New Potentials in Parkinson's Disease Therapy: Neurogenesis

Recently the topic of Parkinson's has come up both here (in regards to more young people getting the disease) and at Neurotopia (who gave a great summary of a paper which suggested that chemicals in pesticides can contribute to Parkinson's symptoms). I want to keep the ball rolling on the topic by offering a silver lining: a promising new therapy for Parkinson's via neurogenesis (replacing or regenerating lost neurons). This post (beginning below the fold) was written by an expert on the dopaminergic system and a fellow Neuroscience PhD student here at the University of Michigan. We'll call him Darkman for now, and he'll be responding to comments. The following post is a great introduction to the disease and to this exciting new discovery in treatment! (Read on below the fold.....)

New research in the field of Parkinson's disease (PD) treatment shows that it might be possible to either slow or reverse the progressive dopaminergic cell loss that is a hallmark of the neurodegenerative disorder. PD is primarily a movement disorder, characterized by muscle rigidity, tremor and bradykinesia (slowing of movement). Most cases are idiopathic, but PD is also attributed to genetic predisposition and environmental factors, toxins that selectively kill neurons. Of primary importance to development of PD are the death of neurons in the substantia nigra pars compacta, a striatal brain region associated with movement control as well as reward mediated behavior.

Traditional pharmacotherapy for PD has relied on L-DOPA, a blood brain barrier permeable precursor to dopamine that alleviates PD symptoms by restoring dopaminergic tone to deficient areas. L-DOPA therapy comes not without its drawbacks though, which include stereotyped motor tics, augmentation (increased intensity of symptoms occurring earlier in the day) and rebound (drug effects wear off sooner requiring additional booster doses). These side effects can be so bad that L-DOPA, though still the gold standard of PD pharmacotherapy, is not an effective chronic treatment. More recently, a new class of therapeutics has been used to treat PD symptoms, called selective dopamine agonists because they preferentially activate one class of dopamine receptors to a greater extent than others. These drugs tend to be comparable to L-DOPA in their ability to relieve symptoms and additionally show significantly less development of side effects during chronic treatment.

To date, PD therapy has primarily relied on treating the symptoms of the disease, not on curing them, potentially by restoring dopaminergic cell functioning to the striatum. Recent work published in the Journal of Neuroscience (Van Kampen and Eckman, 2006) has suggested that stopping or reversing dopaminergic cell loss in PD might be a therapeutic possibility. While several brain regions are known maintain neurogenesis throughout adulthood, including the dentate gyrus and the subventricular zone, only recently have restricted progenitor cells been found in other brain regions, including the striatum. These restricted progenitor cells are partially differentiated, cells that still maintain the capacity to develop into some (not all) cell types depending on the regulating factors to which they are exposed. These cells could potentially be coaxed to develop into fully functioning dopaminergic cells to replace those lost through the progression of Parkinson's disease.

In this astonishing publication by Van Kampen and Eckman they have shown that this is a likely possibility. They use a common animal model of PD in which a chemical toxin is used to lesion the substantia nigra, selectively destroying dopamine neurons on one side of the animals brain. This effectively causes PD-like symptoms in one half of the animal's body, the side opposite that of the brain lesion (due to the motor pathways in the brain crossing sides in the spinal cord). Experimental animals were then treated for 2, 4, 6 or 8 weeks with a dopamine agonist selective for the D3 dopamine receptor called 7-OH-DPAT and compared to control animals that received only saline. The D3 receptor agonist treated animals showed increases in neurogenesis, new cells that not only differentiated into neurons, but that also made functional connections from the substantia nigra to other striatal brain regions.

Figure: Cells in the substantia nigra of 7-OH-DPAT treated animals labeled in green for tyrosine hydroxylase (a dopamine neuron specific marker), in red for BrDU ( selective marker for newly formed cells) and in blue for NeuN (a marker selective for mature neurons) and then a merged image on the right showing co-expression of all these markers implying the D3 agonist promotes development of new dopaminergic neurons in the affected brain region.

What is even more promising is the fact that the D3¬ agonist treated animals showed behavioral recovery. Using two different behavioral assays related to this particular lesion model the researchers showed a progressive, long-lasting recovery of motor function implying that the neurogenesis had behaviorally therapeutic implications.

Figure: Amphetamine induced rotational behavior is significantly reduced in 7-OH-DPAT treated animals relative to saline treated controls (left) and in a skilled reaching paradigm the number of pellets eaten with the contralateral (affected) paw reached control levels after 4 weeks of treatment (red triangles, relative to both red and open square control groups) in the figure on the right.

While it is too early to say that this is a 'cure' for Parkinson's disease, this is definitely one of the most exciting recent discoveries in the field. The potential for research along these lines to lead to restorative treatment for those that suffer from neurodegenerative diseases is starting to be realized. The next steps along these lines will be to determine the underlying mechanism of action of neurogenesis in these brain regions as well as to determine the best way to activate these pathways in those affected patients. I hope to hear more exciting research from this group as well as others as this story continues to unfold.