Inhibitors of the JAK/STAT pathway may provide potential for treating patients with neurodegenerative diseases, particularly Parkinson’s, by reducing the degenerative inflammation in the brain according to the study “Inhibition of the JAK/STAT pathway protects against α-synuclein-induced neuroinflammation and dopaminergic neurodegeneration“, published May 4 in The Journal of Neuroscience.
Parkinson’s disease (PD), a chronic neurodegenerative disorder characterized by the accumulation of α-synuclein in the brain that leads to activation of brain immune cells called microglia, ultimately induces a marked loss of dopamine-producing neurons. Currently, no therapies exist to prevent PD progression, and only recently have researchers begun to suspect that inflammation may be an important factor in disease progression.
An interdisciplinary team from the University of Alabama at Birmingham which works to unravel how the body’s immune system contributes to the development and progression of the pathology in the brain of PD patients, was the first to reveal that disruption of the JAK/STAT pathway using inhibitors commonly called Jakinibs, prevented the neuroinflammation and neurodegeneration seen in PD patients.
“We believe Jakinibs may become a viable therapeutic option for Parkinson’s disease patients,” said Etty Benveniste, Ph.D., the study’s senior author, in a press release. “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.”
Researchers induced α-synuclein overexpression in the brains of rats and then treated them with the JAK/STAT inhibitor AZD1480 through oral administration. The drug was shown to prevent both innate and adaptive immune responses that are triggered in the presence of elevated levels of α-synuclein. Neurodegradation was also prevented when AZD1480 was given to the animals, indicating that suppressing innate and adaptive immune responses against α-synuclein, inhibition of the JAK/STAT pathway can prevent neuroinflammation and neurodegradation.
“This is a very important advance,” said David Standaert, MD, PhD, a collaborator on the project and chair of the UAB Department of Neurology. “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.”