Researchers at Texas A&M University have identified a protective brain pathway — one linked to receptors responsive to nicotine but not requiring the tobacco plant chemical itself — that may be targeted to slow the progression of Parkinson’s disease.
In a mouse model of Parkinson’s, boosting the number of nicotine-responsive receptors in the brain prevented the death of dopamine-producing neurons, the nerve cells whose loss marks the neurodegenerative disorder. These protective effects, however, occurred solely in female mice.
Still, the scientists say that targeting this pathway could potentially help in strengthening the brain’s own dopamine‑producing nerve cells and slowing Parkinson’s progression.
“Every additional year that these neurons remain functional matters,” Rahul Srinivasan, PhD, associate professor of neuroscience at Texas A&M University’s College of Medicine and study lead, said.
“If we can strengthen protective brain pathways early, we may be able to meaningfully slow Parkinson’s progression and improve the quality of life of patients with Parkinson’s,” Srinivasan said.
The study, “Genetically encoded constitutive upregulation of β2 subunit containing neuronal nicotinic acetylcholine receptors is neuroprotective in female parkinsonian mice,” was published in the Journal of Neuroscience.
Parkinson’s is caused by the progressive loss of neurons that produce dopamine, a nerve signalling molecule, or neurotransmitter, that plays a key role in coordinating movement. Available therapies work by replacing dopamine or mimicking its effects, but they don’t prevent the ongoing neuronal death.
Investigating brain receptors responsive to nicotine
Studies suggest that smokers and tobacco users have a lower risk of developing Parkinson’s. Further, the main addictive compound in tobacco, nicotine, has been shown to reduce neuronal death and brain damage.
In previous work, Srinivasan’s team showed that cytisine, a drug used to help people stop smoking, protected dopamine-producing neurons in female mice at low doses. Cytisine activates so-called neuronal nicotinic acetylcholine receptors (nAChRs), which also bind nicotine. More recently, the researchers found that estrogen, a female sex hormone, enhanced the neuroprotective effects of cytisine in female Parkinson’s mice.
“Despite the nicotine connection, these receptors exist to serve normal brain function,” Srinivasan said. “Nicotine just hijacks a receptor system that’s already there.”
Because nicotine and nicotinic ligands can increase the number of nAChRs and confer neuroprotection against Parkinson’s, Srinivasan and colleagues now set out to determine whether this protective effect is driven by receptor activation with a drug such as cytisine or by the number of receptors available.
The team engineered mice to express higher levels of beta-2, a receptor subunit in a class of nAChRs. This was done without exposing the mice to nicotine or any nicotine-like drug. The mice were then exposed to the chemical 6-OHDA, which selectively damages the same dopamine-producing neurons that are lost in people with Parkinson’s.
To assess neuroprotection, the team measured levels of surviving dopamine neurons, a marker of cell death, and GFAP protein in astrocytes, a type of neuron-supporting cell whose elevated activity signals tissue damage. A behavioral test was also used in which the drug apomorphine causes mice with one-sided dopamine loss to rotate.
Across all four assessments, female mice with elevated nAChR levels showed significant neuroprotection, whereas male mice with the same genetic modification showed no protective effect.
“The protective pathway was clearly engaged in females and absent in males,” Srinivasan said.
The mouse line developed in this study is also expected to serve as a research tool for studying the role of nAChRs in other neurological conditions, including addiction, anxiety, depression, and dementia, per the team.
“Our [newly] developed transgenic mice provide a valuable tool to study the role of nAChRs in other major neurological disorders,” the researchers wrote. The model here has shed new light on possible Parkinson’s treatments.
“Our findings suggest that inducing [beta-2] nAChR upregulation alone may be a viable therapeutic strategy for [Parkinson’s],” the researchers wrote.
Srinivasan added that “this work is about keeping neurons alive longer. If you can preserve dopamine‑producing cells, you have a real opportunity to slow the rate at which the disease advances.”
Source:
