Tiny Vesicles Found in Blood Able to Carry Dopamine into Brains of Mice in Parkinson’s Study

dopamine loaded exosomes

Tiny fatty vesicles that naturally circulate in the blood can effectively carry medications into the central nervous system, including into the brain, an early study in mice suggests.

These blood vesicles, called exosomes, were able to successfully deliver dopamine directly to specific areas of the brain affected by Parkinson’s disease.

The study, “Dopamine-loaded blood exosomes targeted to brain for better treatment of Parkinson’s disease,” was published in the Journal of Controlled Release.

Parkinson’s disease is characterized by the progressive degeneration and death of nerve cells in the brain that produce dopamine (called dopaminergic neurons). Dopamine is a critical signaling molecule that regulates brain cell activity and function.

Given the disease’s progressive nature researchers have focused on finding ways to prevent the death of dopaminergic neurons or to restore brain levels of dopamine. But a major challenge has been getting potential therapeutic agents across the blood-brain barrier — a semipermeable membrane that protects the brain — and reach targeted areas.

Researchers at Sichuan University, China, explored the possibility of using tiny fatty vesicles that are naturally produced by cells as a vehicle for dopamine transport.

The team isolated and purified exosomes from blood of mice, and labeled them with a green fluorescent tag to be able to track them easily. When researchers used these exosomes in mouse brain cells grown in the laboratory, they confirmed the vesicles merged with cell membranes, and its content was released inside the cell, turning it green.

Next, they injected the exosomes into live mice and found that the fluorescent dye accumulated in the brain. Further experiments revealed that this brain-targeted activity of exosomes was dependent on the presence of a specific receptor, called transferrin, and its interactions with a protein called transferrin in brain cells.

To better explore their therapeutic potential, researchers also loaded exosomes with dopamine and injected them into mice.

The encapsulated dopamine accumulated in all major organs, including the brain. Mice that were given injections of free dopamine (without exosome use) showed increased levels of the compound in the liver, lung, and kidney, but not in the brain. With exosome-mediated delivery, dopamine levels in the brain were at least 15.7 times higher than those in animals treated with free dopamine.

After analyzing mice brains, researchers found that exosomes could not only pass the blood-brain barrier, but they could reach deep areas such as the striatum and substantia nigra – brain areas most affected in Parkinson’s patients.

Indeed, mice in a model of Parkinson’s disease that were given exosomes loaded with dopamine showed a 56.58% increase in dopamine levels in lesioned striatum areas compared to animals treated with a placebo.

Overall, the investigational treatment strategy was safe for the animals with no changes in heart, liver, or kidney function detected, the researchers reported.

Based on these findings, researchers believe that exosomes could represent an attractive delivery system for targeted therapies against Parkinson’s and other diseases affecting the central nervous system.

“[F]or the first time, we showed blood exosomes without any modification could serve as efficient carriers for brain targeted delivery of drugs and we also revealed the underlying mechanism for their natural distribution to the brain,” they conclude. “We next took full use of dopamine-loaded blood exosomes for targeted therapy against PD [Parkinson’s disease], preferably solving the unmet medical need of treating PD.”

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Source: Parkinson's News Today

Scientists Unraveling How Movement is Translated Into Desired Action

mice movement brain

The findings of a Harvard University study are furthering understanding of the mechanisms involved in movement disorders and may open new therapeutic opportunities to treat Parkinson’s disease.

The mouse study, “The Striatum Organizes 3D Behavior via Moment-to-Moment Action Selection,” was published in the journal Cell.

The brain relies on the balanced activity of two nerve cell populations located in a specific region of the brain — the striatum — to achieve accurate control of body movement. The striatum functions as the coordinating center for motor and action planning. In Parkinson’s disease, striatum nerve cells are those most affected, which partly explains the motor symptoms that characterize the disease.

A previous study identified two groups of nerve cells in the striatum that have opposing activities to control key aspects of movement; those are called direct pathway and indirect pathway neurons.

While direct pathway cells select actions and can trigger movement, the activation of indirect pathway cells works as a stop signal, inhibiting unwanted behaviors. However, some studies suggest both pathways are activated at the same time.

“That didn’t make sense based on what we’ve long thought each pathway did,” the study’s lead author Jeffrey Markowitz, said in a press release.

To evaluate the dynamic activity of both cell populations, Harvard Medical School researchers used a technology called MoSeq (short for motion sequencing) developed by study’s senior author Sandeep Robert Datta. This technology films three-dimensional movements of the mice and uses machine learning to analyze the movements into basic patterns lasting only a few hundred milliseconds apiece. The researchers named those ultra-fast movements “syllables.”

Mice were genetically engineered to display different glowing colors in direct and indirect pathway neurons upon activation, allowing researchers to accurately analyze the simultaneous activity of both cell populations as mice performed several actions.

When mice changed their behavior — from running to stopping, for example — the activity of both pathways increased, which is in agreement with data from previous studies. But when they looked at the syllables identified by the MoSeq system, they found the pattern of activity of both pathways was not the same.

Instead, direct or indirect pathway cells dominated some particular syllables. The association between the type of cell that was activated and syllables was so pronounced that the team could effectively identify syllables based on the pathway activity alone.

To further characterize the role of these cells, the team induced brain injuries in the mice, targeting only the striatum. After a week of recovery, they re-analyzed animals’ behavior and compared them with that of healthy animals.

Mice with brain lesions in this specific area also were able to perform normal syllables, such as sniffing, running, rearing, and turning. However, their brains were unable to sequence these movements correctly.

“… behavioral syllables are associated with characteristic and pathway-specific neural dynamics. These dynamics represent key 2D and 3D movement parameters … the striatum plays a key role in choosing which … behavioral syllable to express at any given moment,” researchers wrote.

“This underscores the importance of order in piecing movements together toward a desired outcome,” Datta said. “Even if you’re able to move your body correctly, if you can’t put actions in the correct order, it’s hard to do even the most basic of things.”

The researchers believe that with additional studies and improved technology it will be possible not only  to replicate these results, but expand this reported relationship between syllables and neural activity to other parts of the brain that control movement.

In addition, these findings may help promote the development of new treatments for Parkinson’s disease and other neurodegenerative disorders in which basic movements become extremely difficult as disease progresses.

“We hope that future work emanating from these findings would address more specifically what exactly happens in these cell types when neurodegenerative disorders rob people’s brains of their ability to generate actions and action sequences.” Datta said. “We believe our observations set the stage for both unraveling how movement gets translated into desired action, and propel us forward in our ability to understand and, eventually, treat devastating neurodegenerative disorders where this process goes awry,” he added.

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Source: Parkinson's News Today