How key circuits in the brain control movement

A new study that has identified how key circuits in the brain control movement could treat movement related disorders, such as Parkinson’s disease. Scientists Anatol Kreitzer, PhD and Karl Deisseroth, MD PhD at the Gladstone Institute of Neurological Disease (GIND) and Stanford University used genetic methods to allow mice to produce a light-sensitive protein in very select group of cells in the brain.

Researchers found that the mouse with the fibre optics implanted in the brain moved normally with the laser turned off and froze when the laser was turned on. With the laser off, and the mouse’s movement was restored. “It’s not something we can do for just a second,” Kreitzer said. “We can do this for as long as the laser is on.” “We generated mice that lacked dopamine, and these mice showed many of the same symptoms found in humans with Parkinson’s disease. But when we activated the ‘go’ pathway in these mice, they began to move around normally again. We restored all of their motor deficits with this treatment, even though the mice still lacked dopamine,” he added.

The research could be important for treating Parkinson’s and also other disorders involving these circuits, such as Huntington’s disease, Tourette’s syndrome, obsessive-compulsive disorder, and addiction.

By http://www.thehindu.com/

The research is published in the journal Nature.

Long-Term Efficacy Of Xenazine® (Tetrabenazine) For The Treatment Of Chorea Associated With Huntington's Disease

Lundbeck Inc. has announced the presentation of results from an open-label extension study of Xenazine® (tetrabenazine) for the treatment of chorea associated with Huntington's disease (HD). Data from this study demonstrated that after an 80-week treatment period, subjects treated with Xenazine experienced a statistically significant reduction in chorea score (p<0.0001) as measured using the Unified Huntington's Disease Rating Scale (UHDRS) compared with baseline.1


These results are consistent with the reduction in chorea score observed in a pivotal Phase 3 randomized, double-blind, placebo-controlled multi-center clinical study in which subjects were treated with Xenazine for 12 weeks.2 Data from the open-label study were presented at the 12th Annual American Society of Experimental NeuroTherapeutics (ASENT) meeting in Bethesda, Maryland (Poster No. 0029). Results of this study are published in BMC Neurology, an online open access journal at http://www.biomedcentral.com/bmcneurol. Xenazine carries a boxed warning for increased risk of depression and suicidality.

The jerky, sporadic movements commonly seen with chorea associated with Huntington's disease may make it difficult for affected individuals to do tasks such as holding on to objects or even walking," said Dr. Samuel Frank, MD, assistant professor of neurology at the Boston University School of Medicine and lead investigator in this study. "Prolonged reduction of chorea associated with HD in some patients, as seen in this open-label study of Xenazine, is highly encouraging and suggests that Xenazine could be an important treatment option for those seeking to lessen chorea."

This open-label, multi-center extension study was designed to assess the long-term use of Xenazine as a treatment for chorea associated with Huntington's disease.1 The study enrolled 75 subjects, all of whom had previously completed 12 weeks of treatment with Xenazine in the pivotal Phase 3 trial, followed by a one week washout period. Xenazine was titrated over a maximum 12 weeks every three to seven days to the best individual dose, up to a maximum of 200 mg/day of Xenazine. Titration was permitted only during the first 11 weeks of the study.1 Patients who appear to require doses of greater than 50 mg/day should be genotyped for CYP2D6. Doses above 100 mg/day are not recommended for any patient in the Xenazine full prescribing information.3

Of the 75 subjects enrolled in the study, 45 subjects completed the 80-week treatment period, of which 42 subjects continued on to complete a one-week washout period.1 Thirty subjects withdrew from the study, of which, three subjects withdrew due to adverse events associated with Xenazine, including depression, delusions associated with previous suicidal behavior and vocal tics, and 26 subjects withdrew for various other reasons. One subject died due to metastatic breast cancer.

The primary efficacy endpoint in this study was the Total Maximal Chorea (TMC) score from the UHDRS at week 80 compared with baseline TMC score.1 TMC score at week 80 was also compared to TMC score at week 81 following the washout period.1 The UHDRS is a validated rating system used to measure the severity of Huntington's disease.2 The rating system ranges from 0 units (absent chorea symptoms) to 28 units (marked/prolonged chorea).

Data from this study demonstrate a statistically significant reduction in chorea in patients compared to baseline who completed 80 weeks of Xenazine treatment, with a mean reduction in the TMC score of 4.6 UHDRS units.1 At week 81, following a one week washout period, the mean TMC score increased 5.3 UHDRS units compared to week 80 (p<0.001), suggesting that continued use of Xenazine at an individualized dose maintains reduction of chorea associated with HD for up to 80 weeks and confirming results from the pivotal study where discontinuation of Xenazine treatment was associated with the return of chorea, but without significant worsening compared to baseline.1

When mild and unrelated adverse events (AEs) were excluded, the most common AEs in this study reported in >5% of subjects (three or more) were sedation/somnolence, depressed mood, anxiety, insomnia, akathisia, fatigue, agitation, fall, dysphagia and dystonia.1 Thirty-nine patients reported at least one AE during the titration phase compared to 20 patients during the maintenance period. Insomnia, somnolence and diarrhea emerged during titration and resolved during the maintenance period. Twelve serious AEs were reported including two falls, two cancer diagnoses, a single suicide attempt, pneumonia, elective hip replacement with post-op agitation, agitation, anxiety, akathisia, and one abnormal CA 27-29 titer in a patient who later died due to metastatic breast cancer.

About Xenazine


Xenazine is the only FDA-approved therapy for the treatment of chorea associated with Huntington's disease. Xenazine was approved by the U.S. Food and Drug Administration (FDA) in August 2008 and was launched by Lundbeck Inc. in November 2008. To learn more about Xenazine, visit http://www.xenazineusa.com.

Xenazine Important Safety Information and Boxed Warning

Xenazine can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Anyone considering the use of Xenazine must balance the risks of depression and suicidality with the clinical need for control of choreiform movements. Close observation of patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior should accompany therapy. Patients, their caregivers, and families should be informed of the risk of depression and suicidality and should be instructed to report behaviors of concern promptly to the treating physician.

Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntington's disease. Xenazine is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression.

Xenazine is also contraindicated in patients with impaired hepatic function, and in patients taking monoamine oxidase inhibitors or reserpine.3 At least 20 days should elapse after stopping reserpine before starting Xenazine. Although Xenazine has been shown to decrease the chorea associated with HD, it was also shown to cause slight worsening in mood, cognition, rigidity and functional capacity and prescribers should periodically re-evaluate the need for therapy. Some adverse effects such as depression, fatigue, insomnia, sedation/somnolence, parkinsonism, akathisia, QTc prolongation and interactions with CYP2D6 inhibitors may be dose dependent, and resolve or lessen with dose adjustment. The most frequent adverse events (over 10% and at least 5% greater than placebo) reported with Xenazine compared to placebo in a randomized, 12-week, placebo controlled clinical trial of HD subjects include sedation/somnolence (31% vs. 3%), fatigue (22% vs. 13%), insomnia (22% vs. 0%), depression (19% vs. 0%), akathisia (19% vs. 0%), anxiety (15% vs. 3%) and nausea (13% vs. 7%). For more information, please see full prescribing information including Boxed Warning or go to http://www.xenazineusa.com.

About Chorea Associated with Huntington's Disease

Chorea is the most common symptom of Huntington's disease (HD), a rare neurodegenerative disease that results in uncontrolled movements, emotional disturbances, and mental deterioration. HD affects approximately 30,000 people in the United States.4 Chorea associated with HD is characterized by irregular, abrupt movements of the face, fingers, arms, legs, or body that can appear as constant jerky, twisting, and uncontrollable, dance-like motions.5,6 As the disease progresses, it may interfere with many voluntary movements, making it more difficult to walk, talk or hold things.7 Currently, there is no known cure for HD and the disease and prognosis is poor.3,8,9 To learn more about chorea associated with Huntington's disease, please visit http://www.xenazineusa.com.

Sources

Frank S. Tetrabenazine as anti-chorea therapy in Huntington disease: an open-label continuation study. BMC Neurol. 2009 Dec 18;9:62.

Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology. 2006 Feb 14;66(3):366-72.

Xenazine® Full Prescribing Information. Deerfield, IL: Lundbeck Inc. September 2009.

What is Huntington's Disease (HD)? Huntington's Disease Society of America. http://www.hdsa.org/about/our-mission/what-is-hd.html. Last accessed 2/22/10.

Huntington Study Group. Unified Huntington's Disease Rating Scale: Reliability and Consistency. Movement Disorders. 1996;2(2):136-142.

Chorea, Huntington's Disease. The Movement Disorder Society. http://www.movementdisorders.org/disorders/chorea.php. Last accessed 02/22/10.

Kirkwood SC, Su JL, Conneally PM, Foroud T. Progression of symptoms in the early and middle stages of Huntington disease. Archives of Neurology 2001;58:273-278.

Huntington's Disease: Hope Through Research. National Institute of Neurological Disorders and Stroke. http://www.ninds.nih.gov/disorders/huntington/detail_huntington.htm. Last accessed 02/22/10.

Huntington's disease. Mayo Clinic. http://www.mayoclinic.com/health/huntingtons-disease/DS00401/METHOD=print. Last accessed 2/22/10.

Source:

Nikki Kidd

Edelman Public Relations

View drug information on Xenazine

Huntington's Disease: Discovery Of Mechanism In Brain Cell Injury Offers New Treatment Approaches

Scientists at the Brain Research Centre and Centre for Molecular Medicine and Therapeutics have uncovered a key cellular mechanism that alters brain cell function in Huntington's disease, and identified a possible treatment for the disease.

The results of the study were published online today and will appear in the January 28 edition of the journal Neuron.

Huntington's disease is an inherited degenerative brain disease that causes cognitive and motor impairment, and eventually death. One in 10,000 Canadians suffers from Huntington's disease.

The researchers found that, in mouse models, the genetic mutation that causes Huntington's disease results in an excessive number of NMDA receptors - special receptors found at the surface of brain cells - to accumulate and be active outside synapses, which are the connections between brain cells. In healthy conditions, there should be few NMDA receptors outside the synapse.

The researchers also found that the over-activation of the NMDA receptors outside the synapse leads to a reduction in brain cell survival signals and disruption in brain function.

"Previous work in cell cultures showed that NMDA receptors located within the synapse can have beneficial effects on brain cells, whereas NMDA receptors outside the synapse, called 'extra-synaptic NMDA receptors,' have a detrimental effect," says Dr. Lynn Raymond, a professor in the UBC Department of Psychiatry, a member of the Brain Research Centre at UBC Hospital, and co-director of the Huntington's Disease Medical Clinic.

"Our study shows an increase in the number of extrasynaptic NMDA receptors, shifting the balance between these opposing cellular mechanisms in animal models of early stages of Huntington's disease," Raymond says.

While further work still needs to be done to determine how the genetic mutation causes the excessive number and activity of NMDA receptors to localize outside the synapses, the researchers did find a way to mitigate damage and slow disease progression at early stages of the disease - using Memantine, a drug currently used to treat Alzheimer's disease.

"Memantine in low dose works by preferentially blocking the activity of NMDA receptors outside the synapse," says Dr. Michael Hayden, director of the Centre for Molecular Medicine and Therapeutics, professor in the UBC Department of Medical Genetics, and co-author on the study.

"It was previously shown to reverse deficits and damage in late stages of animal models of Huntington's disease, but we found it could improve learning and cell survival signaling even at early stages of the disease," says Hayden. "A small human clinical trial of Memantine for Huntington's disease has also recently shown positive effects. Larger, international clinical trials are now being planned."

"Memantine's beneficial effects appear to be dose-specific," Raymond adds. "Before it can be prescribed to treat Huntington's disease, we need to know how to determine appropriate dosing and whether it interferes with other essential cellular and brain functions."

This study was funded by the Canadian Institutes of Health Research, Cure Huntington Disease Initiative, Michael Smith Foundation for Health Research, Heart & Stroke Foundation of BC & Yukon, Huntington's Disease Society of America, and the Huntington Society of Canada.

Source: Melissa Ashman

University of British Columbia

Discovery Of Compounds That Help Protect Nerve Cells

Scientists at Duke University Medical Center have found some compounds that improve a cell's ability to properly "fold" proteins and could lead to promising drugs for degenerative nerve diseases, including Huntington's disease, Alzheimer's disease and Parkinson's disease.

Misfolded proteins in nerve cells (neurons) are a common factor in all of these diseases. The Duke team has identified many new chemicals that activate a master regulator to increase the supply of "protein chaperone" molecules that help fold proteins properly.

The scientists further explored one of the candidate molecules to activate the master regulator of chaperone gene expression, Heat Shock Factor 1 (HSF1), to learn whether it would work in model systems of Huntington's disease, a devastating neurodegenerative disease of protein misfolding.

They were able to show that the molecule stimulated protein chaperones in cells and in an animal system. The damage to early-state rat neurons was much lower in cells pre-treated with the HSF1 activator, and damage to the neurons of fruit flies that had a Huntington's-like disorder was also greatly reduced.

Previous studies suggested that elevating the abundance of protein chaperones is effective in treating cell and animal models of Huntington's and Parkinson's diseases. This work provides a new approach to address the root cause of these diseases -- protein misfolding. Earlier attempts had used heat shock and other approaches that stress a nerve cell in order to produce more chaperone molecules, but at a cost of damaging the cell to save it.

"The advantage of our screen is that it identifies molecules that can elevate the levels of chaperones without inducing cellular stress and that don't inhibit a key protein chaperone called Hsp90 that is needed for cells to function normally," said senior author Dennis J. Thiele, Ph.D., Professor of Pharmacology and Cancer Biology. "We found a creative way to identify new molecules that can activate the body's natural protein folding machinery."

The research was published in the Jan. 19 online issue of PLoS Biology.

Lead author Daniel Neef, Ph.D., says they used genetically altered yeast to find compounds that might aid chaperone development. The scientists took yeast with a deleted HSF1 (master regulator) gene and inserted the related human HSF1 gene. These yeast, however, still weren't able to activate human HSF1 on their own, and in effect, died. They needed an additional molecule to make human HSF1 become active

The team put these "humanized yeasts" into wells and started testing compounds that would provide the missing link. In several of the wells, if the compound worked, the yeast started multiplying. "Out of over 12,000 compounds tested from chemical libraries, about 50 compounds worked," Neef said. The team decided to explore one of these compounds (HSF1A) in further experiments.

"The humanized yeast-based screening results in our study provide a way to identify new classes of small molecules, small enough to penetrate the blood-brain barrier to work in neurons, in flies as well as in humans," Thiele said. "These small molecules may be effective therapies in neurodegenerative diseases caused by protein conformational disorders such as Huntington's, Alzheimer's and Parkinson's disease."
The scientists found that HSF1A could stimulate more protein chaperones and reduce the protein misfolding. They showed that adding a small amount of HSF1A to the developing rat neurons kept the proteins dissolved throughout the cell, rather than clumping visibly as speckled areas (as seen under microscopes).
"We enhanced the cells' viability by four or five times by pre-treating them with this molecule," Neef said. "Otherwise, the cells would have died."

They used fruit flies with Huntington's disease for experiments to prove that the principle would work in an animal. Adding HSF1A to the fly's food produced more chaperone molecules in their neurons. This suggests that the molecule could travel from the fly's stomach into its circulation and cross a barrier to the fly brain.
In the key experiment, the Huntington's disease flies received either their usual food or food plus HSF1A. Those with untreated food developed eyes with dying photoreceptor neurons and lacking the normal red color. Those that ate HSF1A went on to have normal-colored eyes, indicating a repair had taken place, just by eating food laced with the promising compound.

Michelle Turski, now with Stanford University, was a co-author of the study. The work was supported by grants from the National Institutes of Health.

Source: Mary Jane Gore
Duke University Medical Center

Huntington's Disease Defined

Huntington's disease is an inherited, degenerative brain disease, which affects the mind and body. The disease usually begins during mid-life, and is characterized by intellectual decline, and irregular and involuntary movements of the limbs or facial muscles. Other symptoms of Huntington's disease include personality change, memory disturbance, slurred speech, impaired judgment, and psychiatric problems. Huntington's disease currently affects more than 25,000 Americans. The diagnostic process for Huntington's disease includes an evaluation of family medical history, recognition of typical movement disorders, and CAT brain scanning. A genetic marker linked to Huntington's disease has been identified on chromosome 4 and researchers are working on locating the gene itself. Although there is no treatment available to stop the progression of the disease, the movement disorders and psychiatric symptoms can be controlled by drugs.

Early Symptoms
By Huntington's Disease Society of America

Early symptoms of Huntington's Disease may affect cognitive ability or mobility and include depression, mood swings, forgetfulness, clumsiness, involuntary twitching and lack of coordination. As the disease progresses, concentration and short-term memory diminish and involuntary movements of the head, trunk and limbs increase. Walking, speaking and swallowing abilities deteriorate. Eventually the person is unable to care for him or herself. Death follows from complications such as choking, infection or heart failure.
HD typically begins in mid-life, between the ages of 30 and 50, though onset may occur as early as the age of 2. Children who develop the juvenile form of the disease rarely live to adulthood.

HD affects males and females equally and crosses all ethnic and racial boundaries. Each child of a person with HD has a 50/50 chance of inheriting the fatal gene. Everyone who carries the gene will develop the disease. In 1993, the HD gene was isolated and a direct genetic test developed which can accurately determine whether a person carries the HD gene. The test cannot predict when symptoms will begin. However, in the absence of a cure, some individuals "at risk" elect not to take the test.