Compound Used to Stop Smoking Can Protect Neurons in Female Mice

A plant-derived medicine used to help people stop smoking, known as cytisine, might be neuroprotective and a potential Parkinson’s disease treatment, an animal model study reports.

In female mice, the compound appeared to work with estrogen to limit the loss of the dopamine-producing neurons, nerve cells whose death characterizes the disorder. These benefits, however, were not seen in male mice.

The study, “Cytisine is neuroprotective in female but not male 6-hydroxydopamine lesioned parkinsonian mice and acts in combination with 17-β-estradiol to inhibit apoptotic endoplasmic reticulum stress in dopaminergic neurons,” was published in the Journal of Neurochemistry.

Parkinson’s stems from the loss of neurons that produce dopamine (dopaminergic neurons), a neurotransmitter important in directing muscle movement and coordination.

Interestingly, nicotine exposure can limit a cellular process contributing to the death of dopaminergic neurons, called the endoplasmic reticulum stress response. This is supported by observations that smokers and others who habitually consume tobacco have a lower risk of developing Parkinson’s.

Nicotine’s potential as neuroprotective compound, however, has failed in clinical trials using nicotine patches due to the drug’s harmful side effects.

Researchers at Texas A&M University may have found a workaround in a compound called cytisine.

Used for smoking cessation efforts in Europe, cytisine acts upon the same cellular receptors as nicotine but doesn’t carry its degree of side effects.

“What cytisine does is it binds to target receptors but doesn’t activate them as efficiently as nicotine,” Rahul Srinivasan, PhD, the study’s senior author, said in a university press release.

“It keeps the receptors ‘occupied’ and ‘chaperones’ them to the surface of the neuron,” he added. “Since cytisine is a natural compound, is available quite freely and is pretty cheap, I decided to test this concept of chaperoning in an animal model of the disease to see if it works.”

Srinivasan and his colleagues tested cytisine’s neuroprotective potential in a mouse model of Parkinson’s, made using dopaminergic neuron-killing injections of the neurotoxin 6-hydroxydopamine (6-OHDA).

The investigators injected these mice with either cytisine or saline (salt water) — used as a control — starting seven days prior to 6-OHDA treatment, and then every other day for 21 days.

Behavioral tests of the animals’ skills were performed before and after the cytisine and saline injections.

Female cytisine-treated mice showed clear improvements in all tests.

In a gait pattern test, for instance, they showed a 30% increase in normal gait patterns at 21 days after 6-OHDA treatment, compared with no improvement among cytisine-treated male mice.

In a foot-slip test, the cytisine-treated females had about 50% fewer slips than the saline control mice; again, no benefits were seen among the cytisine-treated males.

Alongside these behavioral patterns, females given cytisine treatment lost fewer dopaminergic neurons.

Researchers tracked the female-only effects to the action of estrogen, which degrades a protein called CHOP that is needed for 6-OHDA to kill dopaminergic neurons.

The team drew a parallel to their female neuroprotection finding, and to the observation that human males are twice as likely to develop Parkinson’s.

Srinivasan now hopes to find ways to extend these results to males and to post-menopausal women.

“There are non-feminizing compounds that have been developed and are being researched right now that can activate the receptors that estrogen activates,” he said.

“The goal right now is to understand how estrogen triggers the protection in female animal models,” he added. “Once we fully understand this component, then we can bring in these non-feminizing estrogen analogs, and we will potentially have a combination therapy of cytisine and a non-feminizing estrogen analog for men.”

Possible mechanisms for estrogen’s protective role include the idea that females metabolize cytisine differently than males, and that cytisine triggers a surge in brain-derived estrogen.

“Future studies will systematically dissect these possibilities,” the researchers concluded, “as well as consider sex-dependent genetic factors known to exert neuroprotection in [Parkinson’s].”