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)
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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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