Tuesday, April 30, 2013

EB2013 ASPET Blogging: Smell the Potential Parkinson's Disease Treatments

Sniffing medications (and uh, other things) up your nose is not new. Saline nasal sprays to unclog a stuffy nose have been around for a long time. There are now intranasal (in the nose) treatments for seizures, pain, congestion, and even vaccine administration. As gross as it may seem to squirt liquid up your snout, it’s actually pretty effective. The nostrils have a lot of blood vessels right near the surface so the medication can get into the bloodstream and work faster than an oral dose. You know what else is very near the inside surface of your nostrils? Your brain.

The brain is good at keeping bad things out of it. The blood vessels leading into the brain are made of cells that are tightly packed together so big molecules and molecules that dissolve in water can’t get in. The special vessels make up what is called the blood brain barrier (BBB). Most of the time, the BBB is awesome, but when it comes to medications, it’s a lot of trouble. The vast majority of chemicals do not pass the BBB, and it has been the death of many a new drug development project. So it would be nice if we could get around the BBB with drugs.  It would be especially nice if drugs to treat brain diseases, like Parkinson’s disease, could be delivered directly to the brain.

Parkinson’s disease is a movement disorder caused by the death of brain cells in an area of the brain called the substantia nigra. Parkinson’s is very selective: only cells in the substantia nigra that make and release the chemical dopamine are killed. Dopamine released by these cells is important for movement, and so symptoms of Parkinson’s disease include a shuffling walk, shaky hands, and slow movement initiation. It can also impair cognition and eventually cause dementia. Current treatments for Parkinson’s disease boost the amount of dopamine in the brain, which can temporarily relieve the movement problems. However, adding dopamine does not cure Parkinson’s disease or reverse the damage in the substantia nigra.

Figure 1: Nasal sinus and olfactory bulb (Source)

Dr. Barbara Waszczak’s lab at Northeastern University in Boston wanted to know if a neuroprotective protein, called glial cell-derived neurotrophic factor (GDNF), found normally in the brain could be used as a treatment for Parkinson’s disease. GDNF can specifically rescue damaged dopamine neurons. The downside is that GDNF is a large protein that can’t cross the BBB so in previous studies it was injected directly into the brain. Grandpa will allow sharp pointy objects to be placed directly into his brain as a last resort (see deep brain stimulation) but patients and loved ones alike would prefer a less invasive and safer way to get their treatments. Proteins can’t be given orally and GDNF is too large to cross the BBB if injected outside the brain. To use GDNF as a therapeutic, it must get into the brain another way.

Enter the nose. The sinuses linked to the nose are close to the brain cells of the olfactory bulb (Figure 1). The olfactory bulb is the part of the brain that takes in odor signals and passes them on to brain areas that can process the odor and figure out what it is. There are tiny spaces along the brain cells in this area that lead directly from the nasal cavity into the brain, which means small molecules and proteins can sneak in here like ninjas. Dr. Waszczak wanted to know if it would be possible for GDNF to enter the brain through the nasal route and get to the substantia nigra to relieve the symptoms of Parkinson’s disease.

They had previously shown that intranasal GDNF was effective in a rat model, which is the first step in testing a Parkinson's treatment. The next step was to evaluate the treatment in a model closer to humans, before testing in humans themselves. Marmosets are non-human primates and they’re a good animal model for Parkinson’s disease because they closely resemble human anatomy, physiology (how the body works), and behavior in learning tasks.  There is just one problem: non-human animals like rodents and monkeys don’t get Parkinson’s disease naturally. Injection of the chemical MPTP specially kills brain cells in the substantia nigra and causes similar symptoms as Parkinson’s disease does in humans. This makes it a good way to study Parkinson’s-like symptoms in animals. For this study, they wanted to look at protective effects of GDNF so they gave intranasal GDNF treatments and MPTP injections. The primate work was performed in collaboration with the New England Primate Research Center at Harvard Medical School.

Surprisingly, the motor disabilities after MPTP were very mild and the differences did not reach significance (in science, if it’s not significantly different with statistics, it’s not different). However, the saline group showed an increase in motor activity during the dark cycle (IE sleepytime), which is an early symptom of Parkinson’s disease in humans. The GDNF group was protected from these motor increases. In an object memory task, the GDNF-treated group performed significantly better than the saline group suggesting they recovered from the cognitive deficits induced by MPTP. The substantia nigra lesion was significantly greater in the saline group but there were no differences in the number of dopamine cells in this area. However, GDNF completely protected the terminals of the remaining dopamine cells. The terminals are important because it is the part of the cell that releases dopamine onto neighboring cells. It was surprising then that the terminals were protected but there weren’t significant motor disabilities.

The results suggest that GDNF can provide a protective effect for cognition and dark cycle motor activity during the death of dopamine cells (because it was given at the same time as MPTP). This study was a really important first step in this area of research but the lesion-induced motor disabilities will need to be re-examined. Unfortunately, in humans up to 80% of the dopamine cells in the substantia nigra have died before a diagnosis of Parkinson’s disease is made. While the results of this study are exciting, intranasal GDNF is nowhere near ready for humans. The next step is to test whether intranasal GDNF can help damaged dopamine cells recover after the lesions are established. If GDNF is able to overcome the lesion deficits after the damage, the treatment may go on to clinical studies but there are many steps on the road to widespread use.

Disclosure: Dr. Waszczak collaborates with MedGenesis Therapeutics on this project.

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