Some in the world of Parkinson’s may have heard about the possibility of a drug currently used for Multiple Sclerosis having another application; in Parkinson’s (PD). Here’s the published report. Lisa Vanderburg recently spoke with Neuroscientist Dr. Bobby Thomas – the Lead Scientist on the research being done in this area. He’s Associate Professor of the Departments of Pharmacology, Toxicology and NeurologyMedical College of Georgia, Augusta University; his (et al) results are very promising for PD. Hopefully this will explain why.
DMF (dimethylfumarate) is an FDA-approved drug used in the treatment of MS (multiple sclerosis). It’s the metabolite part of DMF that’s the focus of attention here; the active metabolized bit. Rather like L-Dopa contains an active metabolite to transition into much-needed dopamine in Parkinson’s, it is a process… a chain of events that lead to the best possible effect.But like L-Dopa, introducing pharmaceuticals can often lead to unwanted side-effects. In the process of metabolisation we have to – basically – persuade the brain that what’s being introduced has a plausible function. However, our brains are pretty savvy… We need to think of all products and processes in our brain like an ever-moving conveyor belt of evolving motion; each stage needs to do its part to create the next step. In a normal state of affairs, the metabolite MMF (monomethylfumarate) buddy up with DMF for optimum function.Metabolites work as both products of and intermediates (precursors) to metabolism. As always, crossing the BBB (blood/brain barrier) is a costly and difficult business, so we have to trick the brain into accepting this mimic; that creates a pay-back. Cause and effect.Now that’s all very science-y, so let me draw you and analogy: Dr. Temple Grandin, Professor of Animal Science at Colorado State University has spent the last 30 years re-vamping slaughter house techniques. Why? Because she was diagnosed as Autistic and that ‘disability’ transformed her abilities to see what others could not: the unnecessary suffering of our livestock. Spending years observing and living with the animals led to one of her many achievements; she developed a process to lead bovines to their inevitable end that was not only much more humane, but prevented the animals from releasing adrenaline and cortisol hormones to flood their muscles as a result of panic and stress.She saw a broken system (think: Brain), and fixed it with an ingenious solution… By creating a looping walkway that not only hid the animals from each other, but it wound round (as an animal would naturally do), gently picking them up with a conveyor belt from under their flanks so that, as they arrived to the stun-gun the chance of a near-miss or worse was significantly lessened – and the animal behind didn’t see what was happening.With the idea of process rather than mere static ‘function’ established, let’s move on.Researchers led by Dr. Thomas at the prestigious Medical College of Georgia’s Augusta University have found that the metabolite ends of the oral drug DMF, as well as MMF, both increase the activity of a protein called Nrf2.This is a BIG discovery, and here’s why: Nrf2 is a major player in cellular defence from oxidation, free-radicals and inflammation, and that’s what keeps coming up as a leading factor in degenerative and neurological disease. As I mentioned before, the last thing we want unchecked in our brains is oxygen. It’s toxic as all hell when it is not contained solely at a cellular level as fuel. It comes up time and again in Parkinson’s as the crucial cause for this catastrophic disease.
The downside of DMF as a ‘parent drug’ treatment is its side-effects. These can be pretty hellacious; anything from ‘flushing, diarrhoea, nausea, vomiting, abdominal pain and the brain infection encephalopathy’ said Dr. Thomas, corresponding author of the study in The Journal of Neuroscience. Dr. Morgan points out that ‘the gastrointestinal side effects can exacerbate some problems patients with Parkinson’s already experience’. As I know full well the ravages to the autonomic system in PD in my own husband, I get it that Parkinson’s causes nerve cell death in the gastrointestinal tract and related problems such as severe constipation.But you can’t throw the baby out with the bath water. In this case, what they’re after is the increased production of that super-scrubber deoxygenating Nrf2 protein that both DMF and MMF afford. Nrf2 is a natural protective mechanism we have for oxidative stress. It is also the declining activity of the Nrf2 pathway that is found in both MS and PD – the link between these diseases. Interesting, eh?Certainly in Parkinson’s, once you realize you have it; the horse has bolted, Elvis has left the building and all hell has broken out because, as Dr. Morgan says, “by the time they seek medical care, patients may have lost 30-50 percent of their dopaminergic neutrons.”I have rated this as eight out of ten dopamine production-marbles in the past, based on the work of Bernheimer and colleagues, which was later contested. It depends on what area of the brain you’re talking about, and really; it’s moot – you’ve lost too much by then. More about that in a minute….Here’s a good paper
– if you want to see how complicated the matter truly is.
Dopamine-producing neurons are located in that iddy-biddy part of the brain called the substantia nigra.
Dopamine-producing neurons are located in that iddy-biddy part of the brain called the substantia nigra. “Even in the absence of disease, making dopamine is a stressful job for these neurons that makes them generally more fragile and actually results in oxidative stress, even in a healthy scenario,” Dr. Morgan said. “To make a difficult situation worse, increased oxidative stress can make dopamine toxic to neutrons,” he added.Moreover, Dr. Thomas stated, “To increase Nrf2 activity, the parent drug DMF also appears to first make bad matters worse. DMF increases oxidative stress by depleting the natural antioxidant – glutathione. It also reduces the power of cell powerhouses – called mitochondria – by limiting their ability to use oxygen and glucose to make energy leading to reduced viability of dopamine-producing cells.”Now I know glutathione – my hubby had many IV pushes of the antioxidant as well as phosphatidylcholine, a lecithin (to theoretically break down long trains of trans-fatty acids in the brain). These didn’t work – that comes down to the problems of introducing a mimic again.So, how to get round this problem of side-effects and still keep the Nrf2? It’s actually brilliant; our prestigious researchers switched to MMF… clever dudes. MMF is not quite as potent as the parent drug (DMF) in increasing Nrf2 activity, but (yup, it’s a BIG but) – no side effects.Conversely, the metabolite MMF appears to more directly activate Nrf2, and does not deplete glutathione and improves mitochondrial function, brain cell studies showed. While the parent drug DMF ultimately produces a higher Nrf2 activation, the researchers found the MMF effect was sufficient to stop the dramatic neuron loss in the animal model.Both DMF and MMF slowed neuron loss to a more normal level, and the neurons that survived continued to make dopamine. Inflammation and oxidative stress levels also were significantly reduced, the researchers said.Furthermore, the new study indicates that MMF action is sufficient to dramatically slow the loss of dopamine-producing neurons as well as the parent drug, in an animal model of Parkinson’s.The really relevant bit for those with Parkinson’s:Because DMF is already an FDA-approved drug,we won’t have to wait around for decades – it’s more a matter of re-classification. As DMF’s active metabolite is MMF, both are basically interchangeable by the process of esterase, making them interdependant. What that ultimately means is human trials could start in as little as two to three years. Clinical trials are in planning stage in the UK (because EVERYBODY does that – the US takes too long, even in reassigning drugs).In mid-April I heard from Laurie Hawkins about a small (38 peeps – 29 with PD) trial in Australia for the World’s first blood test for Parkinson’s, led by Professor of Microbiology, Paul Fisher. Now, with MJFF funding, La Trobe University will trial 100 peeps (70 with PD, control of 30).My first thoughts were along the lines of ‘who on earth would wanna know?’ That’s because, since discovery nearly 200 years ago, all we have is L-Dopa and DBS. If you’re not able to have DBS (or elect not to), your PD life is going to be pretty miserable. I have to say here that I’ve recently come under some flak from people with Parkinson’s, who tell me that a good advocate is one that sugar-coats the truth. I don’t agree. I think it rather insulting to those who want the truth.PD will be a long road… downhill all the way. The public needs to be aware just how little we have advanced after two centuries. We need their outrage. The only way I have gotten anywhere (like talking to Dr. Thomas) is because I tell it how it is.In conclusion, if you tie this blood test with what these extraordinary guys from Augusta University are doing, you’ll see the potential for real progress – at the very least for those pre-Parkinson’s. In a touching eulogy to Muhammad Ali, Dr. Peter F. Buckley, Dean of Augusta University, Georgia, adds his weight to this achievement.Many thanks to Dr. Bobby Thomas for helping me understand this very important discovery. We live in hope.