Visualizzazione post con etichetta parkinson. Mostra tutti i post
Visualizzazione post con etichetta parkinson. Mostra tutti i post
mercoledì 1 maggio 2013
Connection Between Inflammatory Stimulus and Parkinson's Disease Examined
From ScienceDaily website
Apr. 29, 2013 — Parkinson's disease (PD) is a progressive degenerative disease affecting a person's ability to coordinate and control their muscle movement.
What starts out as a tremor in a finger will eventually lead to difficulty in writing and speaking, and ultimately the inability to walk without assistance.
Since the 1950s research has shown that people with Parkinson's have decreased levels of the chemical dopamine in their brains, which is involved in sending messages to the part of the brain that controls coordination and movement.
Subsequent research has found that dopamine-generating cells, known as dopaminergic neurons, are also absent in a specific area of the brain in those with PD.
The precise cause or causes of PD is unknown, but there is a consensus that an inflammatory event or episode is involved in the initiation of neurodegeneration, and that chronic neuroinflammation is a sustaining and exacerbating reason for the loss of the dopaminergic neurons.
A new study conducted by a team of Texas researchers brings the understanding of inflammation's role a step further.
They have found that a single, high-dose exposure of an experimental inflammatory agent in an animal model causes changes in brain tissue that are similar to those associated with the development of the disease.
The study was conducted by Roger Bick and his colleagues Marie-Francoise Doursout, Michael S. Schurdell, Lauren M. Young, Uzondu Osuagwu, Diana M. Hook, Brian J. Poindexter, Mya C. Schiess, and Diane L. M. Bick, all at The University of Texas Health Science Center at Houston (UTHealth), Houston, TX.
Dr. Schiess presented the team's findings at last week's Experimental Biology 2013 meeting, held at the Boston Convention and Exhibition Center, Boston, Mass.
Their poster presentation was entitled, "Inflammatory cells and cytokines in the olfactory bulb of a rat model of neuroinflammation; Insights into neurodegeneration?" The full study will appear in an upcoming edition of the Journal of Interferon & Cytokine Research.
Methodology
In the study, the researchers examined inflammatory cell and cytokine production in brain tissue from a lipopolysaccharide (LPS)-treated rat model that mimics many of the neuropathologic changes associated with PD.
Concurrently, they monitored the appearance of glial cell line-derived neurotrophic factor (GDNF), a neuronal protective agent, and circulating nitric oxide (NO) levels. They also examined the immune system associated cells in the olfactory bulb of the brain. It is known that Parkinson's starts with this mechanism.
Twelve male Sprague-Dawley rats were treated with intravenous LPS in saline, 12 control rats were treated with saline, and all were maintained for up to 48 hours before euthanasia and brain removal.
Brains were removed from both groups at defined times, blood and other tests were conducted, and images of various sections of the brain, including the olfactory bulb, cortex and cerebellum, were taken using fluorescent microscopy.
Results and Conclusions
In general, the researchers found that a single injection of LPS elicited a systemic inflammatory response in the rats, as indicated by an elevation in certain circulatory cytokines. Tissue taken from the olfactory bulb showed the presence of immune associated cells.
Individual cytokines within the olfactory bulb showed an increase in certain types of cytokines.
Taken together, the complete analysis indicated that the single dose of LPS stimulated an inflammatory response that closely resembled the hallmarks of the development of the disease.
The results suggest an involvement of both the peripheral and the central nervous system immune components in response to inflammation and inflammatory episodes.
As a result, the researchers suggest:
(1) inflammation initiates an immune response;
(2) the presence of continuing and increasing pro-inflammatory mechanisms results in a process whereby cellular protective mechanisms are overcome and the more susceptible cells, such as the dopaminergic neurons, enter into cell death pathways; and
(3) this leads to a series of events that are a key part of the progression of PD.
Next Steps
Neuroinflammation is a significant problem for those with PD, and it persists throughout the course of this debilitating illness.
Understanding of the essential processes behind it is the best pathway to finding therapeutic approaches to address it.
This study highlights an opportunity to better understand the role inflammation plays in the process.
martedì 8 gennaio 2013
Pesticides and Parkinson's: Further Proof of a Link Uncovered
From Science Daily website (see original article).
Jan. 3, 2013 — For several years, neurologists at UCLA have been building a case that a link exists between pesticides and Parkinson's disease. To date, paraquat, maneb and ziram -- common chemicals sprayed in California's Central Valley and elsewhere -- have been tied to increases in the disease, not only among farmworkers but in individuals who simply lived or worked near fields and likely inhaled drifting particles.
Now, UCLA researchers have discovered a link between Parkinson's and another pesticide, benomyl, whose toxicological effects still linger some 10 years after the chemical was banned by the U.S. Environmental Protection Agency.
Even more significantly, the research suggests that the damaging series of events set in motion by benomyl may also occur in people with Parkinson's disease who were never exposed to the pesticide, according to Jeff Bronstein, senior author of the study and a professor of neurology at UCLA, and his colleagues.
Benomyl exposure, they say, starts a cascade of cellular events that may lead to Parkinson's. The pesticide prevents an enzyme called ALDH (aldehyde dehydrogenase) from keeping a lid on DOPAL, a toxin that naturally occurs in the brain. When left unchecked by ALDH, DOPAL accumulates, damages neurons and increases an individual's risk of developing Parkinson's.
The investigators believe their findings concerning benomyl may be generalized to all Parkinson's patients. Developing new drugs to protect ALDH activity, they say, may eventually help slow the progression of the disease, whether or not an individual has been exposed to pesticides.
The research is published in the current online edition of Proceedings of the National Academy of Sciences.
Parkinson's disease is a debilitating neurodegenerative disorder that affects millions worldwide. Its symptoms -- including tremor, rigidity, and slowed movements and speech -- increase with the progressive degeneration of neurons, primarily in a part of the mid-brain called the substantia nigra. This area normally produces dopamine, a neurotransmitter that allows cells to communicate, and damage to the mid-brain has been linked to the disease. Usually, by the time Parkinson's symptoms manifest themselves, more than half of these neurons, known as dopaminergic neurons, have already been lost.
While researchers have identified certain genetic variations that cause an inherited form of Parkinson's, only a small fraction of the disease can be blamed on genes, said the study's first author, Arthur G. Fitzmaurice, a postdoctoral scholar in Bronstein's laboratory.
"As a result, environmental factors almost certainly play an important role in this disorder," Fitzmaurice said. "Understanding the relevant mechanisms -- particularly what causes the selective loss of dopaminergic neurons -- may provide important clues to explain how the disease develops."
Benomyl was widely used in the U.S. for three decades until toxicological evidence revealed it could potentially lead to liver tumors, brain malformations, reproductive effects and carcinogenesis. It was banned in 2001.
The researchers wanted to explore whether there was a relationship between benomyl and Parkinson's, which would demonstrate the possibility of long-lasting toxicological effects from pesticide use, even a decade after chronic exposure. But because a direct causal relationship between the pesticide and Parkinson's can't be established by testing humans, the investigators sought to determine if exposure in experimental models could duplicate some of the pathologic features of the disease.
They first tested the effects of benomyl in cell cultures and confirmed that the pesticide damaged or destroyed dopaminergic neurons.
Next, they tested the pesticide in a zebrafish model of the disease. This freshwater fish is commonly used in research because it is easy to manipulate genetically, it develops rapidly and it is transparent, making the observation and measurement of biological processes much easier. By using a fluorescent dye and counting the neurons, the researchers discovered there was significant neuron loss in the fish -- but only to the dopaminergic neurons. The other neurons were left unaffected.
Until now, evidence had pointed to one particular culprit -- a protein called α-synuclein -- in the development of Parkinson's. This protein, common to all Parkinson's patients, is thought to create a pathway to the disease when it binds together in "clumps" and becomes toxic, killing the brain's neurons.
The identification of ALDH activity now gives researchers another target to focus on in trying to stop this disease.
"We've known that in animal models and cell cultures, agricultural pesticides trigger a neurodegenerative process that leads to Parkinson's," said Bronstein, who directs the UCLA Movement Disorders Program. "And epidemiologic studies have consistently shown the disease occurs at high rates among farmers and in rural populations. Our work reinforces the hypothesis that pesticides may be partially responsible, and the discovery of this new pathway may be a new avenue for developing therapeutic drugs."
Other authors of the study included Lisa Barnhill, Hoa A. Lam, Aaron Lulla, Nigel T. Maidment, Niall P. Murphy, Kelley C. O'Donnell, Shannon L. Rhodes, Beate Ritz, Alvaro Sagastig and Mark C. Stahl, all of UCLA; John E. Casida of UC Berkeley; and Myles Cockburn of the University of Southern California. The authors declare no conflict of interest.
Jan. 3, 2013 — For several years, neurologists at UCLA have been building a case that a link exists between pesticides and Parkinson's disease. To date, paraquat, maneb and ziram -- common chemicals sprayed in California's Central Valley and elsewhere -- have been tied to increases in the disease, not only among farmworkers but in individuals who simply lived or worked near fields and likely inhaled drifting particles.
Now, UCLA researchers have discovered a link between Parkinson's and another pesticide, benomyl, whose toxicological effects still linger some 10 years after the chemical was banned by the U.S. Environmental Protection Agency.
Even more significantly, the research suggests that the damaging series of events set in motion by benomyl may also occur in people with Parkinson's disease who were never exposed to the pesticide, according to Jeff Bronstein, senior author of the study and a professor of neurology at UCLA, and his colleagues.
Benomyl exposure, they say, starts a cascade of cellular events that may lead to Parkinson's. The pesticide prevents an enzyme called ALDH (aldehyde dehydrogenase) from keeping a lid on DOPAL, a toxin that naturally occurs in the brain. When left unchecked by ALDH, DOPAL accumulates, damages neurons and increases an individual's risk of developing Parkinson's.
The investigators believe their findings concerning benomyl may be generalized to all Parkinson's patients. Developing new drugs to protect ALDH activity, they say, may eventually help slow the progression of the disease, whether or not an individual has been exposed to pesticides.
The research is published in the current online edition of Proceedings of the National Academy of Sciences.
Parkinson's disease is a debilitating neurodegenerative disorder that affects millions worldwide. Its symptoms -- including tremor, rigidity, and slowed movements and speech -- increase with the progressive degeneration of neurons, primarily in a part of the mid-brain called the substantia nigra. This area normally produces dopamine, a neurotransmitter that allows cells to communicate, and damage to the mid-brain has been linked to the disease. Usually, by the time Parkinson's symptoms manifest themselves, more than half of these neurons, known as dopaminergic neurons, have already been lost.
While researchers have identified certain genetic variations that cause an inherited form of Parkinson's, only a small fraction of the disease can be blamed on genes, said the study's first author, Arthur G. Fitzmaurice, a postdoctoral scholar in Bronstein's laboratory.
"As a result, environmental factors almost certainly play an important role in this disorder," Fitzmaurice said. "Understanding the relevant mechanisms -- particularly what causes the selective loss of dopaminergic neurons -- may provide important clues to explain how the disease develops."
Benomyl was widely used in the U.S. for three decades until toxicological evidence revealed it could potentially lead to liver tumors, brain malformations, reproductive effects and carcinogenesis. It was banned in 2001.
The researchers wanted to explore whether there was a relationship between benomyl and Parkinson's, which would demonstrate the possibility of long-lasting toxicological effects from pesticide use, even a decade after chronic exposure. But because a direct causal relationship between the pesticide and Parkinson's can't be established by testing humans, the investigators sought to determine if exposure in experimental models could duplicate some of the pathologic features of the disease.
They first tested the effects of benomyl in cell cultures and confirmed that the pesticide damaged or destroyed dopaminergic neurons.
Next, they tested the pesticide in a zebrafish model of the disease. This freshwater fish is commonly used in research because it is easy to manipulate genetically, it develops rapidly and it is transparent, making the observation and measurement of biological processes much easier. By using a fluorescent dye and counting the neurons, the researchers discovered there was significant neuron loss in the fish -- but only to the dopaminergic neurons. The other neurons were left unaffected.
Until now, evidence had pointed to one particular culprit -- a protein called α-synuclein -- in the development of Parkinson's. This protein, common to all Parkinson's patients, is thought to create a pathway to the disease when it binds together in "clumps" and becomes toxic, killing the brain's neurons.
The identification of ALDH activity now gives researchers another target to focus on in trying to stop this disease.
"We've known that in animal models and cell cultures, agricultural pesticides trigger a neurodegenerative process that leads to Parkinson's," said Bronstein, who directs the UCLA Movement Disorders Program. "And epidemiologic studies have consistently shown the disease occurs at high rates among farmers and in rural populations. Our work reinforces the hypothesis that pesticides may be partially responsible, and the discovery of this new pathway may be a new avenue for developing therapeutic drugs."
Other authors of the study included Lisa Barnhill, Hoa A. Lam, Aaron Lulla, Nigel T. Maidment, Niall P. Murphy, Kelley C. O'Donnell, Shannon L. Rhodes, Beate Ritz, Alvaro Sagastig and Mark C. Stahl, all of UCLA; John E. Casida of UC Berkeley; and Myles Cockburn of the University of Southern California. The authors declare no conflict of interest.
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