CYP2D6 Enzyme Could Be Therapeutic Target in Parkinson’s, Study Suggests

JUNE 26, 2019 BY JOSE MARQUES LOPES, PHD IN NEWS.

Blocking an enzyme that converts compounds derived from certain foods and tobacco in the brain may become a therapeutic target for people with Parkinson’s, according to a new study of mice.

The research, “Mitochondria-targeted cytochrome P450 CYP2D6 is involved in monomethylamine-induced neuronal damage in mouse models,” was published in the Journal of Biological Chemistry.

Prior research has shown that a synthetic opioid known as MPTP and related compounds can induce alterations similar to Parkinson’s in rodents and primates. It is thought that an enzyme called monoamine oxidase B (MAO-B), present in the nervous system’s glial cells, oxidizes MPTP into a toxic metabolite called MPP+. This metabolite is then transferred by dopamine transporter proteins to dopamine-producing neurons, which are typically affected in people with Parkinson’s disease.

Scientists at University of Pennsylvania had already found that the CYP2D6 enzyme, present in mitochondria — the cells’ power plants — also could be involved in transforming MPTP to MPP+.

“CYP2D6 is known to play a role in influencing the activity of a number of drugs,” Narayan Avadhani, PhD, the study’s senior author, said in a press release. These include antidepressants, antihypertensive medications, opioids, selective estrogen receptor modulators, and antidiabetic therapies, among other types of treatments.

The researchers focused on toxins called beta-carbolines and isoquinolines, which resemble MPTP and are produced by the body from compounds found in tobacco smoke, alcohol, and some foods. Prior studies indicated these toxins may induce Parkinson’s-related changes in rodents, but the mechanisms remained unclear.

Using a mouse model, the results showed that CYP2D6 activates beta-carbolines and isoquinolines inside dopamine-producing nerve cells, leading to cell damage, oxidative stress (cellular damage as a consequence of high levels of oxidant molecules) and impaired mitochondrial function, as occurs in Parkinson’s disease.

Then, the team observed that mice lacking CYP2D6 did not show the same disease-related alterations and that administering CYP2D6 blockers — quinidine or ajmalicine — could prevent neuronal damage.

Experiments in a type of cells that mimic human dopaminergic neurons, called Neuro2a, revealed that cells mainly producing mitochondria-targeted CYP2D6 were more sensitive to toxin-mediated respiratory impairment than those predominantly expressing endoplasmic reticulum-targeted CYP2D6. Of note, the endoplasmic reticulum is a key cellular structure in the production, folding, modification, and transport of proteins.

Upon exposure to the toxins, nerve cells expressing mitochondrial CYP2D6 also showed production of Parkin and Drp1, protein markers of autophagy — a cellular process in the removal of aggregated and toxic proteins, as well as other components — and mitochondrial fission.

The findings also suggest that targeting CYP2D6 may be a better approach than targeting MAO-B, which has led to mixed success in previous work. “We believe that mitochondrial CYP2D6 is the more direct drug target, which might prove better in treating idiopathic Parkinson’s,” Avadhani said.

Avadhani also said that ajmalicine, found in the medicinal plant Rauwolfia serpentine long had been used in India for treating mental disorders such as paranoia and schizophrenia.

“Mitochondrial targeting of such compounds is likely to be effective in treating Parkinson’s patients, and pursuing that is our future strategy,” he said.

https://parkinsonsnewstoday.com/2019/06/26/cyp2d6-enzyme-therapeutic-target-parkinsons-disease-study/