An extract from three plant species reduced signs of motor disturbances in rodent models of Parkinson’s disease and lessened the associated molecular defects of the cellular recycling process known as autophagy, a study showed.
Further research is needed to confirm that the active component of the plant extract could serve as a potential treatment for Parkinson’s. But such a therapy might be able to restore autophagy-related deficiencies found in patients with the neurodegenerative disease, the scientists said.
The study, “Extract of Polygala tenuifolia, Angelica tenuissima, and Dimocarpus longan Reduces Behavioral Defect and Enhances Autophagy in Experimental Models of Parkinson’s Disease,” was published in the journal NeuroMolecular Medicine.
A common theme underlying various proposed causes of Parkinson’s disease is autophagy — a process to degrade, recycle, and eliminate unused proteins and other cellular components.
Some mutations linked to familial Parkinson’s are found in genes related to autophagy. These alterations cause an accumulation of toxic proteins that leads to cell damage and death.
A water-based extract called WIN-1001X, found in three plant species — Polygala tenuifolia, Angelica tenuissima, and Dimocarpus longan — has been shown to have protective properties by modulating autophagy in brain cells from mice with chemically induced Parkinson’s.
Further research identified a specific component in the extract, called onjisaponin B, that was responsible for activating autophagy processes.
Based on these findings, investigators centered at the Natural Product Research Center, Korea Institute of Science and Technology, in South Korea, examined the impact of an optimized extract of WIN-1001X in Parkinson’s-induced rodent models.
The optimized plant extract was prepared with a 20% ethanol solvent to increase fat-based components.
To induce Parkinson’s-like symptoms, the mice were injected with a compound called MPTP, which led to neurotoxicity in cells that produce dopamine. Dopamine is the chemical messenger deficient in Parkinson’s patients that is used by nerve cells to communicate and control body movements.
The researchers used a rotating rod test to measure motor coordination in the mice. The animals injected with MPTP showed significantly less time on the rod compared with control mice. Induced mice then treated with WIN-1001X showed a significant recovery compared with MPTP mice.
As a positive control, another group of mice was treated with the approved Parkinson’s medicine ropinirole (sold as Requip by GlaxoSmithKline), which mimics the action of dopamine. In the rotating rod experiment, ropinirole showed a non-significant tendency for recovery.
The pole test is another behavioral assessment for motor control, which measures the time to rotate the body, called a T-turn, and the time to climb down the pole, known as T-LA. In MPTP-induced mice, both T-turn and T-LA was significantly longer than control mice. However, the T-turn value was significantly shortened with WIN-1001X treatment, similar to the ropinirole-treated group.
The enzyme tyrosine hydroxylase (TH), which converts the amino acid tyrosine to the dopamine precursor L-Dopa, is a method to detect dopamine-producing (dopaminergic) neurons in the regions of the brain most affected, specifically the substantia nigra and the striatum. Of note, amino acids are the building blocks of proteins.
While control mice showed high levels of tyrosine hydroxylase, MPTP-injected mice showed a significant decrease in tyrosine hydroxylase-positive cells, which were rescued by WIN-1001X treatment. The ropinirole-treated group, however, exhibited no significant difference in tyrosine hydroxylase-positive cells in both regions.
Lower doses of MPTP induced a more delayed (sub-chronic) cell death and loss of dopamine than the higher-dose acute disease model. Here, MPTP-induction led to a significant reduction in tyrosine hydroxylase production than controls in the substantia nigra and striatum. Ropinirole treatment increased tyrosine hydroxylase production levels, while WIN-1001X treatment increased tyrosine hydroxylase even further.
Autophagy-related proteins, including LC3, beclin-1, mTOR, and p62, were measured to assess the impact of WIN-1001X on autophagy.
Compared with the control group, WIN-1001X treatment increased LC3, while ropinirole treatment showed no change. Likewise, WIN-1001X exposure significantly elevated the production of beclin-1, which also was unaffected by ropinirole.
The level of mTOR, a negative regulator of autophagy, did not change with MPTP injection. However, both ropinirole and WIN- 1001X-treated groups showed a reduced trend of mTOR protein expression. Similarly, WIN-1001X significantly reduced the p62 protein expression levels.
A second rodent model tested rats exposed to 6-OHDA, a neurotoxic chemical used to induce Parkinson’s progression, but with gradual neuron loss and partial dopamine depletion. That test measured rotational behavior in rats due to dopamine depletion in one side of the brain.
Although the 6-OHDA-injected rats showed significantly increased average rotational behavior compared with controls, this behavior was significantly suppressed with L-Dopa (positive control) as well as WIN-1001X treatments. Like with the mouse model, treatment with the plant extract increased tyrosine hydroxylase production and the autophagy markers LC3 and beclin-1, while it down-regulated mTOR.
To show relevance to people with Parkinson’s, human neural cells called SH-SY5Y, a standard model for neurodegenerative disorders, were exposed to 6-OHDA, decreasing the cells’ viability. WIN-1001X treatment protected cells from 6-OHDA toxicity and increased tyrosine hydroxylase, LC3, and beclin-1 production.
Finally, to confirm onjisaponin B as the active component of WIN-1001X, SH-SY5Y cells treated with purified onjisaponin B showed a significant increase of LC3 levels in a dose-dependent manner.
“Collectively, our data presented in this study suggest that WIN-1001X treatment can effectively relieve the Parkinsonism symptoms induced by the chemical toxin challenges,” the researchers wrote.
“WIN-1001X may hold a position of new therapeutic candidate against the [Parkinson’s disease] and further detailed mechanism studies would be beneficial in revealing [Parkinson’s disease] treatment partially via modulation of autophagy.”
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