more than dopamine cell loss?
 

LOSS OF TWO TYPES OF NEURONS TRIGGERS PARKINSON'S SYMPTOMS, STUDY SUGGESTS
Science Daily — New evidence indicates that the loss of two types of brain cells--not just one as previously thought--may trigger the onset of symptoms associated with Parkinson's disease.

The evidence, based on mouse models, shows a link between the loss of both norepinephrine and dopamine neurons and the delayed onset of symptoms associated with Parkinson's disease. It was originally thought that the loss of only dopamine neurons triggered symptoms. Dopamine is a neurotransmitter critical for coordinating movement.


The research was conducted by Karen Rommelfanger, graduate student in the laboratory of David Weinshenker, PhD, assistant professor of human genetics in Emory University School of Medicine and Gary Miller, PhD, associate professor in Emory's Rollins School of Public Health. The team also included Gaylen Edwards and Kimberly Freeman at the University of Georgia.


Parkinson's disease affects motor coordination and is characterized by symptoms such as tremors of hands, arms, legs, jaw and face; rigidity or stiffness of limbs and trunk; bradykinesia, or slowness of movement; and postural instability. The disease most often occurs in those over 50.

"People don't start showing symptoms of Parkinson's disease until about 80 percent of their dopamine neurons are gone, which is when you cross some sort of threshold. Our study looked at what happens while the dopamine neurons are dying and people still appear fine, says Dr. Weinshenker. "The lack of symptoms until the death of most of the dopamine neurons suggested the existence of a system that can temporarily compensate for the loss of the dopamine."

"The dogma in the field is that Parkinson's disease involves a selective loss of dopamine neurons. The truth is, if you look at postmortem Parkinson's disease brains, you will see that both dopamine and norepinephrine neurons are gone," Dr. Weinshenker explains. "We know that norepinephrine is important for regulating the activity of dopamine neurons, so we suspected that the dopamine neurons and the norepinephrine neurons function in concert. As the dopamine neurons start dying, the norepinephrine neurons compensate by signaling the surviving dopamine cells to dramatically increase their activity and the output of dopamine. Eventually, the norepineprhine neurons die, the surviving dopamine neurons lose their ability to release extra dopamine, and symptoms start to appear."



To test their hypothesis, the researchers gave healthy, one-year-old mice the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) at a dose that kills about 80 percent of the dopamine cells, but observed no motor impairments in the mice. Surprisingly, when they tested mice unable to synthesize norepinephrine and that have trouble releasing dopamine properly, they observed symptoms of Parkinson's disease including resting tremor, hunched posture and deficits in coordinated movement. These results indicate that having a normal complement of dopamine neurons is not enough for normal motor function; norepinephrine also needs to be present to ensure proper dopamine release.


"Although there are no cures for Parkinson's disease, some moderately effective treatments are available, but most target the dopamine neurons only and are effective for only a limited amount of time. In light of this study, it's quite possible that simultaneously treating both the dopamine and norepinephrine loss could further ameliorate the symptoms of Parkinson's disease,Ó says Dr. Weinshenker.


Results of the study by Emory scientists, along with the University of Georgia, will appear in the Proceedings of the National Academy of Sciences, Early Edition online during the week of Aug. 13-17 and in the Aug. 21 print edition.
The work was funded in part by the National Institutes of Health.
Note: This story has been adapted from a news release issued by Emory University.

Dr. Michel Levesque's
 

research suggests the same thing. He grew a porpouri of cells from his donors and re-implanted them. His early success seemed to bear the Emory researchers findings out.

Unfortunately it is my understanding that his trial has been suspended due to patient deaths.

Charlie

I'm not surprised..
 

How is it that there are people who "survive" the most debilitating symptoms of PD for many years, before they finally start complaining about things that have "hit" the rest of us like a ton of bricks early after dx?
It must have something to do with the norepinephrine "pump". When i take Ritalin, on a good day, i can actually do things and go places that i simply cannot on bad days. Thus a "stimulatory" component that is missing, i feel generally is part and parcel to the manifestations of PD symptoms. However, focusing in on the cholinergic system is not the whole story either, while anticholinergics generally help with PD symptoms, we have not seen the wide use of amphetamine like norepinephrine mimetics to help combat PD symptomology.

Not much here but...
 

...I had to post it just for the scientist's name. :) I hope I haven't offended the entire Rommelfanger clan. We Southerners can be touchy that way. :D

1: Biochem Pharmacol. 2007 Jul 15;74(2):177-90. Epub 2007 Feb 3.

Norepinephrine: The redheaded stepchild of Parkinson's disease.

Rommelfanger KS, Weinshenker D.

Department of Human Genetics, Emory University, Atlanta, GA 30322, United States.

Parkinson's disease (PD) affects approximately 1% of the world's aging
population. Despite its prevalence and rigorous research in both humans and
animal models, the etiology remains unknown. PD is most often characterized by
the degeneration of dopamine (DA) neurons in the substantia nigra pars compacta
(SNc), and models of PD generally attempt to mimic this deficit. However, PD is a
true multisystem disorder marked by a profound but less appreciated loss of cells
in the locus coeruleus (LC), which contains the major group of noradrenergic
neurons in the brain. Historic and more recent experiments exploring the role of
norepinephrine (NE) in PD will be analyzed in this review. First, we examine the
evidence that NE is neuroprotective and that LC degeneration sensitizes DA
neurons to damage. The second part of this review focuses on the potential
contribution of NE loss to the behavioral symptoms associated with PD. We propose
that LC loss represents a crucial turning point in PD progression and that
pharmacotherapies aimed at restoring NE have important therapeutic potential.

PMID: 17416354 [PubMed - in process]

thank you dear charlie -
 

PARKINSON’S DISEASE Lévesque M and Neuman T, “Autologous transplantation of adult human neural stem cells and differentiated dopaminergic neurons for Parkinson disease: 1-year postoperative clinical and functional metabolic result”, American Association of Neurological Surgeons annual meeting, Abstract #702; 8 April 2002 Gill SS et al.; “Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease”; Nature Medicine 9, 589-595; May 2003 (published online 31 March 2003)

See also July 14, 2004 Senate testimony by Dr. Michel Lévesque: http://commerce.senate.gov/hearings/...68&wit_id=3670 and Mr. Dennis Turner: http://commerce.senate.gov/hearings/...68&wit_id=3676

SPINAL CORD INJURY See July 14, 2004 Senate testimony by Dr. Jean Peduzzi-Nelson: http://commerce.senate.gov/hearings/...68&wit_id=3671 and a more extensive testimony at: http://www.stemcellresearch.org/test...zzi-nelson.htm and Ms. Laura Dominguez: http://commerce.senate.gov/hearings/...68&wit_id=3673 and Ms. Susan Fajt: http://commerce.senate.gov/hearings/...68&wit_id=3674 For appended paper, see http://bioethics.gov/reports/stemcell/appendix_k.html

Thanks for this. I take doxepin, a tricyclic AD, that blocks reuptake of serotonin and norepinephrine. I wonder how it affects my PD symptoms. (Effexor does the same thing.) It's probably good for my dopamine levels. It does reduce my pain.

flexeril
 

My husband with pd finds that taking flexeril (cyclobenzaprine) extends his Sinemet. We wondered how this works, but flexeril works similarly to tricyclicics. He takes it at bedtime, and if he misses a dose, the next day or so his chin quivvers, and he becomes shakey. The generic does not work as well.

Thanks, TRfan. I hadn't realized flexeril was a tricyclic. I'd tried it for the muscle spasms in my leg and foot, and it didn't help much at all. Baclofen does help a great deal.