Parkinson’s disease pathogenesis is reduced in a rat model using a cell-signaling inhibitor drug
By Jeff Hansen
UAB Media Relations
Results show that JAK/STAT pathway inhibitors may be a new class of therapeutic treatments for patients with Parkinson’s disease. Acting by reducing inflammation, they prevent neurodegeneration in animal models and may be an important new approach to slow progression of the disease.
Etty “Tika” Benveniste
University of Alabama at Birmingham researchers report the first documentation that suppressing a key cell-signaling pathway in a rat model of Parkinson’s disease reduces pathogenesis. Oral administration of AZD1480 — one of the JAK/STAT pathway inhibitors generally known as Jakinibs — lessened the destructive inflammation and nerve cell degradation in the area of the brain affected by Parkinson’s.
At present, there are no therapies available to patients to prevent progression of Parkinson’s disease, the chronic neurodegenerative movement disorder marked by profound loss of dopamine-producing neurons in the brain.
“We believe Jakinibs may become a viable therapeutic option for Parkinson’s disease patients,” said Etty “Tika” Benveniste, Ph.D., professor in the Department of Cell, Developmental and Integrative Biology and lead author of a paper published May 4 in The Journal of Neuroscience. “They are already being studied for other conditions, are orally bioavailable, seem to be well-tolerated, and do not promote troublesome immunosuppression. Furthermore, there may also be other ways of targeting the JAK/STAT pathway as a neuroprotective therapy for neurodegenerative disease.”
A variety of Jakinibs are in Phase I, II or III clinical trials for several other diseases. The current UAB study, funded by the Michael J. Fox Foundation for Parkinson Research and the National Institutes of Health, is the first to show that disrupting the JAK/STAT pathway prevents the neuroinflammation and neurodegradation specific to Parkinson’s disease.
“This is a very important advance,” said David Standaert, M.D., Ph.D., professor and chair of the UAB Department of Neurology and a collaborator on the project. “It shows that anti-inflammatory strategies have real potential. The next steps will be to validate some of the inflammatory changes seen in the animals in patients with Parkinson’s disease, which in turn will enable planning of clinical studies of anti-inflammatory therapies in patients with Parkinson’s.”
|“This is a very important advance. It shows that anti-inflammatory strategies have real potential. The next steps will be to validate some of the inflammatory changes seen in the animals in patients with Parkinson’s disease, which in turn will enable planning of clinical studies of anti-inflammatory therapies in patients with Parkinson’s.” — David Standaert, M.D., Ph.D.|
Benveniste and Standaert are part of an interdisciplinary UAB team focusing on neuroinflammatory mechanisms in Parkinson’s disease. The group — co-led by Benveniste, Standaert and Andrew West, Ph.D., associate professor of neurology — seeks to understand how the body’s immune system contributes to the pathology seen in the brains of Parkinson’s disease patients and to the development and progression of the disease. Only recently have researchers begun to suspect an important role for inflammation in the disease, and this is still largely uncharted territory.For the current paper, UAB researchers, led by Hongwei Qin, Ph.D., associate professor of cell, developmental and integrative biology, either challenged rat immune cells in vitro with aggregated human α-synuclein, or induced overexpression of α-synuclein carried by a virus vector in brains of rats. Untreated, this in vivo model leads to neuroinflammation in the brain and degradation of dopamine-producing neurons in the substantia nigra, the portion of the midbrain marked by cell death in Parkinson’s patients. Accumulation of α-synuclein in the brains of patients is a core feature of Parkinson’s disease, and this leads to the activation of the brain immune cells called microglia, the production of inflammatory signaling chemicals, and ultimately, neurodegradation.
In vitro and in vivo experiments showed AZD1480 inhibited JAK/STAT activation and downstream gene induction after a challenge by α-synuclein. The genes that are induced by α-synuclein, but not induced in the presence of α-synuclein and AZD1480, are associated with the proinflammatory phenotype. The inhibition by AZD1480 dampened both innate and adaptive immune responses.
Altogether, the researchers say, the results show the potential of Jakinibs to protect against the degradation of dopamine-producing neurons.
DetailsFor the in vivo neuroinflammation experiments, α-synuclein overexpression was induced, and two weeks later rats were given AZD1480 by oral gavage for 14 days. Then the researchers analyzed the inflammatory response in the substantia nigra of the midbrain for AZD1480-treated and -untreated animals. AZD1480 prevented the increased numbers of microglia and macrophages seen after α-synuclein overexpression. AZD1480 also prevented inflammatory activation of the microglia, as measured by Iba1-positive cells, and it prevented upregulation of genes for the proinflammatory markers TNF-α, iNOS, IL-6 and CCL2.
AZD1480 also prevented neurodegradation. For the in vivo neurodegradation experiments, α-synuclein overexpression was induced, and four weeks later — at the peak of neuroinflammation — rats were given a four-week treatment of AZD1480 oral gavage. At 12 weeks, the brains were analyzed for nigral neurons of the substantia nigra. Benveniste and colleagues found that overexpression of α-synuclein caused a 50 percent loss of nigral neurons at three months. But when the α-synuclein rats were also treated with AZD1480, that loss was prevented, and the numbers of nigral cells were similar to those of the controls.
In Parkinson’s disease, chronic inflammation in the brain makes the blood-brain barrier more permeable, allowing immune system T-cells to infiltrate into the brain from the bloodstream, potentially adding to neuroinflammation. In the rat model, α-synuclein overexpression increased the infiltration of CD4+ T-helper cells and induced activation of the STAT3 signaling protein. AZD1480 treatment inhibited both of these immune responses. AZD1480 also inhibited induction of two genes for proinflammatory markers, CIITA and MHC Class II.
The UAB researchers further found that α-synuclein overexpression significantly upregulated 186 genes in the midbrains of rats, while AZD1480 treatment of α-synuclein-overexpression rats inhibited the expression levels of 59 genes, the majority being genes that were induced by α-synuclein. Genes induced by α-synuclein overexpression include many that are implicated in cell signaling, inflammatory and neurological diseases, and antigen presentation (a step in the adaptive immune response).
Besides Benveniste, Qin and Standaert, authors of the paper, “Inhibition of the JAK/STAT pathway protects against α-synuclein-induced neuroinflammation and dopaminergic neurodegeneration,” are Jessica A. Buckley, Yudong Liu, Thomas H. Fox III, Gordon P. Meares, Hao Yu and Zhaoqi Yan, all of the UAB Department of Cell, Developmental and Integrative Biology; Xinru Li and Ashley S. Harms, UAB Department of Neurology; and Yufeng Li, UAB Department of Medicine.
At UAB, Benveniste holds the Charlene A. Jones Endowed Chair in Neuroimmunology, and Standaert holds the John N. Whitaker Endowed Chair in Neurology. West holds the John A. and Ruth R. Jurenko Endowed Professorship in Neurology.
Research support came from the M.J. Fox Foundation, and from NIH grants RO1 NS57563-05, P20 NS095230, P30 AR48311, P30 NS47466, P30 CA13148 and P30 AI027767.
UAB presents first results of CBD oil studies at neurology meeting
UAB Media Relations
Investigators with the University of Alabama at Birmingham Cannabidiol Program will present the first results drawn from the CBD oil studies underway at UAB and Children’s of Alabama. Three abstracts will be presented at the annual meeting of the American Academy of Neurology in Vancouver, Canada.The abstracts describe results from the first 51 subjects enrolled in the studies. Among other findings, the researchers report that approximately 50 percent of the subjects responded to the CBD oil therapy with overall sustained improvement inseizure control over a six-month period. Seizures declined between 32 and 45 percent in the responders, depending on the CBD dose. Two patients were seizure-free, and nine dropped out due to side effects or lack of efficacy.
UAB launched the studies of CBD oil as a treatment for severe, intractable seizures in April of 2015. The studies, an adult study at UAB and a pediatric study at Children’s of Alabama, were authorized by the Alabama Legislature in 2014 by legislation known as Carly’s Law.
The studies are designed to test the safety and tolerability of CBD oil in patients with intractable seizures. CBD oil, a derivative of the cannabis plant, is delivered orally as an oily liquid.
“The studies are ongoing, and we have a lot more to learn; but these preliminary findings are encouraging,” said Jerzy Szaflarski, M.D., Ph.D., professor in the Department of Neurology, principal investigator of the adult study. “Among our goals was to determine the safety of CBD oil therapy, and it appears that, in many cases, patients tolerate the oil quite well. The evidence of seizure reduction gives us hope that, the more we learn about CBD oil, the better we will be able to tailor this therapy to provide relief for those with severe epilepsy.”
The oil used in the studies is produced under stringent requirements of the United States Food and Drug Administration by a licensed pharmaceutical company. It contains only traces of THC, the psychoactive component of marijuana. The process developed by GW Pharmaceuticals guarantees the consistency of the product that is provided to study participants.
|“Some patients respond well, but others either have no improvement or experience significant side effects. CBD is not a panacea, and it’s not for everyone. But many patients do have a reduction in seizure activity, and we hope our efforts will further define how to best utilize CBD oil for maximum benefit to the appropriate patient population.”|
Tyler Gaston, M.D., a clinical neurophysiology fellow, led a study of potential interactions between CBD and clobazam, a commonly prescribed anti-epileptic medication. The investigators suspected that CBD treatment might cause an increase in the blood levels of clobazam and its metabolite, N-desmethylclobazam, leading to adverse events including sedation. Seventeen patients in the studies were taking clobazam, and investigators found clear evidence for an interaction, with rising clobazam levels during CBD therapy. This finding highlights the importance of monitoring clobazam and N-desmethylclobazam levels when treating patients with CBD, and the results underscore the importance of the new knowledge gained through the UAB CBD program.
A study headed by Leslie Perry, M.D., also a clinical neurophysiology fellow, looked at the effect of CBD oil therapy on electroencephalography, or EEG. EEG is the standard test to measure electrical activity in the brain. The same cohort of 51 patients received EEG tests prior to beginning CBD therapy and then again after CBD therapy had begun. The investigators report that CBD does not appear to have a negative effect on standard EEG parameters. However, the authors acknowledge that the conclusion is limited by the relatively short duration of both the EEG and the length of time from the tests done prior to beginning CBD therapy and then during therapy.
Another abstract, led by Jane Allendorfer, Ph.D., assistant professor of neurology, will be presented at the annual meeting of the Organization for Human Brain Mapping in Geneva, Switzerland. In her work, she evaluated the effects of CBDtreatment on attention circuits in the brain using functional MRI. Eight patients underwent fMRI before treatment with CBD and while taking CBD. Their scanning showed improved activation of brain regions important for attention. The authors conclude that these preliminary results are promising and illustrate the potential of CBD treatment to improve not only seizure control but also cognition in patients with poorly controlled epilepsy.
The ongoing UAB CBD studies currently have 40 children and 39 adults enrolled.
Regulation of Parkinson’s disease inflammatory responses by a microRNA
by Jeff Hansen
A small regulatory RNA called microRNA-155 appears to play a key role in the brain inflammation that helps foster Parkinson’s disease. This finding, using a mouse model, implicates microRNA-155 as both a potential therapeutic target and biomarker for this progressive neurodegenerative disorder, according to a University of Alabama at Birmingham study published Feb. 23 in The Journal of Neuroscience.
Parkinson’s disease, the most common neurodegenerative movement disorder, affects as many as 1 million Americans, more than multiple sclerosis, muscular dystrophy and Lou Gehrig’s disease combined. About 60,000 new U.S. cases are diagnosed each year, and thousands more go undetected.
Parkinson’s disease can progress undetected for years before symptoms appear. The UAB researchers, led by David Standaert, M.D., Ph.D., professor and chair of the UAB Department of Neurology, write that their results “suggest that microRNA-155 is involved early in Parkinson’s disease pathogenesis and is important for initiating the inflammatory response to alpha-synuclein.”
Widespread intracellular aggregates of alpha-synuclein protein, or α-syn, are a hallmark of Parkinson’s disease, along with progressive loss of neurons in a region of the brain called the substantia nigra pars compacta, or SNpc.
The mouse model used by the UAB team uses a virus to deliver a human α-syn gene to the brain, where it is overexpressed, leading to inflammation and neurodegeneration. The researchers examined whether this overexpression α-syn also changed expression of any microRNAs. MicroRNAs — which interact with messenger RNAs after their export from the cell nucleus — act to regulate gene expression in cells, and there are more than 1,300 distinct microRNAs at work in the brain.
The UAB researchers probed with an array of 84 inflammation- and autoimmune-associated microRNAs and found that microRNA-155 was significantly overexpressed in the SNpc, two weeks after viral delivery of the α-syn gene.
To see whether microRNA-155 was involved in inflammation and neurodegeneration, they tested mice with a deletion of the microRNA-155 gene. In the mouse α-syn model, this deletion prevented the increased expression two immune-cell markers — MHCII and CD68 — in the SNpc. Similarly, knock-out of the microRNA-155 gene prevented the α-syn-associated neurodegeneration that is seen six months later in wild-type mice challenged with α-syn.
The toll of Parkinson’s
“Our studies suggest,” the authors wrote, “that microRNA-155 is a key inflammation-initiating molecule that could be a viable target for Parkinson’s disease therapeutics.”
Authors of the paper, “MicroRNA-155 Regulates Alpha-Synuclein-Induced Inflammatory Responses in Models of Parkinson Disease,” are Aaron D. Thome, Ashley S. Harms, Laura A. Volpicelli-Daley and David G. Standaert, all of the Center for Neurodegeneration and Experimental Therapeutics, UAB Department of Neurology.
The work was supported by the American Parkinson Disease Association, and NIH grants F31 NS084722 and P20 NS092530.
UAB’s Roberson joins celebrity chef B. Smith for a discussion on Alzheimer’s disease at local book signing
|B. Smith — restaurateur, magazine publisher, celebrity chef and nationally known lifestyle maven — and her husband, Dan Gasby, will visit the Barnes & Noble store at The Summit in Birmingham for a special event to discuss and sign copies of their book, “Before I Forget,” written with Vanity Fair contributing editor Michael Shnayerson. Smith has been diagnosed with Alzheimer’s disease, and “Before I Forget” describes her and Gasby’s journey with the disease and offers practical advice about dealing with Alzheimer’s day-to-day challenges, the family realities and tensions, ways of coping, and lessons learned along the way.
Erik Roberson, M.D., Ph.D., Virginia B. Spencer Professor of Neuroscience and director of the Alzheimer’s Disease Center at the University of Alabama at Birmingham School of Medicine, will participate in the discussion to share research on the disease and answer questions from the audience.
The event is at 7 p.m., Tuesday, Feb. 23, at the Barnes & Noble at The Summit, 201 Summit Blvd., Suite 100.
By Bob Shepard
UAB Media Relations