Jakinibs prevent neurodegeneration in rat models of Parkinson’s disease

Researchers have reported the first documentation that suppressing a key cell-signalling 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.

“We believe Jakinibs may become a viable therapeutic option for Parkinson’s disease patients,” said Etty “Tika” Benveniste, Ph.D., University of Alabama at Birmingham (UAB). “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., 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.”

Benveniste and Standaert are part of an interdisciplinary UAB team focusing on neuroinflammatory mechanisms in Parkinson’s disease. The group 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.

Inhibition by AZD1480 dampened both innate and adaptive immune responses

For the current study, 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 signalling 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.