Investigación

New insight into what freezes Parkinson's patients and drives drug addicts

el . Publicado en Investigación Parkinson

 

CHICAGO -- Parkinson's disease and drug addiction are polar opposite diseases, but both depend upon dopamine in the brain. Parkinson's patients don't have enough of it; drug addicts get too much of it. Although the importance of dopamine in these disorders has been well known, the way it works has been a mystery.

New research from Northwestern University's Feinberg School of Medicine has revealed that dopamine strengthens and weakens the two primary circuits in the brain that control our behavior. This provides new insight into why a flood of dopamine can lead to compulsive, addictive behavior and too little dopamaine can leave Parkinson's patients frozen and unable to move.

"The study shows how dopamine shapes the two main circuits of the brain that control how we choose to act and what happens in these disease states, " said D. James Surmeier, lead author and the Nathan Smith Davis Professor and chair of physiology at the Feinberg School. The paper is published in the August 8 issue of the journal Science.

These two main brain circuits help us decide whether to act out a desire or not. For example, do you get off the couch and drive to the store for an icy six-pack of beer on a hot summer night, or just lay on the couch?

One circuit is a "stop" circuit that prevents you from acting on a desire; the other is a "go" circuit that provokes you to action. These circuits are located in the striatum, the region of the brain that translates thoughts into actions.

In the study, researchers examined the strength of synapses connecting the cerebral cortex, the region of the brain involved in perceptions, feelings and thought, to the striatum, home of the stop and go circuits that select or prevent action.

Scientists electrically activated the cortical fibers to simulate movement commands and boosted the natural level of dopamine. What happened next surprised them. The cortical synapses connecting to the "go" circuit became stronger and more powerful. At the same time, dopamine weakened the cortical connections in the "stop" circuit.

"This could be what underlies addiction," Surmeier said. "Dopamine released by drugs leads to abnormal strengthening of the cortical synapses driving the striatal 'go' circuits, while weakening synapses at opposing 'stop' circuits. As a result, when events associated with drug taking – where you took the drug, what you were feeling – occur, there is an uncontrollable drive to go and seek drugs."

"All of our actions in a healthy brain are balanced by the urge to do something and the urge to stop," Surmeier said. "Our work suggests that it is not just the strengthening of the brain circuits helping select actions that is critical to dopamine's effects, it is the weakening of the connections that enable us to stop as well. "

In the second part of the experiment, scientists created an animal model of Parkinson's disease by killing dopamine neurons. Then they looked at what happened when they simulated cortical commands to move. The result: the connections in the "stop" circuit were strengthened, and the connections in the "go" circuit were weakened.

"The study illuminates why Parkinson's patients have trouble performing everyday tasks like reaching across a table to pick up a glass of water when they are thirsty," Surmeier said.

Surmeier explained the phenomenon using the analogy of a car. "Our study suggests that the inability to move in Parkinson's disease is not a passive process like a car running out of gas," he said. "Rather, the car doesn't' move because your foot is jammed down on the brake. Dopamine normally helps you adjust the pressure on the brake and gas pedals. It helps you learn that when you see a red light at an intersection, you brake and when the green light comes on, you take your foot off the brake and depress the gas pedal to go. Parkinson's disease patients, who have lost the neurons that release dopamine, have their foot perpetually stuck on the brake."

Understanding the basis for these changes in brain circuitry moves scientists closer to new therapeutic strategies for controlling these brain disorders and other involving dopamine like schizophrenia, Tourette's syndrome and dystonia.

Contact: Marla Paul
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312-503-8928
Northwestern University

De la piel del enfermo a modelos de investigación en el laboratorio

el . Publicado en Investigación Parkinson

 

Actualizado jueves 07/08/2008 20:22 (CET)

ÁNGELES LÓPEZ

MADRID.- Son sólo unas células recogidas de la piel de unos pocos pacientes. Sin embargo, gracias a que han sido reprogramadas para devolverlas a un estadio primitivo, similar al de las células madre embrionarias, podrán utilizarse como modelo de estudio de 10 enfermedades genéticas como el síndrome de Down o el Parkinson.

Durante años, los investigadores han cultivado células humanas en el laboratorio para intentar imitar diferentes enfermedades genéticas, pero las técnicas disponibles presentaban defectos significativos. Las células que se obtenían de los pacientes tienen una vida muy limitada, lo que reduce el tipo de investigación con ellas. Por eso, en muchas ocasiones se recurre a experimentos con animales, como los ratones. Sin embargo, la fisiología de estos roedores y otros modelos con seres vivos no siempre se corresponde con la humana y no sirve para estudiar ciertos trastornos.

Hace unas semanas, investigadores estadounidenses mostraban cómo, por primera vez, habían conseguido neuronas a partir de células de la piel de una paciente con esclerosis lateral amiotrófica. Como explicaban esos expertos, la enfermedad podría estudiarse mejor al contar con neuronas que, genéticamente, estaban predestinadas a desarrollar ese trastorno. Así, se puede ver la evolución de estas células en una placa de laboratorio.

Algo parecido es lo que ha conseguido un grupo de científicos dirigidos por George Q. Daley, del Howard Hughes Medical Institute, y cuyos datos publica la revista 'Cell'. Estos expertos consiguieron células de la piel de nueve personas y de la médula de otro sujeto, para posteriormente reprogramarlas, con la técnica de Yamanaka, y obtener líneas celulares similares a las células madre embrionarias (iPS, siglas en inglés). Todos los participantes, cuya edad oscilaba entre el mes y los 57 años, presentaban una enfermedad originada por una alteración genética.

Herramienta de investigación

"Queríamos producir un gran número de modelos de enfermedades para nosotros, nuestros colaboradores y la comunidad científica que trabaja con células madre con el objetivo de acelerar la investigación", explica Daley. "Estas nuevas líneas son herramientas muy valiosas porque abordan el origen de las enfermedades. Nuestro trabajo es sólo el comienzo para el estudio de miles de patologías en una placa de Petri", declara.

Mediante la inserción de cuatro factores de crecimiento, los investigadores lograron reprogramar las células adultas y convertirlas en células 'bebé' capaces de convertirse en cualquier otro tipo de células. De esta manera, consiguieron 20 líneas (cultivos de células) pluripotentes pero con los mismos errores genéticos que contribuyeron a que cada uno de los pacientes desarrollara una de las siguientes enfermedades: Parkinson, diabetes tipo 1, enfermedad de Huntington, síndrome de Down, inmunodeficiencia combinada severa (niños 'burbuja'), síndrome de Lesch-Nyhan, enfermedad de Gaucher, síndrome de Shwachman-Diamons y dos formas de distrofia muscular.

"La falta de modelos accesibles de tejidos normales y patológicos ha hecho que muchas e importantes cuestiones sobre el desarrollo humano y la patogénesis [causa y formación] de enfermedades sean inaccesibles", explican los autores. El trabajo de ahora, la obtención de líneas celulares pluripotentes de pacientes con trastornos de un único gen, "nos permitirá conseguir modelos de miles de patologías utilizando las técnicas clásicas de cultivos celulares, y es una oportunidad para reparar los defectos genéticos".

El Instituto Harvard Stem Cell (IHSC) ha puesto en marcha una serie de recursos para establecer un centro en el que producir líneas celulares específicas de una enfermedad, con el propósito de ponerlas a disposición de la comunidad biomédica para su investigación. "Tenemos buenas razones para pensar que será posible encontrar nuevos tratamientos, y finalmente fármacos, para retrasar o incluso parar el curso de una serie de patologías. En los próximos años, este estudio será visto como una puerta abierta a una nueva forma de desarrollar terapias", explica Doug Melton del IHSC.

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Molecular Biometrics Announces Results of Parkinson's Disease Research and Receipt of Grant From Michael J. Fox Foundation to Advance Diagnostic Technology

el . Publicado en Investigación Parkinson

Molecular Biometrics Announces Results of Parkinson's Disease Research and Receipt of Grant From Michael J. Fox Foundation to Advance Diagnostic Technology
Tuesday August 5, 10:44 am ET

New research demonstrates proof-of-concept for diagnosing Parkinson's disease using non-invasive, biospectroscopy technology

Michael J. Fox Foundation awards grant to Molecular Biometrics for further development of Parkinson's diagnostic

CHESTER, N.J. and MONTREAL, Aug. 5 /PRNewswire/ -- A study published in the June issue of the peer-reviewed journal, Biomarkers in Medicine, demonstrated proof-of-concept for the use of a minimally-invasive technology being developed by Molecular Biometrics, LLC, to diagnose Parkinson's disease (PD). In the study, researchers used spectroscopy to develop a metabolic profile (or chemical signatures) of biological markers for PD. There is currently no definitive laboratory diagnostic for Parkinson's disease.

The company also announced receipt of an award from The Michael J. Fox Foundation for Parkinson's Research supporting further development of its technology platform to validate its PD diagnostic methodology.

"The lack of an objective biomarker to aid diagnosis and therapeutics development is one of the single greatest challenges facing the Parkinson's research field," said Katie Hood, CEO of The Michael J. Fox Foundation. "We are enthusiastic about helping to keep Molecular Biometrics' novel metabolomic diagnostic technology moving forward toward validation and clinical testing."

Researchers at Molecular Biometrics, Lady Davis Institute (LDI), Sir Mortimer B. Davis - Jewish General Hospital and McGill University have shown that, using biospectroscopy methods to create a specific biomarker profile, they can distinguish idiopathic Parkinson's disease from normal aging and other neurodegenerative conditions. Diagnosis of PD is currently based solely on a patient's medical history and neurological examination, making Parkinson's difficult to diagnose, particularly during early stages of the disease.

"We created a biomarker profile, using biospectroscopy techniques, to delineate a chemical signature in blood that identifies patients with Parkinson's disease," said Hyman M. Schipper, MD, PhD, FRCPC, lead author of the study and member of the Faculty of Medicine, Department of Neurology and Neurosurgery, and Department of Medicine, McGill University, and member of the Attending Staff in Neurology at Sir Mortimer B. Davis - Jewish General Hospital, in Montreal, Canada. "This proof-of-concept gives us great hope that biospectroscopy will offer a new approach to the early diagnosis of Parkinson's disease and other neurodegenerative disorders." Dr Schipper is a noted expert in brain aging and neurodegeneration, and a Founding Scientist and Medical Director (Neurosciences) at Molecular Biometrics.

In the study, fifty-two patients, 20 with mild or moderate stages of Parkinson's disease and 32 age-matched control subjects were recruited at the Jewish General Hospital. Whole blood samples were analyzed using near- infrared (NIR) spectroscopy and Raman spectroscopy (RS) methods which have previously been used to create metabolomic profiles (chemical signatures) of human biofluids, including serum and whole blood.

Both NIR and RS methods were applied to measure the degree of oxidative stress (OS) present in each sample. OS has been considered to be a potential biomarker for Parkinson's disease. However, to date, chemical markers have not proven sufficiently robust to serve as an accurate or reliable biomarker of the disease. OS is caused by a chemical imbalance that can damage critical components of a cell, including proteins, lipids and DNA. OS is known to be involved in many diseases, including PD and Alzheimer's disease. The data from this study showed that the two independent biospectroscopy measurement techniques yielded similar and consistent results. In differentiating Parkinson's disease patients from the control group, RS achieved a sensitivity of 74% and specificity of 72%, with eight false positives and four false negatives. NIR achieved a sensitivity of 74% and specificity of 76%, with four false positives and five false negatives.

"We are greatly encouraged by these results and will continue our research and development efforts to further explore the application of our proprietary technology in the development of an accurate, minimally invasive and cost- effective diagnostic tool for Parkinson's disease," added James T. Posillico, PhD, President and Chief Executive Officer, Molecular Biometrics.

"Spectroscopy of human plasma for diagnosis of idiopathic Parkinson disease," was published in Biomarkers in Medicine (June 2008, Vol. 2, No. 3, Pages 229-238).

Molecular Biometrics was one of six industry research teams to receive a total of $2.7 million in funding granted under The Michael J. Fox Foundation's Therapeutics Development Initiative (TDI) program. TDI is the cornerstone of the Foundation's venture philanthropy efforts to help push promising candidate therapeutics forward in industry pipelines by allowing the Foundation to share the risk of product development.

"We are honored to be a grant recipient of The Michael J. Fox Foundation, and are excited to have our technology recognized for its potential to positively impact the future of PD diagnosis and treatment," said Posillico.

About Parkinson's Disease

Parkinson's disease is a chronic, degenerative neurological disorder that affects one in 100 people over age 60. This degenerative disorder of the central nervous system often affects motor skills and speech, as well as other functions, and is characterized by muscle rigidity, tremor, a slowing of physical movement and, in extreme cases, a loss of physical movement. Parkinson's disease belongs to a group of conditions called movement disorders. While the average age at onset is 60, disease onset starts by age 40 in an estimated five to 10 percent of patients, and people as young as 30 can also be affected. It is estimated that at least one million people in the United States, and six million worldwide, have Parkinson's disease.

About Metabolomics

Metabolomics is a complex scientific process that identifies and measures individual signals from many molecular compounds produced by cellular metabolism which, when evaluated as a whole, represent unique biomarkers of biologic function in health and disease.

Molecular Biometrics uses near infrared (NIR) biospectroscopy in its metabolomic applications. NIR is a robust platform that rapidly measures the vibrational energy absorbed by molecular functional groups, creating a profile of molecules that are descriptive of cellular function.

The spectral signatures are further analyzed by proprietary bioinformatics and chemometrics that result in the creation of a novel "metabolomic profile" or "fingerprint" that can be used to distinguish systematically between the often subtle differences that separate normal physiology from the onset or progression of disease, or an individual's response to therapeutic intervention. Metabolomics is commonly used in pharmaceutical research, molecular diagnostics and food and agrichemical industries.

About The Michael J. Fox Foundation

Founded in 2000, The Michael J. Fox Foundation for Parkinson's Research is dedicated to ensuring the development of a cure for Parkinson's disease within the coming decade through an aggressively funded research agenda. The Foundation has funded approximately $126 million in research to date. For more information, please visit www.michaeljfox.org.

About Molecular Biometrics

Molecular Biometrics, LLC, is applying novel metabolomic technologies to develop accurate, non-invasive clinical tools for use in personalized medicine to evaluate normal biologic function in health and in disease, and for drug discovery and development. The company's proprietary technology is being applied in reproductive health and IVF, neurodegenerative disease (e.g., Alzheimer's disease and Parkinson's disease), maternal fetal medicine, pulmonary metabolism and edema, and lactate metabolism. Molecular Biometrics is privately held and headquartered in Chester, NJ, with research and development facilities in New Haven, CT, and Montreal, Quebec. For more information, please visit www.molecularbiometrics.com.


Source: Molecular Biometrics

Neuroprotective effects of edaravone-administration on 6-OHDA-treated dopaminergic neurons

el . Publicado en Investigación Parkinson

BMC Neuroscience 2008, 9:75doi:10.1186/1471-2202-9-75

Published:
1 August 2008

Abstract (provisional)

Background

Parkinson's disease (PD) is a neurological disorder characterized by the degeneration of nigrostriatal dopaminergic systems. Free radicals induced by oxidative stress are involved in the mechanisms of cell death in PD. This study clarifies the neuroprotective effects of Edaravone (MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one), which has already been used for the treatment of cerebral ischemia in Japan, on dopaminergic neurons using PD model both in vitro and in vivo. 6-hydroxydopamine (6-OHDA), a neurotoxin for dopaminergic neurons, was added to cultured dopaminergic neurons derived from murine embryonal ventral mesencephalon with subsequet administration of edaravone or saline. The number of surviving dopaminergic neurons and the degree of cell damage induced by free radicals were analyzed. In parallel, edaravone or saline was intravenously administered for PD model of rats receiving intrastriatal 6-OHDA lesion with subsequent behavioral and histological analyses.

Results

In vitro study showed that edaravone significantly ameliorated the survival of dopaminergic neurons in a dose-responsive manner. The number of apoptotic cells and HEt-positive cells significantly decreased, thus indicating that the neuroprotective effects of edaravone might be mediated by anti-apoptotic effects through the suppression of free radicals by edaravone. In vivo study demonstrated that edaravone-administration at 30 minutes after 6-OHDA lesion reduced the number of amphetamine-induced rotations significantly in a dose-responsive manner than edaravone-administration at 24 hours. Tyrosine hydroxylase (TH) staining of the striatum and substantia nigra pars compacta revealed that edaravone might exert neuroprotective effects on nigrostriatal dopaminergic systems. The neuroprotective effects were prominent when edaravone was administered early and in high concentration. Furthermore, Iba-1 staining revealed that the inflammation was suppressed in rats receiving edaravone-administration.

Conclusions

Edaravone exerts neuroprotective effects on PD model both in vitro and in vivo through the anti-apoptotic effects via the suppression of free radicals with subsequent anti-inflammatory effects. Edaravone might be a safe and hopeful therapeutic option for PD.

Zenobia Therapeutics, Inc. Receives Michael J. Fox Foundation For Parkinson's Research Award For Work On PD-implicated Protein LRRK2

el . Publicado en Investigación Parkinson

July 31, 2008

La Jolla, CA - Zenobia Therapeutics, Inc. (Zenobia) announced recently that it has received a Therapeutics Development Initiative award from The Michael J. Fox Foundation for Parkinson's Research. The program targets industry-based research with potential to fundamentally alter the course of Parkinson's disease (PD) treatment. In collaboration with Dr. Christopher Ross of Johns Hopkins University, Zenobia will discover and develop compounds that block the activity of LRRK2, a protein that is believed to be overactive in PD patients. The goal is to preserve brain function by stopping the effects of the overactivity. If successful, the work could lead to a neuroprotective treatment for PD with potential to slow or stop the course of the disease -- something no currently available therapy has been proven to do. Current treatments alleviate the symptoms but do not attack the underlying disease, or alter its course.

Zenobia will use its fragment-based lead discovery (FBLD) expertise to discover compounds that bind to LRRK2. FBLD is a proven drug discovery approach where fragments of drugs are screened for ability to bind to a target. Fragments will be visualized bound to LRRK2 and evolved into compounds that block its activity. These compounds will be tested for their ability to protect neurons in cell culture, and to reverse effects of the overactive protein in animal models. "I believe Zenobia's methods represent a unique and tremendously exciting approach to drug discovery," said Christopher A. Ross, M.D., Ph.D, Professor of Psychiatry, Neurology and Neuroscience at Johns Hopkins University, and chair of Zenobia's Scientific Advisory Board. "The fragment-based screening method has the potential to identify and develop novel compounds not present in the libraries of large pharmaceutical companies. It also is more likely to identify small ligands with a better chance of good penetration into the brain, making it especially suitable for targeting neurological and psychiatric diseases."

Dr. Ross is a leader in neurodegenerative disease research; he helped to define LRRK2 as a PD target, and is an expert in its biology. As part of the collaboration, Zenobia will have access to cell assays and animal models developed by the Ross laboratory. "We are very excited to combine our expertise in fragment-based lead discovery with the expertise of Dr. Ross," said Vicki Nienaber, Ph.D., President and Founder of Zenobia. "We are a long way from a cure, but we took the first step this week with the help of the Michael J. Fox foundation."

Zenobia's research is focused on debilitating, limited-population diseases that have no cure. Zenobia combines fragment-based lead discovery with the expertise of biologists and clinicians to find treatments for illnesses such as Parkinson's disease, Huntington's disease and Muscular Dystrophy. In the future, Zenobia will focus on psychiatric diseases in parallel with increased understanding of the biology of these diseases.

SOURCE: Zenobia Therapeutics, Inc.

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