Serotonin 1B receptor agonists may block l-dopa side effects
 

New Parkinson's disease research points to serotonin
Medical Research News
Published: Monday, 4-Feb-2008



For most people with Parkinson's disease, the only relief from the tremors, rigidity and impaired movement associated with the progressive loss of their motor skills is a drug called L-DOPA. But as the disease progresses, L-DOPA can cause prominent side effects that counteract its effectiveness.

Now, Rockefeller University's Paul Greengard and colleagues at the Karolinska Institute in Sweden provide evidence that serotonin, a well-studied neurotransmitter involved in regulating mood, appetite, sexuality and sleep, also plays a crucial role in Parkinson's disease.

Using a mouse model of the disease, Greengard's team shows that side effects associated with repeated L-DOPA treatment can be blocked by manipulating a specific serotonin receptor.

The finding, reported this week in Proceedings of the National Academy of Sciences Early Edition online, points to a new target for developing treatments for this disorder, which is the second most common neurodegenerative disease after Alzheimer's.

"Our study provides a scientific rationale for developing drugs that act on the serotonin 1B receptor for the treatment of advanced Parkinsonism," says senior co-author Per Svenningsson, a visiting professor in Greengard's lab and a group leader at the Karolinska Institute in Sweden........

Two years ago, Greengard and Svenningsson identified a protein, called p11, that acts as a regulator of serotonin signaling in the brain. The researchers showed that p11 increases the concentration of the serotonin 1B receptor at synapses, thereby increasing the efficiency of serotonin signaling, and linked this interaction to an individual's susceptibility to depression and his or her response to antidepressant treatments.

In the new study, Greengard, Svenningsson and their colleagues show that p11 and serotonin also play a role in the L-DOPA-induced symptoms of advanced Parkinson's disease. Svenningsson and Xiaoqun Zhang, a graduate student at Karolinska, used a mouse model of Parkinson's disease in which a substance called 6-OHDA causes the destruction of dopamine neurons in one hemisphere of the brain. L-DOPA, because it is a dopamine replacement and a stimulant, causes the 6-OHDA-treated mice to rotate their bodies in the opposite direction of the dopamine-depleted brain hemisphere.

When the researchers gave these mice L-DOPA, they found increased levels of the serotonin 1B receptor and the protein p11 in the striatum. The researchers then used a molecule called CP94253, which binds to the serotonin 1B receptor and mimics the action of serotonin. CP94253 was given to two sets of 6-OHDA-treated mice: one in which p11 was "knocked out" and another with p11 intact.......

The researchers believe that CP94253, and similar serotonin 1B receptor agonists, may counteract L-DOPA-induced behaviors by reducing the release of GABA, a chemical messenger that inhibits the transmission of nerve impulses. GABA is released from neurons that contain the dopamine D1 receptor.

"Blocking the dopamine D1 receptor is not a treatment option for L-DOPA-induced side effects, since it would diminish the therapeutic efficiency of L-DOPA," says Greengard, who is Vincent Astor Professor and head of the Laboratory of Molecular and Cellular Neuroscience at Rockefeller. "Developing compounds that target the serotonin 1B receptor may offer an alternative approach for treating advanced Parkinson's disease."

http://www.news-medical.net/?id=34873

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Industry Teams Receive Awards From Michael J. Fox Foundation

http://www.medicalnewstoday.com/articles/95895.php

......Chronic inflammation plays a role in the death of the dopamine-producing neurons that are lost in Parkinson's disease. Patrick Flood, PhD, of TheraLogics, Inc., and his group will test compounds that specifically target the inflammatory pathway in a PD animal model to determine whether certain drugs can protect against this neuronal loss. The team will assess whether blocking inflammation reverses destruction of dopamine-producing neurons, and actually leads to regeneration of these cells within the brain, to determine the most effective dose and timing for therapeutic intervention.

The blood-brain barrier is a thin layer of tightly packed cells separating the central nervous system from the body's bloodstream. This layer is crucial to protecting the brain from foreign substances, but also poses a major challenge in delivering potentially therapeutic treatments via orally administered drugs. Antonia Orsi, PhD, and her team from Phytopharm have developed a small orally active molecule that crosses the blood-brain barrier. In vivo and in vitro, the molecule increases levels of trophic factors, specialized proteins that potently promote survival of neurons. The team has already demonstrated that the compound can increase the number of dopaminergic neurons in a mouse model of PD. The goal now is to gain greater understanding of the neurorestorative properties of this compound in mice and, if successful, test the compound in a primate model of Parkinson's disease.

Mitochondria are the "energy factories" of body cells. It is believed that mitochondrial function is decreased in people with Parkinson's disease and that mitochondrial toxins induce parkinsonian symptoms in animal models. Rebecca Pruss, PhD, and her colleagues at Trophos are developing unique compounds that improve mitochondrial function and that are currently being evaluated in patients for the treatment of ALS and diabetic neuropathy. Dr. Pruss will test whether these compounds are neuroprotective in an animal model of Parkinson's disease. .......

yes. these are paths of hope
 

Thanks a million Z-flower and Paula for highlighting M J Fox supported Pharam companies research ..
My brain is sloooow so I decided to put Paula and Z-flower posts together and we have 4 or 5 lines of hope (Are lines 1 and 4 actually the same ????) :
1) COGANE / GDNF: PHYTOPHARM, the quoted Cambridgeshire drug developer that makes products from medicinal plants, is to receive a $1.2m (£613,000) grant from the Michael J Fox Foundation to help to fund its research into treatment of Parkinson’s disease.

It will get money over two years to fund preclinical trials of Cogane, a treatment that helps to stimulate production in the brain of the protein GDNF, which is known to ease symptoms of Parkinson’s disease.
Injecting GDNF into the part of the brain involved can be effective but is exceptionally risky. GDNF cannot be taken orally.

Cogane is being developed to bypass these hurdles and this funding will be used to research the most effective dosing of the drug.
2) Christine Bulawa, PhD, of FoldRx Pharmaceuticals Inc., will work to develop a disease-modifying drug that could block the toxicity associated with clumping of the protein alpha-synuclein, a hallmark of PD pathology. Dr. Bulawa¡'s team has identified chemical compounds that protect neurons from alpha-synuclein toxicity and will now work with the compounds in a rodent model of Parkinson's. The researchers hope to identify promising small molecules that, with further optimization, can be developed into drug candidates to be tested in PD patients in clinical trials.
3) Chronic inflammation plays a role in the death of the dopamine-producing neurons that are lost in Parkinson's disease. Patrick Flood, PhD, of TheraLogics, Inc., and his group will test compounds that specifically target the inflammatory pathway in a PD animal model to determine whether certain drugs can protect against this neuronal loss. The team will assess whether blocking inflammation reverses destruction of dopamine-producing neurons, and actually leads to regeneration of these cells within the brain, to determine the most effective dose and timing for therapeutic intervention.
4) The blood-brain barrier is a thin layer of tightly packed cells separating the central nervous system from the body's bloodstream. This layer is crucial to protecting the brain from foreign substances, but also poses a major challenge in delivering potentially therapeutic treatments via orally administered drugs. Antonia Orsi, PhD, and her team from Phytopharm have developed a small orally active molecule that crosses the blood-brain barrier. In vivo and in vitro, the molecule increases levels of trophic factors, specialized proteins that potently promote survival of neurons. The team has already demonstrated that the compound can increase the number of dopaminergic neurons in a mouse model of PD. The goal now is to gain greater understanding of the neurorestorative properties of this compound in mice and, if successful, test the compound in a primate model of Parkinson's disease.
5) Mitochondria are the "energy factories" of body cells. It is believed that mitochondrial function is decreased in people with Parkinson's disease and that mitochondrial toxins induce parkinsonian symptoms in animal models. Rebecca Pruss, PhD, and her colleagues at Trophos are developing unique compounds that improve mitochondrial function and that are currently being evaluated in patients for the treatment of ALS and diabetic neuropathy. Dr. Pruss will test whether these compounds are neuroprotective in an animal model of Parkinson's disease.