July 27, 2012 § Leave a comment
Parkinson’s disease is an incurable, progressive neurodegenerative disorder that affects 1 million Americans, and between 50,000 and 60,000 new cases are found annually. It is the second most common neurodegenerative disease after Alzheimer’s. It results in slowness of movement, rigidity, and tremors. PD is known to instigate cell loss, which often results in mild to acute brain damage.
Lithium has long been the gold standard for treatment of bipolar disorder. Now scientists at the Buck Institute for Research on Aging have discovered through rodent experimentation that Lithium also profoundly prevents the toxic protein aggregation that causes PD-related brain damage. Researchers at the Buck Institute are now ready to move into the preclinical stage to determine the correct dosages for the drug.
According to the June 24th edition of the Journal of Neuroscience Research, Buck researchers are working towards a Phase II human clinical study, using Lithium in concurrence with customary PD therapy. Lead author, Professor Julie Anderson, Ph.D., explains, “The fact that Lithium’s safety profile in humans is well understood greatly reduces trial risk.” Anderson explains that Lithium has significant anti-aging effects in animals. She mentions that, in contrast to the neurodegenerative properties of conditions such as Huntington’s disease, Alzheimer’s disease, and Amyotrophical Lateral Sclerosis, Lithium has recently been suggested to be neuroprotective.
Although overuse of Lithium has been known to cause hyperthyroidism and kidney toxicity, low dosages of the drug were given to the mice used in the Buck experimentation. Anderson remarks, “The possibility that Lithium could be effective in PD patients at subclinical levels is exciting, because it would avoid many side effects associated at the higher dose range.”
Although the Buck Institute’s research is still pre-clinical, success in previous experiments regarding the use of Lithium in humans is a predictor of future success in the case of patients with PD. In fact, research shows that many PD patients are already using Lithium, “off label,” in conjunction with their normal PD treatment regime. Also, Lithium salt supplements are available in some health food stores.
The familiarity of Lithium provides a better chance for the Buck Institute’s exploration with the drug. As Anderson explains, Lithium’s popularity, “lowers a significant hurdle to getting it into the clinic.”
“Lithium Profoundly Prevents Brain Damage Associated with Parkinson’s Disease”. (June 24, 2011). Neuroscience News. February 15, 2012. http://neurosciencenews.com/lithium-prevents-brain-damage-parkinsons-disease/.
July 4, 2012 § 2 Comments
Parkinson’s Disease is a neurological disorder that affects millions of people worldwide. Although many effective treatments have been developed, none have proven successful in slowing its progression.
The cause of Parkinson’s is as of yet unknown, but a protein called α-synuclein is thought to be the culprit. This protein is found in all Parkinson’s patients. Its tendency to collect together in the brain forms toxic clumps that destroy brain neurons.
In an experiment published in the online edition of the journal Neurotherapeutics, scientists at UCLA have discovered a way to break up these aggregates and prevent the proteins from clumping in the first place. Jeff Bronstein, UCLA professor of neurology, along with Gal Bitan, associate UCLA professor of neurology, and their colleagues, have developed a new compound that they call a “molecular tweezer”.
The UCLA tweezer compound is able to prevent the protein clumps from forming, stop them from becoming toxic, and are also able to break up the clumps that have already accumulated, all without hampering normal brain function.
Protein aggregation is the cause of many diseases for which there is no cure. Alzheimer’s, Parkinson’s, and Type 2 Diabetes are all the result of protein aggregation. If doctors are able to prevent the clumping altogether, they can prevent these diseases from forming, without having to find a cure. The difficulty with finding a therapy that targets only protein aggregates is due to the natural ubiquity of α-synuclein all through the brain. The aggregation and toxicity of α-synuclein must be prevented, but not α-synuclein’s regular functioning. Bronstein believes this protein aids communication between neurons, but this is mere speculation.
The compound developed through the Bronstein-Bitan collaboration – CLR01 – was very successful at attacking the targeted aggregates and leaving other normal brain functions untouched. Bronstein explains, “The most surprising aspect of the work is that despite the ability of the compound to bind to many proteins, it did not show toxicity or side effects to normal, functioning brain cells.” Bitan added, “We call this unique mechanism ‘process-specific,’ rather than the common protein-specific inhibition.”
The next step for the researchers was to try the compound in a living organism. They tested it on the zebrafish. This fish is common for animal research because it can be easily genetically manipulated, develops rapidly, and it is transparent, making observation and measurement a simple task.
The researchers used a transgenic zebrafish and used fluorescent proteins to track the added CLR01’s effects on the aggregates. Indeed, the tweezer prevented α-synuclein aggregation and, by extension, neural death. This halted the progression of Parkinson’s in the live animal model. Bronstein says, “CLR01 holds great promise as a new drug that can slow or stop the progression of Parkinson’s and related disorders. This takes us one step closer to a cure.”
Researchers are currently studying the CLR01 in a mouse model of Parkinson’s. Each new animal species trial takes them one step closer to human clinical trials, along the path to finding a cure.
“Parkinson’s Disease Stopped in Animal Model”. (March 2, 2012). Neuroscience News. March 8, 2012. http://neurosciencenews.com/parkinsons-disease-stopped-animal-model-clr01/.
May 4, 2012 § Leave a comment
A report published in the March 2 issue of Cell reveals a finding that may link microRNAs to memory and the learning process in general. Scientists at the John Hopkins University School of Medicine studied genetic material that controls protein formation in the brain and found that certain microRNAs control the actions of brain-derived neurotrophic factor (BDNF), which are linked to brain cell survival, learning, and memory boosting. These findings implicate that the use of a drug meant to enhance this function may prevent the mental illness that results from brain wasting diseases such as Huntington’s, Alzheimer’s, and Parkinson’s disease.
BDNF, a growth-factor protein, is released in the hippocampus during the learning process. This protein increases the activity of other proteins involved in memory formation, but only increases production of less than 4% of the brain cell proteins. Mollie K. Meffert, M.D., Ph.D., associate professor of biological chemistry and neuroscience at John Hopkins was determined to find out how BDNF decides which proteins to stimulate, and what is the role of the regulatory microRNAs – small molecules that block protein blueprint messages from being transferred to proteins by binding to them. Too many of these within a cell will halt protein production. Likewise, a loss of certain microRNAs will cause a higher production of proteins.
The researchers compared microRNA levels in the brain cells treated with BDNF to those left untreated. The former had lower levels of microRNAs, suggesting that BDNF controls the levels of these microRNAs, in turn affecting protein production. The microRNAs that were disappearing in the presence of BDNF were all Let-7 microRNAs.
The team then genetically engineered neurons that would stop decreasing Let-7 microRNAs to see if the loss of Let-7 microRNAs would cause BDNF to increase production of proteins. Treating the neurons with the BDNF no longer resulted in decreased microRNA levels (or increased learning and memory proteins). The researchers also found more than 174 microRNAs that increased due to the BDNF therapy, suggesting it may also increase other microRNAs, possibly decreasing the production of proteins that need to be decreased in learning and memory formation.
To confirm these findings, the researchers observed living brain cells to find out how brain messaging responds to the BDNF. The ones that are never translated into the production of proteins can build up within cells. The researchers observed through microscope a lab dish that contained brain cells that had been denoted with a fluorescent molecule. This labeled the formations with glowing spots. Those cells treated with BDNF cells increased in size and number, indicated by the glowing spots. The researchers learned that BDNF uses the microRNA to deliver messages to the spots, where they can be dispelled from the translating apparatus that renders them into proteins.
Meffert said, “Monitoring these fluorescent complexes gave us a window that we needed to understand how BDNF is able to target the production of only certain proteins that help neurons to grow and make learning possible.” He goes on to say that because the team is now aware of how BDNF increases proteins involved in learning and memory formation, they will be able to explore a possible therapy targeted to improve the mechanism in order to treat patients with mental disorders and neurodegenerative diseases.
“Making Memories: How 1 Protein Does It”. (March 5, 2012). Neuroscience News. March 9, 2012. http://neurosciencenews.com/bdnf-micro-rna-protein-making-memories/.
March 31, 2012 § Leave a comment
According to a study issued in March’s edition of Archives of Neurology, one of the JAMA Archives journals, the regular use of cholesterol-lowering statin drugs might modestly reduce the risk of the development of Parkinson’s disease.
Statins are one of the most commonly issued classes of drugs in the United States. Many researchers think the anti-inflammatory and immunomodulating effects of statins might be neuroprotective. But they also have adverse effects on lowering the level of plasma coenzyme Q10, which may be neuroprotective in Parkinson’s patients.
Xiang Gao, M.D., Ph.D., of Brigham and Women’s Hospital and Harvard School of Public Health, Boston, and colleagues embarked upon a probable study that included 38,192 men and 90,874 women participating in the Health Professional Follow-up study and the Nurses’ Health study.
During the follow up, from 1994-2006, the researchers documented 644 occurrences (388 in women and 306 in men.)
The researchers explained, “In summary, we observed an association between regular use of statins and lower risk of developing PD, particularly among younger patients. However, our results should be interpreted with caution because only approximately 70 percent of users of cholesterol-lowering drugs at baseline were actual statin users. Further, the results were only marginally significant and could be due to chance.”
The researchers found that, because they had previously classified the use of any cholesterol-lowering drugs before 2000 as “statin use,” some misclassification occurred. They also failed to collect information on the use of each specific statin, each of which could have different effects on the central nervous system.
However, the researchers did observe a noteworthy interface between statin usage and age concerning PD risk. It was recognized in those study participants below the age of 60 at the start of the follow-up, but not among those older than 60.
Authors also wrote that these epidemiologic studies result in mixed outcomes regarding statin use and PD risk, and also noted that statins might have adverse effects on the central nervous system.
Authors concluded, “In contrast with use of ibuprofen, which has been consistently found to be inversely associated with PD risk in these cohorts as well as in other longitudinal studies, the overall epidemiological evidence relating stain use to PD risk remains unconvincing. Given the potential adverse effects of statins, further prospective observational studies are needed to explore the potential effects of different subtypes of statin on risk of PD and other neurodegenerative diseases.”
“Statin Use Appears Associated with Modest Reduction in Parkinson Disease Risk”. (March 12, 2012). Neuroscience News. March 18, 2012. http://neurosciencenews.com/ statin-use-reduction-parkinson-disease-risk/.