the initial experience of setting up the program:

Title: The Nigeria Parkinson Disease Registry: Process, Profile, and Prospects of a Collaborative Project.
Authors: Ojo OO, Abubakar SA, Iwuozo EU, Nwazor EO, Ekenze OS, Farombi TH, Akinyemi RO, Williams UE, Bello AH, Wahab KW, Iyagba AM, Arigbodi O, Erameh CO, Komolafe MA, Fawale MB, Onwuegbuzie GA, Obiabo YO, Taiwo FT, Agu CE, Ekeh BC, Osaigbovo GO, Achoru CO, Arabambi B, Adeniji O, Nwani PO, Nwosu CM, Ademiluyi BA, Oyakhire SI, Nyandaiti Y, Rabiu M, Chapp-Jumbo EN, Balarabe SA, Otubogun FM, Obehighe EE, Kehinde AJ, Ani-Osheku I, Imarhiagbe FA, Dike FO, Adebowale AA, Agabi OP, Akpekpe JE, Ali MW, Odeniyi OA, Odiase FE, Abiodun OV, Olowoyo P, Osemwegie N, Oshinaike OO, Owolabi LF, Zubair YA, Rizig M, Okubadejo NU.
Journal: Mov Disord. 2020 Aug;35(8):1315-1322.
PMID: 32557840

The registry records anonymised basic data for PD cases attending the clinical practices
(inpatient or outpatient) of the participating neurologists in Nigeria. The network of neurologists maintains an online WhatsApp group and email contact for information sharing and troubleshooting purposes.

The basic information that is collected includes “age, self-declared ethnicity, site of onset of motor features of PD, earliest motor feature, age at onset, side of onset, family history of PD, and tremors in first- or second-degree relatives” as well as current medications, and permission to be re-contacted for future studies.

As of July 2019, the registry had captured 578 participants across 5 of 6 geopolitical zones in Nigeria.

Source: Wikipedia

Of the 578 individuals registered, most were men (72.5%). A family history of tremor was reported in 71 (12.3%) cases, while a family history of Parkinson’s was present in 42 (7.3%) cases. Anti-Parkinsonian medications had been prescribed in 540 (93.4%) of the individuals, while 38 (6.6%) were not on any medication at all when being recruited on to the registry. The most commonly used medication was levodopa/carbidopa or
benserazide monotherapy (N=315, 54.5%). Dopamine agonists were only used by 4 (0.7%) individuals and monoamine oxidase B inhibitors by 2 people.

The per-capita direct cost for the registry was $3.37 (or $1946 for the entire project). The researchers behind the project concluded their report by stating that they have demonstrated “the feasibility, at relatively low cost, of establishing a physician-driven PD registry in a resource limited setting”

Impressive. Have there been any clinical trials for Parkinson’s in Nigeria?

If you go to the ClinicalTrials.gov website, and conduct a search for the keywords “Parkinson” and “Nigeria”, you will find only one study which is being conducted by researchers at the University of Ibadan College of Medicine.

Source: COM

But it is a very interesting study!

Professor Adesola Ogunniyi and colleagues are investigating the effects of hypoestoxide in Parkinson’s, in the PECKO-D study (Click here to read more about the details of this trial).

What is hypoestoxide?

Hypoestoxide is an active ingredient purified from an herbal plant, Hypoestes rosea, which is indigenous to the region between Nigeria and Cameroon.

Hypoestes rosea. Source: Leafyplace

Researchers have found that hypoestoxide possesses anti-inflammatory, anticancer and antimalarial properties (Click here to read more about this).

And it has also demonstrated neuroprotective properties in a model of Parkinson’s:

Title: Hypoestoxide reduces neuroinflammation and alpha-synuclein accumulation in a mouse model of Parkinson’s disease.
Authors: Kim C, Ojo-Amaize E, Spencer B, Rockenstein E, Mante M, Desplats P, Wrasidlo W, Adame A, Nchekwube E, Oyemade O, Okogun J, Chan M, Cottam H, Masliah E.
Journal: J Neuroinflammation. 2015 Dec 18;12:236. doi: 10.1186/s12974-015-0455-9.
PMID: 26683203                     (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers assessed 4 weeks of daily administration of hypoestoxide in a mouse model of Parkinson’s (mThy1-α-syn). The mice used in this study had been genetically engineered to produce high levels of the PD-associated protein alpha synuclein. The investigators found that hypoestoxide treatment decreased pro-inflammatory signals as well as alpha synuclein pathology. This led to a reduction in levels of neurodegeneration and motor impairments in these mice.

The results provided justification for clinically testing hypoestoxide in a cohort of people with Parkinson’s.

The PECKO-D study is involving 30 individuals with mild to moderate Parkinson’s (Stages 1-3 on the Hoehn and Yahr scale) who will be treated with either hypoestoxide or placebo for an 8-week period (Click here to read more about the details of this trial).

The study is small and not very long, but it will provide a useful assessment of whether daily hypoestoxide is safe and well tolerated in people with Parkinson’s. In addition, the study participants will be using mobile phones with an established quantitative assessment tool, mPower2.0 to assess improvements in motor ability of the 8 week study.

Source: mPower2.0

mPower2.0 is a free, 2 year mobile phone-based research study set up by Sage Bionetworks with the goal of better understanding the progression of Parkinson’s.

While the study is focused on PD, you don’t need to have PD to take part – click here to learn more about this study.

I really like the way the Nigerian researchers are employing this free mobile phone app in their study. It will hopefully provide them with a very rich set of data to analyse.

The PECKO-PD study is scheduled to finish in the second half of this year, so we will hopefully learn the results in the near term.

Interesting. So what does it all mean?

The challenges involved with conducting research in any area of the world are significant. But in some areas they are difficult to even fathom.

Remember, at the top of this post I mentioned that Nigeria has 220 million people who speak over 500 different languages? Question: how do you provide information about Parkinson’s across all of those different dialects? In addition, there are significant cultural obstacles. In the Western world, we have no issues with blood samples being taken, but many folks in West Africa would be extremely reluctant to provide any kind of biosample.

I am truly in awe of the researchers who are findings ways to conduct research in under-represented regions of the world, and helping to provide a better quality of life to their local populations affected by PD. For those interested in learning more about the Parkinson’s research being conducted in Nigeria – beyond what has already been discussed above – I would recommend to look at Parkinson’s Africa.

 

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