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Awakening Dormant Neurons Could Provide Disease-modifying Parkinson’s Treatment, Early Study Suggests

dormant neurons

Together with dying nerve cells, dormant neurons also may be at the root cause of Parkinson’s disease, according to a recent study in animal models.

Reawakening these neurons by targeting a type of brain cells called astrocytes can restore dopamine production in the brain and reverse Parkinson’s motor symptoms, the study found. These findings could lead to a potential new disease-modifying treatment, especially at the early stages of Parkinson’s.

The study, “Aberrant Tonic Inhibition of Dopaminergic Neuronal Activity Causes Motor Symptoms in Animal Models of Parkinson’s Disease,” was published in the journal Current Biology.

Despite its prevalence and debilitating consequences, current medical therapy for Parkinson’s relies on alleviating symptoms. Research investigating ways of modifying the disease or reversing its symptoms is scarce, based on the firm belief that Parkinson’s is caused by the irreversible death of nerve cells — also called neurons — in a region of the brain called the substantia nigra.

In this brain region, nerve cells known as dopaminergic neurons are responsible for producing the neurotransmitter dopamine, a chemical messenger that allows nerve cells to communicate. Dopamine plays a key role in motor function control and also is involved in behavior and cognition, memory and learning, sleep, and mood.

Levodopa, a mainstay of Parkinson’s treatment, works by supplying extra dopamine to the brain. However, it only alleviates motor symptoms and does not alter the disease course. Moreover, its long-term use can cause serious side effects, including involuntary, erratic, and writhing movements.

Now, a team of Korean researchers have discovered additional clues about the underlying mechanisms of Parkinson’s that may offer hope for the development of disease-modifying treatments that could reverse the condition.

Using mouse and rat models of Parkinson’s, they found that the motor abnormalities that mark the disease begin earlier than was previously thought. They are triggered when dopaminergic neurons in the substantia nigra are still alive but in a dormant state, unable to produce dopamine.

However, what holds the key to that dormant state is another type of cells called astrocytes, star-shaped cells present in the brain and spinal cord that play important roles in the protection and regulation of the nervous system.

When neurons die, nearby astrocytes react by proliferating, and start to release an inhibitory neurotransmitter called gamma-aminobutyric acid (GABA) at excessive levels. This puts neighboring neurons “on hold,” suspending their production of dopamine.

GABA prevents the neurons from firing electrical impulses and causes them to stop making an enzyme, called tyrosine hydroxylase, that’s essential for the production of dopamine. In effect, GABA puts the neurons into a dormant, or sleeping state.

One of the most important discoveries of the study was that surviving dormant neurons could actually be “awakened” from their “sleeping” state and rescued to alleviate motor symptoms.

“Everyone has been so trapped in the conventional idea of the neuronal death as the single cause of PD. That hampers efforts to investigate roles of other neuronal activities, such as surrounding astrocytes,” C. Justin Lee, PhD, the study’s corresponding author, said in a press release.

“The neuronal death ruled out any possibility to reverse PD. Since dormant neurons can be awakened to resume their production capability, this finding will allow us to give PD patients hopes to live a new life without PD,” Lee added.

Treatment with two different compounds that block GABA production in astrocytes, called monoamine oxidase-B, or MAO-B, inhibitors, was sufficient for neurons to recover the enzymatic machinery necessary to produce dopamine, the study found. This significantly alleviated Parkinson’s motor symptoms in the study animals.

In fact, the MAO-B inhibitors used for the study — selegiline (brand names EldeprylCarbex, Zelapar, among others), and safinamide (brand name Xadago) — are already prescribed to Parkinson’s patients as an add-on therapy to levodopa. They are believed to prevent the break down of dopamine in the brain.

Importantly, the existence of dormant neurons was observed in the brains of human patients. Analysis of postmortem brains of individuals with mild and severe Parkinson’s had a significant population of dormant neurons surrounded by numerous GABA-producing astrocytes.

The researchers hope that “awakening” neurons using MAO-B inhibition could be an effective disease-modifying therapeutic strategy for Parkinson’s, especially for patients in the early stages of the disease. At that time, inactive, yet live dopaminergic neurons are still present.

Although the results from several clinical trials have cast doubt on the therapeutic efficacy of traditional MAO-B inhibitors, researchers say they have recently developed a new inhibitor, KDS2010. KDS2010 effectively inhibits astrocytic GABA production with minimal side effects in Alzheimer’s animal models and also could be effective for alleviating Parkinson’s motor symptoms, the investigators said.

“This research refutes the common belief that there is no disease-modifying treatment for PD due to its basis on neuronal cell death,” said Hoon Ryu, PhD, a researcher at KIST Brain Science Institute, in South Korea, and one of the senior authors of the study.

“The significance of this study lies in its potential as the new form of treatment for patients in early stages of PD,” Ryu said.

The fact that inhibition of dopaminergic neurons by surrounding astrocytes is one of the core causes of Parkinson’s should be a “drastic turning point” in understanding and treating not only Parkinson’s but also other neurodegenerative diseases, added Sang Ryong Jeon, MD, PhD, also a researcher at KIST and a study co-author.

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Levodopa-Sparing Medications May Help Patients in Early Stages of Parkinson’s, Study Suggests

Early stage Parkinson's, Levodopa-Sparing Medications

Neurologists treating patients with early-stage Parkinson’s disease should prescribe more often therapies that spare patients from starting levodopa too soon in order to delay onset of side effects associated with long-term use of the medicine, findings from a study conducted in Romania suggest.

Researchers believe that even if a doctor believes a patient’s clinical situation required management with levodopa, they should first try to combine it with other antiparkinsonian therapies — such as other dopamine agonists or monoamine oxidase B inhibitors — in order to allow lower levodopa doses.

These findings resulted from a study, “Therapeutic strategies in the early stages of Parkinson’s disease: a cross-sectional evaluation of 15 years’ experience with a large cohort of Romanian patients,” which was published in the journal Neuropsychiatric Disease and Treatment.

Currently, the most effective and cost-saving therapy for lessening Parkinson’s symptoms is substitution therapy with levodopa. However, a major drawback of this therapy is the side effects associated with its long-term use.

After four to six years of treatment with levodopa, many patients may start experiencing spontaneous involuntary movements (dyskinesia), with some patients also having impulsive and compulsive behaviors. Its effectiveness can also reduce over time, causing patients to experience wearing-off effects, meaning that the therapy loses its ability to effectively manage Parkinson’s symptoms before it is time for the next dose.

Some clinical evidence seems to indicate that in many cases “if the therapy is started too early and with high doses, these complications may appear earlier and can be more severe, especially in younger patients,” the researchers wrote. This leads clinicians to try to avoid these side effects and adverse reactions by limiting levodopa doses as much as possible.

Based on clinical efficacy data from newer antiparkinsonian therapies in younger patients (under 60 years), European guidelines propose the use of levodopa-sparing medications as a first option for early-stage patients to delay the onset of motor and non-motor complications. But there is little real-world data to confirm how these therapeutic recommendations are being applied in clinical practice.

Therefore, the researchers reviewed the medical records of patients with early-stage Parkinson’s hospitalized between 2003 and 2017 at Târgu Mures Emergency County Hospital, in Romania, to gather real-world data on the use of levodopa and alternative therapies.

During this 15-year period, a total of 2,379 patients with Parkinson’s were hospitalized, of whom 1,237 had received the diagnosis for five years or less. The researchers justified this time window because most practicing neurologists consider that the efficacy of levodopa-sparing treatment strategies is significantly reduced after a five-year period. Only patients with early-stage disease were included in the study.

In this group, 18 patients (1.5%) were receiving monoamine oxidase-B inhibitors (MAO-Bi). A total of 665 patients were taking dopamine agonists, of whom 120 were taking the therapy alone (9.7%) and  83 patients (6.7%) in combination with MAO-Bi. Many of the patients (42%) were only taking levodopa, while 481 patients (38.8%) were taking levodopa in combination with other antiparkinsonian therapies.

Assessment of levodopa daily doses, either alone or in combination with other therapies, did not reveal any significant differences between patients grouped by age (younger than 50, 50–65, or older than 65).

“The therapeutic strategies used in the early stages of Parkinson’s disease in the study period are similar to those found in the literature,” the researchers wrote. Still, they recommend that “neurologists treating this disease should, with due diligence, apply a greater proportion of different levodopa-sparing combinations, especially if they are not financially burdensome.”

What makes clinicians decide to prescribe levodopa or other dopamine agonists in the first place is difficult to access through this study, and can be influenced by a number of factors, the researchers said.

“Because our study looks at a long period it is hard to retrospectively assess how much of the clinical decisions was influenced by the early optimism (as reflected in the initial studies) regarding the potential disease-modifying effect as well as the magnitude of the clinical efficacy of dopamine agonists,” they added.

Still, “if the severity of the clinical image requires substitution therapy, the use of combined therapies can significantly reduce levodopa doses and thus the requirement to use the minimum efficient levodopa dose can be achieved,” they concluded.

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8 Common Treatments for Parkinson’s Disease

Parkinson’s disease is a long-term degenerative disease that affects the central nervous system. To date, there is no cure for the condition, but there are medications and therapies available to address some of the symptoms and improve quality of life for patients.

Here are eight of the main drugs and therapies used in the treatment of Parkinson’s disease, according to the Mayo Clinic:

MORE: Discover 10 early signs of Parkinson’s disease

1. Carbidopa-levodopa: Levodopa is a naturally occurring chemical which can enter the brain and be converted to dopamine when combined with carbidopa. The carbidopa also prevents the levodopa from converting into dopamine before it enters the brain.

The is one of the most effective treatments for Parkinson’s although after long-term use, the effects start to fluctuate.

Some people may experience side effects such as nausea, feeling lightheaded, and making sudden involuntary movements.

2. Carbidopa-levodopa infusion: In 2015, the FDA approved Duopa, which is a combination of carbidopa and levodopa in a gel form which is administered via a feeding tube into the small intestine.

Duopa is generally given to patients with advanced Parkinson’s disease whose response to carbidopa-levodopa is varied. The drug is infused continuously so the level of the drugs remains constant.

The risks associated with Duopa are infections at the site of the feeding tube and the tube falling out.

3. Dopamine agonists: Dopamine agonist mimic the effects of dopamine in the brain. They are generally not as effective as levodopa but the effects last longer and they can be used in conjunction with levodopa to counter any fluctuation in efficiency.

These medications can be administered through a patch, oral medications or as an injection. The side effects are also nausea and lightheadedness, but may also cause drowsiness, hallucinations and compulsive behaviors such as gambling, overeating, and hypersexuality — which will need to be addressed by a doctor.

MORE: Find out about the four possible causes of Parkinson’s disease here.

4. MAO-B inhinitors: Medications such as selegiline and rasagiline help to prevent dopamine breaking down in the brain by releasing monoamine oxidase B (MAO-B) enzymes.

Generally, these types of medications should not be taken in conjunction with certain narcotics or antidepressants as occasionally patients will suffer from severe reactions. Side effects of MAO-B inhibitors include insomnia and nausea and if taken with carbidopa-levodopa they can also cause hallucinations.

5. Catechol-O-methyltransferase (COMT) inhibitors: These types of medications help to prolong the effects of levodopa by blocking brain enzymes that deplete dopamine.

The side effects are the same as taking levodopa, mainly involuntary movements and diarrhea.

6. Anticholinergics: Traditionally, anticholinergics have been used over the years to help combat tremors commonly experienced in Parkinson’s disease patients.

However, side effects such as confusion, hallucinations, memory loss, constipation, and urination problems are often more troublesome than the tremors.

MORE: Seven ways to make your home safer for people with Parkinson’s disease

7. Amantadine: Amantadine can be prescribed to patients in the early stages of Parkinson’s to offer relief from their symptoms. In can also be taken in combination with carbidopa-levodopa in the later stages of the disease to help control side effects such as involuntary movements.

8. Deep brain stimulation: Most regularly used in advanced cases of Parkinson’s disease for patients who no longer respond to levodopa, deep brain stimulation involves the insertion of electrodes in the brain which are connected to a generator implanted in the chest area. The electrical pulses sent from the generator to the electrodes can reduce the symptoms of Parkinson’s disease.

The surgery carries serious risks such as brain hemorrhage, stroke, and infection. In addition, patients may need the equipment adjusting or parts replaced which involves more surgery.

MORE: Discover seven ways to help you self-manage Parkinson’s disease

 Parkinson’s News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.

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