Plant compound eases motor, cognitive symptoms in mice
Gardenin A slows loss of nerve cells, decreases protein clumps, study finds
Gardenin A, a compound found in a common South Asian shrub, lessened both cognitive and motor symptoms of Parkinson’s in a mouse model of the disease, according to a study.
The compound reduced the loss of dopaminergic neurons — nerve cells that are gradually lost in Parkinson’s— and decreased the levels of phosphorylated alpha-synuclein. Alpha-synuclein is a protein that tends to form clumps in the brains of people with Parkinson’s disease.
Gardenin A seemed to work by increasing antioxidant responses and lowering brain inflammation, the researchers said.
“When people speak about Parkinson’s, they often focus on the motor dysfunction,” Lukasz Ciesla, PhD, professor at the University of Alabama and senior author of the study, said in a university news story. “We found this molecule not only improves the mobility in mice, but it also seems to improve memory.”
The study, “Gardenin A treatment attenuates inflammatory markers, synuclein pathology and deficits in tyrosine hydroxylase expression and improves cognitive and motor function in A53T-α-syn mice,” was published in Biomedicine & Pharmacotherapy.
Neurons and cognitive impairment
The exact cause of dopaminergic neuron loss in Parkinson’s disease is unknown. These neurons are responsible for producing dopamine, a key neurotransmitter involved in movement control. However, several factors including neuroinflammation, oxidative stress – a type of cell damage – and alpha-synuclein clumping, are thought to play a role.
The dysfunction and death of these neurons result in the disease’s motor and nonmotor symptoms, including cognitive impairment.
A previous study from the same team tested a range of flavonoids — naturally occurring compounds found in various plants, fruits, and vegetables — in a toxin-induced fruit fly model of Parkinson’s disease.
“A few years ago, a study found that certain diets reduce the risk of Parkinson’s disease and other neurodegenerative conditions,” Ciesla said. “Much of the focus was on flavonoids, but we didn’t know why they provided this protective effect.”
Researchers found that gardenin A, a flavonoid found in Gardenia, a type of flowering shrub common in South Asia, reduced the loss of dopaminergic neurons in flies. A similar compound, gardenin B, did not induce neuroprotection.
The two compounds have antioxidant properties, but gardenin B does not have anti-inflammatory action. The researchers said suggested that gardenin A could be neuroprotective by reducing inflammation.
They set out to determine whether gardenin A could have similar effects in a mouse model of Parkinson’s. They used a genetic model of the disease, in which the mouse recapitulates symptoms of Parkinson’s, including motor and cognitive issues.
Mice were exposed to one of two doses of gardenin A, 25 mg/kg and 100 mg/kg three times a week, for four weeks. Control groups included Parkinson’s mice and healthy mice not exposed to gardenin A.
Treatment with the highest gardenin A dose improved memory and decreased motor and gait abnormalities in mice with Parkinson’s. At the molecular level, it reduced the levels of phosphorylated alpha-synuclein, the form of alpha-synuclein that is more prone to form clumps, as well as the loss of dopaminergic neurons in the brain.
The compound also boosted the activity of genes associated with antioxidant activity, specifically those regulated by a protein called Nrf2. Simultaneously, it lowered the activity of genes linked to inflammation, such as tumor necrosis factor and interleukin-6.
Gardenin A was found to effectively reach the brain at both tested doses, moving the composition of the brain’s gray matter, which primarily consists of neuron cell bodies and support cells, towards a profile more similar to healthy mice.
“The fact that [gardenin A] improves both motor and cognitive deficits in a [Parkinson’s] mouse model makes it particularly attractive to pursue as a therapeutic agent given the dearth of therapies with … effects that can modify both symptoms,” the researchers wrote.
They also noted that gardenin A showed benefits both in the toxin model of Parkinson’s in fruit flies and in the mouse genetic model of the disease. As both genetic and environmental factors are believed to increase the risk of developing Parkinson’s, this indicates the compound could be broadly effective at treating the disease.
“While the beneficial effects of [gardenin A]on cognitive deficits, motor dysfunction and [Parkinson’s disease] pathology are promising, future studies are needed to further fully elucidate the mechanism of action … optimizing dosing and confirm these effects in other [Parkinson’s] models,” the researchers wrote.
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