Mice in a model of Parkinson’s disease treated at higher doses with the anti-anxiety drug buspirone showed fewer signs of nerve cell degeneration in the brain and more normalized behaviors than untreated mice, two researchers reported. Australians.
“To our knowledge, this is the first study to investigate the ability of buspirone to prevent inflammation and promote neuroprotection in a model of PD. [Parkinson’s disease]they wrote. A trial of this treatment in patients, the researchers also noted, had mixed results at best.
Parkinson’s disease is caused by the death and dysfunction of dopaminergic nerve cells (dopamine-producing neurons) in the brain. Although the drivers of this cell death remain incompletely understood, neuroinflammation – inflammation of the brain – is thought to play a key role in disease progression.
Buspirone, sold under brands such as BuSpar and Vanspar, is an oral therapy for anxiety. Buspirone is thought to work primarily by modulating serotonin signaling – a neurotransmitter or chemical messenger – in the brain. Studies over the past decade have shown that the drug also blocks the activity of a specific dopamine receptor protein called D3R.
In particular, the D3R protein is known to be involved in the activation of microglia. These resident immune cells in the brain help protect it against infection, but also play a central role in disease-causing neuroinflammation.
“It is well accepted that blocking microglia-induced inflammation reduces neurodegeneration and slows disease progression,” wrote the researchers, both from the Laboratory of Cellular and Molecular Neurosciences at the University of Technology Sydney. .
The known importance of microglia in neuroinflammation, combined with recent evidence that buspirone can block the D3R protein necessary for their activation, “prompted us to investigate whether buspirone can protect against dopaminergic degeneration by attenuating neuroinflammation in” a mouse model of Parkinson’s disease, the researchers wrote. .
The researchers specifically used a mouse model where Parkinson-like symptoms and brain damage were induced by a chemical insecticide called rotenone. Some mice were injected with buspirone at doses ranging from 1 to 10 mg/kg, while others were left untreated to serve as a control group.
Rotenone-induced Parkinson’s mice showed abnormal behaviors, in particular a reduced tendency to explore during open-field tests. They also tended to walk shorter total distances, reflecting motor deficits.
But mice treated with buspirone, especially at the higher doses tested, showed none of these abnormalities.
“When the drug [buspirone] was co-administered with rotenone at the highest doses (3 and 10 mg/kg), it was successful in preventing insecticide-induced behavioral disturbances,” the researchers wrote.
Brain tissue analyzes also revealed that high-dose buspirone (10 mg/kg) prevented the loss of dopaminergic neurons in several brain regions of mice.
“We report that buspirone prevented rotenone-induced deficits in locomotor and exploratory behavior, and dose-dependently rescued dopaminergic degeneration in the substantia nigra pars compacta, midbrain and striatum,” the team wrote.
Further analyzes showed that buspirone treatment reduced levels of pro-inflammatory signaling molecules (cytokines) in mouse brains, such as IL-1 beta and IL-6. Its use also increased the levels of several signaling molecules that promote brain cell survival, such as BDNF and ADNP.
These results suggest “that buspirone is able to provide some of its beneficial effects by modulating the immune response and promoting the release of protective factors,” the researchers write.
Noting that a clinical trial (NCT02803749) on the use of buspirone in 21 patients with Parkinson’s disease, with results published in 2020reported both tolerability issues and “a signal for efficacy”, the team stressed the need for further work on “the exact role performed” by agents like buspirone in the brain and suggested further refine their “receptor selectivity”.