Treating parkinsonism require targeted therapies that restore the balance between dopamine and acetylcholine

Alteration in neurotransmitters signaling in basal ganglia has been consistently shown to significantly contribute to the pathophysiological basis of Parkinson’s disease and Huntington’s disease. Dopamine is an important neurotransmitter which plays a critical role in coordinated body movements. Alteration in the level of brain dopamine and receptor radically contributes to irregular movements, glutamate mediated excitotoxic neuronal death and further leads to imbalance in the levels of other neurotransmitters viz. GABA, adenosine, acetylcholine and endocannabinoids. This review is based upon the data from clinical and preclinical studies to characterize the role of various striatal neurotransmitters in the pathogenesis of Parkinson’s disease and Huntington’s disease. Further, we have collected data of altered level of various neurotransmitters and their metabolites and receptor density in basal ganglia region. Although the exact mechanisms underlying neuropathology of movement disorders are not fully understood, but several mechanisms related to neurotransmitters alteration, excitotoxic neuronal death, oxidative stress, mitochondrial dysfunction, neuroinflammation are being put forward. Restoring neurotransmitters level and downstream signaling has been considered to be beneficial in the treatment of Parkinson’s disease and Huntington’s disease. Therefore, there is an urgent need to identify more specific drugs and drug targets that can restore the altered neurotransmitters level in brain and prevent/delay neurodegeneration.

Treatments for Parkinson’s disease have most recently focused on increasing dopamine, a chemical messenger in the brain that affects reward-based behaviors and motivation, as well as movement.

A new study by Yale researchers challenges long-held assumptions about dopamine’s sole role in this disorder.

In people with Parkinson’s disease, nerve cells that produce dopamine slowly die.

The loss of dopamine leads to slower movements, resting tremors, and other symptoms that worsen over time.

To reverse parkinsonism – the collection of symptoms seen in Parkinson’s disease – doctors provide a treatment that increases dopamine levels in the striatum, a portion of the brain that is responsible for motor learning.

However, medical treatments do not consider the effects of parkinsonism on another neurotransmitter, acetylcholine.

Scientists had previously believed that when dopamine levels dropped, acetylcholine levels increased.

However, this relationship had never been thoroughly investigated, despite acetylcholine’s likely role in creating a movement disorder called dyskinesia, which develops in most patients after several years of dopamine treatment for parkinsonism.

To investigate, senior author Nigel S. Bamford and the research team studied healthy mice and mice genetically modified to exhibit parkinsonism with progressively decreasing dopamine levels.

In healthy mice, the researchers observed, the ratio of dopamine and acetylcholine remains in equilibrium, and small changes in these chemicals do not significantly impact motor function.

In mice with parkinsonism, the reduction in dopamine decreases the activity of a small population of cells within the striatum that are responsible for making acetylcholine.

While the concentrations of both dopamine and acetylcholine decline, the balance between these two neurotransmitters shifts to favor acetylcholine.

Under these conditions, Bamford and his co-authors learned, motor function in parkinsonism becomes dependent on both dopamine and acetylcholine.

These findings suggest that treating parkinsonism may require targeted therapies that restore the balance between these two chemicals, instead of focusing solely on dopamine, said the researchers.

The study is published in the journal Neuron.

Types of anticholinergics used in Parkinson’s disease

Anticholinergics were the first form of treatment for Parkinson’s disease and have been used to treat Parkinson’s-related tremors and dystonia for a long time.

The earliest reports of anticholinergic medications for Parkinson’s are from the 19th century. Many anticholinergic medications have been developed, with a wide assortment marketed in the mid-20th century.

The two most commonly prescribed anticholinergics are Cogentin (benztropine) and Artane (trihexyphenidyl), both available as generics.

Other anticholinergics include Norflex (orphenadrine), also available as a generic,  and profenamine, available in Canada. 

Kemadrin (procyclidine) is no longer available in the U.S. but is available in Europe and as a generic in Canada.

Anticholinergics in clinical trials for Parkinson’s disease

Several studies have shown that anticholinergics are useful in reducing tremors.

Two studies, one published in Movement Disorders and the other in Archives of Neurology, found that anticholinergics, as well as dopamine agonists (medications that mimic the effect of dopamine), are  effective at reducing tremors in Parkinson’s disease.

Some patients responded better to one treatment than the other.

Studies have also shown, however, that anticholinergics may be associated with greater cognitive decline in Parkinson’s patients.

A meta-analysis study (a study of many previous studies) showed that anticholinergics lead to a definite improvement in motor symptoms but are also associated with side effects including cognitive decline and hallucinations.

The study analyzed six anticholinergics but did not have enough evidence to compare their efficacy.

Additional information

The most common side effects of anticholinergics include blurred vision, dry mouth, constipation, nausea, difficulty emptying the bladder, impaired sweating, and rapid heart rate. Some side effects that are usually more noticeable in older adults include issues with memory, confusion, and hallucinations.

For this reason, anticholinergics are usually not prescribed to patients over age 70.

More information: Jonathan W. McKinley et al. Dopamine Deficiency Reduces Striatal Cholinergic Interneuron Function in Models of Parkinson’s Disease, Neuron (2019). DOI: 10.1016/j.neuron.2019.06.013

Journal information: Neuron
Provided by Yale University


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