Posts tagged substantia nigra
Articles and news from the latest research reports.
Anti-inflammatory drug can prevent neuron loss in Parkinson’s model
An experimental anti-inflammatory drug can protect vulnerable neurons and reduce motor deficits in a rat model of Parkinson’s disease, researchers at Emory University School of Medicine have shown.
The results were published Thursday, July 24 in the Journal of Parkinson’s Disease.
The findings demonstrate that the drug, called XPro1595, can reach the brain at sufficient levels and have beneficial effects when administered by subcutaneous injection, like an insulin shot. Previous studies of XPro1595 in animals tested more invasive modes of delivery, such as direct injection into the brain.
“This is an important step forward for anti-inflammatory therapies for Parkinson’s disease,” says Malu Tansey, PhD, associate professor of physiology at Emory University School of Medicine. “Our results provide a compelling rationale for moving toward a clinical trial in early Parkinson’s disease patients.”
The new research on subcutaneous administration of XPro1595 was funded by the Michael J. Fox Foundation for Parkinson’s Research (MJFF). XPro1595 is licensed by FPRT Bio, and is seeking funding for a clinical trial to test its efficacy in the early stages of Parkinson’s disease.
“We are proud to have supported this work and glad to see positive pre-clinical results,” said Marco Baptista, PhD, MJFF associate director of research programs. “A therapy that could slow Parkinson’s progression would be a game changer for the millions living with this disease, and this study is a step in that direction.”
In addition, Tansey and Yoland Smith, PhD, from Yerkes National Primate Research Center, were awarded a grant this week from the Parkinson’s Disease Foundation to test XPro1595 in a non-human primate model of Parkinson’s.
Evidence has been piling up that inflammation is an important mechanism driving the progression of Parkinson’s disease. XPro1595 targets tumor necrosis factor (TNF), a critical inflammatory signaling molecule, and is specific to the soluble form of TNF. This specificity would avoid compromising immunity to infections, a known side effect of existing anti-TNF drugs used to treat disorders such as rheumatoid arthritis.
“Inflammation is probably not the initiating event in Parkinson’s disease, but it is important for the neurodegeneration that follows,” Tansey says. “That’s why we believe that an anti-inflammatory agent, such as one that counteracts soluble TNF, could substantially slow the progression of the disease.”
Postdoctoral fellow Christopher Barnum, PhD and colleagues used a model of Parkinson’s disease in rats in which the neurotoxin 6-hydroxydopamine (6-OHDA) is injected into only one side of the brain. This reproduces some aspects of Parkinson’s disease: neurons that produce dopamine in the injected side of the brain die, leading to impaired movement on the opposite side of the body.
When XPro1595 is given to the animals 3 days after 6-OHDA injection, just 15 percent of the dopamine-producing neurons were lost five weeks later. That compares to controls in which 55 percent of the same neurons were lost. By reducing dopamine neuron loss with XPro1595, the researchers were also able to reduce motor impairment. In fact, the degree of dopamine cell loss was highly correlated both with the degree of motor impairment and immune cell activation.
When XPro1595 is given two weeks after injection, 44 percent of the vulnerable neurons are still lost, suggesting that there is a limited window of opportunity to intervene.
“Recent clinical studies indicates there is a four or five year window between diagnosis of Parkinson’s disease and the time when the maximum number of vulnerable neurons are lost,” Dr. Tansey says. “If this is true, and if inflammation is playing a key role during this window, then we might be able to slow or halt the progression of Parkinson’s with a treatment like XPro1595.”
(Source: news.emory.edu)
Researchers Show Human Learning Altered by Electrical Stimulation of Dopamine Neurons
Stimulation of a certain population of neurons within the brain can alter the learning process, according to a team of neuroscientists and neurosurgeons at the University of Pennsylvania. A report in the Journal of Neuroscience describes for the first time that human learning can be modified by stimulation of dopamine-containing neurons in a deep brain structure known as the substantia nigra. Researchers suggest that the stimulation may have altered learning by biasing individuals to repeat physical actions that resulted in reward.
"Stimulating the substantia nigra as participants received a reward led them to repeat the action that preceded the reward, suggesting that this brain region plays an important role in modulating action-based associative learning," said co-senior author Michael Kahana, PhD, professor of Psychology in Penn’s School of Arts and Sciences.
Eleven study participants were all undergoing deep brain stimulation (DBS) treatment for Parkinson’s disease. During an awake portion of the procedure, participants played a computer game where they chose between pairs of objects that carried different reward rates (like choosing between rigged slot machines in a casino). The objects were displayed on a computer screen and participants made selections by pressing buttons on hand-held controllers. When they got a reward, they were shown a green screen and heard a sound of a cash register (as they might in a casino). Participants were not told which objects were more likely to yield reward, but that their task was to figure out which ones were “good” options based on trial and error.
When stimulation was provided in the substantia nigra following reward, participants tended to repeat the button press that resulted in a reward. This was the case even when the rewarded object was no longer associated with that button press, resulting in poorer performance on the game when stimulation was given (48 percent accuracy), compared to when stimulation was not given (67 percent).
"While we’ve suspected, based on previous studies in animal models, that these dopaminergic neurons in the substantia nigra - play an important role in reward learning, this is the first study to demonstrate in humans that electrical stimulation near these neurons can modify the learning process," said the study’s co-senior author Gordon Baltuch, MD, PhD, professor of Neurosurgery in the Perelman School of Medicine at the University of Pennsylvania. “This result also has possible clinical implications through modulating pathological reward-based learning, for conditions such as substance abuse or problem gambling, or enhancing the rehabilitation process in patients with neurological deficits.”
(Source: uphs.upenn.edu)
Tell-tail MRI image diagnosis for Parkinson’s disease
An image similar in shape to a Swallow’s tail has been identified as a new and accurate test for Parkinson’s disease. The image, which depicts the healthy state of a group of cells in the sub-region of the human brain, was singled out using 3T MRI scanning technology – standard equipment in clinical settings today.
The research was led by Dr Stefan Schwarz and Professor Dorothee Auer, experts in neuroradiology in the School of Medicine at The University of Nottingham and was carried out at the Queen’s Medical Centre in collaboration with Dr Nin Bajaj, an expert in Movement Disorder Diseases at the Nottingham University Hospitals NHS Trust.
The findings have been published in the open access academic journal PLOS one.
The work builds on a successful collaboration with Professor Penny Gowland at the Sir Peter Mansfield Magnetic Resonance Centre at The University of Nottingham.
‘The ‘Swallow Tail’ Appearance of the Healthy Nigrosome – A New Accurate Test of Parkinson’s Disease: A Case-Control and Retrospective Cross-Sectional MRI Study at 3T’ – describes how the absence of this imaging sign can help to diagnose Parkinson’s disease using standard clinical Magnetic Resonance Scanners.
Parkinson’s disease is a progressive neurodegenerative disorder which destroys brain cells that control movement. Around 127,000 people in the UK have the disease. Currently there is no cure but drugs and treatments can be taken to manage the symptoms.
The challenges of diagnosing Parkinson’s
Until now diagnosing Parkinson’s in clinically uncertain cases has been limited to expensive nuclear medical techniques. The diagnosis can be challenging early in the course of the condition and in tremor dominant cases. Other non-licensed diagnostic techniques offer a varying range of accuracy, repeatability and reliability but none of them have demonstrated the required accuracy and ease of use to allow translation into standard clinical practice.
Using high resolution, ultra high filed 7T magnetic resonance imaging the Nottingham research team has already pinpointed the characteristic pathology of Parkinson’s with structural change in a small area of the mid brain known as the substantia nigra. The latest study has shown that these changes can also be detected using 3T MRI technology which is accessible in hospitals across the country. They subsequently coined the phrase the ‘swallow tail appearance’ as an easy recognizable sign of the healthy appearing substantia nigra which is lost in Parkinson’s disease. A total of 114 high-resolution scans were reviewed and in 94 per cent of cases the diagnosis was accurately made using this technique.
New findings give new hope
Dr Schwarz said: “This is a breakthrough finding as currently Parkinson’s disease is mostly diagnosed by identifying symptoms like stiffness and tremor. Imaging tests to confirm the diagnosis are limited to expensive nuclear medical techniques which are not widely available and associated with potentially harmful ionizing radiation.
“Using Magnetic Resonance Imaging (no ionizing radiation involved and much cheaper than nuclear medical techniques) we identified a specific imaging feature which has great similarity to a tail of a swallow and therefore decided to call it the ‘swallow tail sign’. This sign is absent in Parkinson’s disease.”
Uncovering the underlying causes of Parkinson’s disease
A breakthrough investigation by UTS researchers into the underlying causes of Parkinson’s disease has brought us a step closer to understanding how to manage the condition.
The team, led by UTS postdoctoral fellow Dr Dominic Hare and Professor Philip Doble, has produced the first empirical evidence that an imbalance of iron and dopamine in the substantia nigra pars compacta (SNc) region of the brain is the root cause of the neurodegenerative condition.
Caused by the slow loss of neurons in the SNc that control autonomous movement, Parkinson’s disease causes persistent shaking, gastrointestinal problems and a variety of other ailments.
More than 80,000 Australians suffer from the illness, most over the age of 60.
Hare’s findings, before only assumptions in the scientific community, finally validate the theory that iron and dopamine react to create free radicals in the brain that slowly destroy neuron pathways and bring about the onset of Parkinson’s.
"When these two chemicals react, it forms a toxic species of dopamine that essentially reacts like bleach in the brain," said Hare.
To conduct their research Hare and his team used a unique tagging technique using antibodies labelled with gold nanoparticles that acted as proxies for dopamine molecules. This enabled the team to monitor and “co-localise” metals with other molecules and proteins in the brain.
And the findings of this work, said Hare, were revelatory.
"What we found is those particular cells (in the SNc) have what you could call an ‘anti-Goldilocks effect’ – they have just the right amount of iron and just the right amount of dopamine to cause damage," said Dr Hare.
"When we give mice a toxin that mimics the effects of Parkinson’s disease, these cells degenerate."
Hare theorises that this effect is likely a natural result of aging, when the brain’s ability to securely store iron diminishes and allows iron molecules to “leak” into critical areas such as the SNc.
Finding ways to design drugs that can get into the brain and eliminate surplus iron – an initiative that is already well underway in the process of treating other illnesses like cancer and Alzheimer’s disease – is now the next step forward in research.
Preventative measures to halt the build-up of iron in the brain as humans undergo the aging process are also touted by Hare as an important next step, and is something he is now working on.
"I think the real hope is, while we might not necessarily find a cure, prevention is actually not that far away," said Hare.
"So it’s a case where you can wake up and say, ‘my Parkinson’s is flaring up again’, take a tablet and go about your business."
Putting the brakes on Parkinson’s
The earliest signs of Parkinson’s disease can be deceptively mild. The first thing that movie star Michael J. Fox noticed was twitching of the little finger of his left hand. For years, he made light of the apparently harmless tic. But such tremors typically spread, while muscles stiffen up and directed movements take longer to carry out. Research groups led by Armin Giese of LMU Munich and Christian Griesinger at the Max Planck Institute for Biophysical Chemistry in Göttingen have developed a chemical compound that slows down the onset and progression of Parkinson’s disease in mice. The scientists hope that this approach will give them a way to treat the cause of Parkinson’s and so arrest its progress.
The disease usually becomes manifest between the ages of 50 and 60, and results from the loss of dopamine-producing nerve cells in the substantia nigra, which is part of the midbrain. Under the microscope, the affected cells are seen to contain insoluble precipitates made up of a protein called alpha-synuclein. As an early step in the pathological cascade, this protein forms so-called oligomers, tiny aggregates consisting of small numbers of alpha-synuclein molecules, which are apparently highly neurotoxic. By the time the first overt symptoms appear in humans, more than half of the vulnerable cells have already been lost. Many researchers therefore focus on developing methods for early diagnosis of the condition. However, current therapies only alleviate symptoms, so the research teams led by Armin Giese and Christian Griesinger set out to address the underlying cause of nerve-cell death.
Together, the scientists have developed a substance which, in mouse models of the disease, reduces the rate of growth of the protein deposits and delays nerve cell degeneration to a yet unprecedented degree. As a consequence, mice treated with this agent remain disease-free for longer than non-medicated controls. “The most striking feature of the new compound is that it is the first that directly targets oligomers and interferes with their formation,” explains Christian Griesinger, head of the Department of NMR-based Structural Biology and Director at the Max Planck Institute for Biophysical Chemistry. The discovery is the result of years of hard work. “Combining skills from a range of disciplines has been the key to our success. Biologists, chemists, clinicians, physicists, and veterinarians have all contributed to the development of the therapeutic compound,” adds Armin Giese, who leads a research group at LMU’s Center for Neuropathology and Prion Research.
Giese and his colleagues systematically tested 20,000 candidate substances for the ability to block formation of the protein deposits that are typical for the disease. The screen made use of an extremely sensitive laser-based assay developed by Giese years ago when he was working together with Nobel Laureate Manfred Eigen at the Max Planck Institute for Biophysical Chemistry in Göttingen. Some interesting lead compounds identified during the very first phase of the screening program served as starting point for further optimization. Ultimately, one substance proved to be particularly active. Andrei Leonov a chemist in Griesinger’s team, finally succeeded in synthesizing a pharmaceutically promising derivative. This is well tolerated at dosage levels with significant therapeutic effects, can be administered with the food, and penetrates the blood-brain barrier, reaching high levels in the brain. The two teams have already applied for a patent on the compound which they called Anle138b – an abbreviation of Andrei Leonov’s first name and surname.
A complex series of experiments has provided encouraging indications that Anle138b could also be of therapeutic use in humans. These tests involved not only biochemical and structural investigations of Anle138b’s mode of action but also employed several animal models of Parkinson’s which are under study in Munich and in laboratories of the Excellence Cluster “Nanoscale Microscopy and Molecular Physiology of the Brain” in Göttingen. Mice exposed to Anle138b were found to display better motor coordination than their untreated siblings. “We use a kind of fitness test to evaluate muscle coordination,” Giese explains. “The mice are placed on a rotating rod and we measure how long the animals can keep their balance.”
Generally speaking, the earlier the onset of treatment, the longer the animals remained disease free. What’s more, the beneficial effects of Anle138b are not restricted to animals with Parkinson’s disease. “Creutzfeldt-Jakob disease is caused by toxic aggregates of the prion protein,” Griesinger points out. “And here too, Anle138b effectively inhibits clumping and significantly increases survival times.” These findings hint that Anle138b might also prevent the formation of insoluble deposits formed by other proteins, such as the tau protein that is associated with Alzheimer’s disease. Further experiments will address this issue. Anle138b will therefore be a useful research tool in medicine, as it will enable scientists to study the process of oligomer formation in the test-tube and to determine how their assembly is inhibited. The researchers hope ultimately to gain new insights into the mechanisms into how neurodegenerative disorders develop.
The drugs so far available for treatment of Parkinson’s disease only control its symptoms by enhancing the function of the surviving nerve cells in the substantia nigra. “With Anle138b, we may have the first representative of a new class of neuroprotective agents allowing to retard or even halt the progression of conditions such as Parkinson’s or Creutzfeldt-Jakob disease,” Griesinger says. However, he warns that the findings in mice cannot immediately be applied to humans. The next step will be to carry out toxicity tests in non-rodent species. Only if these are successful will clinical trials in patients become a realistic possibility. As clinician Giese emphasizes: “To successfully establish a novel therapeutic agent for treatment of real patients is a laborious task that requires a lot of work as well as serendipity.”
A noninvasive avenue for Parkinson’s disease gene therapy
Researchers at Northeastern University in Boston have developed a gene therapy approach that may one day stop Parkinson’s disease (PD) in it tracks, preventing disease progression and reversing its symptoms. The novelty of the approach lies in the nasal route of administration and nanoparticles containing a gene capable of rescuing dying neurons in the brain. Parkinson’s is a devastating neurodegenerative disorder caused by the death of dopamine neurons in a key motor area of the brain, the substantia nigra (SN). Loss of these neurons leads to the characteristic tremor and slowed movements of PD, which get increasingly worse with time. Currently, more than 1% of the population over age 60 has PD and approximately 60,000 Americans are newly diagnosed every year. The available drugs on the market for PD mimic or replace the lost dopamine but do not get to the heart of the problem, which is the progressive loss of the dopamine neurons.
The focus of Dr. Barbara Waszczak’s lab at Northeastern University in Boston is to find a way to harvest the potential of glial cell line-derived neurotrophic factor (GDNF) as a treatment for PD. GDNF is a protein known to nourish dopamine neurons by activating survival and growth-promoting pathways inside the cells. Not surprisingly, GDNF is able to protect dopamine neurons from injury and restore the function of damaged and dying neurons in many animal models of PD. However, the action of GDNF is limited by its inability to cross the blood-brain barrier (BBB), thus requiring direct surgical injection into the brain. To circumvent this problem, Waszczak’s lab is investigating intranasal delivery as a way to bypass the BBB. Their previous work showed that intranasal delivery of GDNF protects dopamine neurons from damage by the neurotoxin, 6-hydroxydopamine (6-OHDA), a standard rat model of PD.
Taking this work a step further, Brendan Harmon, working in Waszczak’s lab, has adapted the intranasal approach so that cells in the brain can continuously produce GDNF. His work utilized nanoparticles, developed by Copernicus Therapeutics, Inc., which are able to transfect brain cells with an expression plasmid carrying the gene for GDNF (pGDNF). When given intranasally to rats, these pGDNF nanoparticles increase GDNF production throughout the brain for long periods, avoiding the need for frequent re-dosing. Now, in new research presented on April 20 at 12:30 pm during Experimental Biology 2013 in Boston, MA, Harmon reports that intranasal administration of Copernicus’ pGDNF nanoparticles results in GDNF expression sufficient to protect SN dopamine neurons in the 6-OHDA model of PD.
Waszczak and Harmon believe that intranasal delivery of Copernicus’ nanoparticles may provide an effective and non-invasive means of GDNF gene therapy for PD, and an avenue for transporting other gene therapy vectors to the brain. This work, which was funded in part by the Michael J. Fox Foundation for Parkinson’s Research and Northeastern University, has the potential to greatly expand treatment options for PD and many other central nervous system disorders.
(Source: eurekalert.org)
Shedding Light on Early Parkinson’s Disease Pathology
In a mouse model of early Parkinson’s disease (PD), animals displayed movement deficits, loss of tyrosine-hydroxylase (TH)-positive fibers in the striatum, and astro-gliosis and micro-gliosis in the substantia nigra (SN), without the loss of nigral dopaminergic neurons. These findings, which may cast light on the molecular processes involved in the initial stages of PD, are available in the current issue of Restorative Neurology and Neuroscience.
“The most intriguing finding of our study was the lack of a significant decrease of TH levels in the SN of the low-dose MPTP-treated mice, suggesting that this treatment does not induce a direct loss of nigral dopaminergic neurons,” says Joost Verhaagen PhD, lead investigator of the study. “These findings appear to support the ‘dying back’ hypothesis of PD, which proposes that the TH-positive terminal loss in the striatum is the first neurodegenerative event in PD, which later induces neuronal degeneration in the SN.” Dr. Verhaagen is Head of the Workgroup on Neuroregeneration at the Netherlands Institute for Neuroscience and Professor at the Free University in Amsterdam.
The neurotoxin MPTP (1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine) was used to induce the degenerative changes. Chronic 5 week administration of 25 mg/kg MPTP combined with probenecid (250 mg/kg), which inhibits MPTP clearance and promotes its crossing of the blood-brain barrier, is known to cause dopaminergic neuron degeneration in the SN and decrease striatal dopaminergic nerve terminals. In the current study, 7 mice were treated with 25 mg/kg MPTP plus probenecid, 6 mice received a lower dose of MPTP (15 mg/kg) plus probenecid, and 8 control mice received saline plus probenecid. A grid test, known to be sensitive to striatal dopaminergic input, was used to detect motor deficits.
Immunohistochemical analysis using TH fluorescence revealed that only the higher dose of MPTP produced significant dopaminergic neuronal cell loss in the SN (65% fluorescence loss, p<0.001). The 15 mg/kg dose produced an 18% decline in fluorescence which was not significantly different than control.
Both dose levels significantly reduced TH immunoreactivity of the striatum. The authors believe that the motor deficits seen at both MPTP dose levels relate to the striatal dopamine depletion.
The study is also the first to report that low-dose MPTP produces astrogliosis and microgliosis in the SN and formation of α-synuclein positive inclusions. “The data suggests that gliosis in the substantia nigra plays a prominent initiating role in the introduction of dopaminergic deficits after MPTP treatment, and may be sufficient to significantly reduce TH levels in the striatum,” says Dr. Korecka, first author and principal investigator of the study and a post-doctoral fellow at the Netherlands Institute for Neuroscience in Amsterdam.
“We are the first to report that this early PD model provides an interesting window of opportunity to study the mechanisms that underlie the early neurodegenerative events that initiate the cellular death of dopaminergic neurons,” write the authors. They suggest that the model can be used to develop potential treatment strategies to counteract early PD cellular changes.
(Image: iStock)
Breaking down the Parkinson’s pathway
The key hallmark of Parkinson’s disease is a slowdown of movement caused by a cutoff in the supply of dopamine to the brain region responsible for coordinating movement. While scientists have understood this general process for many years, the exact details of how this happens are still murky.
“We know the neurotransmitter, we know roughly the pathways in the brain that are being affected, but when you come right down to it and ask what exactly is the sequence of events that occurs in the brain, that gets a little tougher,” says Ann Graybiel, an MIT Institute Professor and member of MIT’s McGovern Institute for Brain Research.
A new study from Graybiel’s lab offers insight into some of the precise impairments caused by the loss of dopamine in brain cells affected by Parkinson’s disease. The findings, which appear in the March 12 online edition of the Journal of Neuroscience, could help researchers not only better understand the disease, but also develop more targeted treatments.
The neurons responsible for coordinating movement are located in a part of the brain called the striatum, which receives information from two major sources — the neocortex and a tiny region known as the substantia nigra. The cortex relays sensory information as well as plans for future action, while the substantia nigra sends dopamine that helps to coordinate all of the cortical input.
“This dopamine somehow modulates the circuit interactions in such a way that we don’t move too much, we don’t move too little, we don’t move too fast or too slow, and we don’t get overly repetitive in the movements that we make. We’re just right,” Graybiel says.
Parkinson’s disease develops when the neurons connecting the substantia nigra to the striatum die, cutting off a critical dopamine source; in a process that is not entirely understood, too little dopamine translates to difficulty initiating movement. Most Parkinson’s patients receive L-dopa, which can substitute for the lost dopamine. However, the effects usually wear off after five to 10 years, and complications appear.