Cough Medicine Shows Promise in Slowing Parkinson’s Dementia

 Didn't your competent? doctor start working on GCase a long time ago? NO? So, you DON'T have a functioning stroke doctor, do you?

Antioxidants Early in Parkinson's Disease May Halt Degeneration

 September 2017

Cough Medicine Shows Promise in Slowing Parkinson’s Dementia

Summary: A clinical trial has revealed that Ambroxol, a common cough medicine in Europe, may help slow cognitive decline in people with Parkinson’s disease dementia. The 12-month study found that the drug stabilized psychiatric symptoms, protected against brain damage, and even improved cognition in genetically at-risk participants.

Ambroxol boosts an enzyme called GCase, which is often deficient in Parkinson’s patients, contributing to brain cell damage. While not yet approved for use in North America, the drug’s safety profile and early benefits make it a compelling candidate for further study.

Key Facts:

• Stabilized Symptoms: Ambroxol halted psychiatric decline seen in the placebo group.
• Genetic Benefit: Cognition improved in those with GBA1 gene variants.
• Brain Protection: GFAP, a marker of brain damage, remained stable on Ambroxol.

Source: Lawson Research Institute

Dementia poses a major health challenge with no safe, affordable treatments to slow its progression.

Researchers at Lawson Research Institute (Lawson), the research arm of St. Joseph’s Health Care London, are investigating whether Ambroxol – a cough medicine used safely for decades in Europe – can slow dementia in people with Parkinson’s disease.

When this enzyme doesn’t work properly, waste builds up in brain cells, leading to damage. Credit: Neuroscience News

Published today in the prestigious JAMA Neurology, this 12-month clinical trial involving 55 participants with Parkinson’s disease dementia (PDD) monitored memory, psychiatric symptoms and GFAP, a blood marker linked to brain damage.

Parkinson’s disease dementia causes memory loss, confusion, hallucinations and mood changes. About half of those diagnosed with Parkinson’s develop dementia within 10 years, profoundly affecting patients, families and the health care system.

Led by Cognitive Neurologist Dr. Stephen Pasternak, the study gave one group daily Ambroxol while the other group received a placebo.

“Our goal was to change the course of Parkinson’s dementia,” says Pasternak. “This early trial offers hope and provides a strong foundation for larger studies.”

Key findings from the clinical trial include:

• Ambroxol was safe, well-tolerated and reached therapeutic levels in the brain

• Psychiatric symptoms worsened in the placebo group but remained stable in those taking Ambroxol.

• Participants with high-risk GBA1 gene variants showed improved cognitive performance on Ambroxol

 • A marker of brain cell damage (GFAP) increased in the placebo group but stayed stable with Ambroxol, suggesting potential brain protection.

Although Ambroxol is approved in Europe for treating respiratory conditions and has a long-standing safety record – including use at high doses and during pregnancy – it is not approved for any use in Canada or the U.S.

“Current therapies for Parkinson’s disease and dementia address symptoms but do not stop the underlying disease,” explains Pasternak.

“These findings suggest Ambroxol may protect brain function, especially in those genetically at risk. It offers a promising new treatment avenue where few currently exist.”

Ambroxol supports a key enzyme called glucocerebrosidase (GCase), which is produced by the GBA1 gene. In people with Parkinson’s disease, GCase levels are often low. When this enzyme doesn’t work properly, waste builds up in brain cells, leading to damage.

Pasternak learned about Ambroxol during a fellowship at The Hospital for Sick Children (SickKids) in Toronto, where it was identified as a treatment for Gaucher disease – a rare genetic disorder in children caused by a deficiency of GCase.

He is now applying that research to explore whether boosting GCase with Ambroxol could help protect the brain in Parkinson’s-related diseases.

“This research is vital because Parkinson’s dementia profoundly affects patients and families,” says Pasternak. “If a drug like Ambroxol can help, it could offer real hope and improve lives.”

Funded by the Weston Foundation, this study is an important step toward developing new treatments for Parkinson’s disease and other cognitive disorders, including dementia with Lewy bodies. Pasternak and his team plan to start a follow-up clinical trial focused specifically on cognition later this year.

About this neuropharmacology and Parkinson’s disease research news

Author: Debora Flaherty
Source: Lawson Research Institute
Contact: Debora Flaherty – Lawson Research Institute
Image: The image is credited to Neuroscience News

Original Research: Closed access.
“Ambroxol as a Treatment for Parkinson Disease Dementia A Randomized Clinical Trial” by Stephen Pasternak et al. JAMA Neurology

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Antioxidants Early in Parkinson's Disease May Halt Degeneration

Northwestern Medicine scientists have identified a toxic cascade that leads to neuronal degeneration in patients with Parkinson's disease (PD) and figured out how to interrupt it, reports a study published September 7 in the journal Science.
Intervening with an antioxidant early in the disease process may break the degenerative cycle and improve neuron function in PD, the study showed.
The scientists also discovered that mouse models of PD didn't have the same abnormalities they found in human PD neurons, revealing the importance of studying human neurons to develop new therapies.
Dr. Dimitri Krainc, the Aaron Montgomery Ward Professor and chair of neurology at Northwestern University Feinberg School of Medicine, is the study senior author. Lena Burbulla, a postdoctoral fellow in Krainc's laboratory, is first author.
The research was started about six years ago in Krainc's lab at Massachusetts General Hospital and Harvard Medical School and was completed in the last four years at Feinberg.
PD is the second most common neurodegenerative disorder, primarily caused by the death of dopamine-containing neurons in the substantia nigra, a region of the brain involved in motor control. While people naturally lose dopamine neurons as they age, patients with PD lose a much larger number of these neurons and the remaining cells are no longer able to compensate.
Understanding how and why these neurons die is an important step in identifying treatments, Krainc said. While previous research indicated that the cellular mechanism behind the cell death involved the mitochondria and lysosomes, how these two pathways converge in dopamine neurons to cause cell death remained unknown up until now.
Using human neurons from Parkinson's patients, Krainc and colleagues identified a toxic cascade of mitochondrial and lysosomal dysfunction initiated by an accumulation of oxidized dopamine and a protein called alpha-synuclein. Specifically, the current study demonstrated that an accumulation of oxidized dopamine depressed the activity of lysosomal glucocerebrosidase (GCase), an enzyme implicated in PD. That depression in turn weakened overall lysosomal function and contributed to degeneration of neurons.
The accretion of oxidized dopamine didn't just interfere with lysosomes, however. Krainc and his colleagues discovered that the dopamine also damaged the neurons' mitochondria by increasing mitochondrial oxidant stress. These dysfunctional mitochondria led to increased oxidized dopamine levels, creating a vicious cycle.
"The mitochondrial and lysosomal pathways are two critical pathways in disease development," said Krainc, who also is the director of the Center for Rare Neurological Diseases and a professor of neurological surgery and of physiology. "Combined with the alpha-synuclein accumulation, this study links the major pathological features of PD."
Once they had catalogued this toxic cascade, Krainc and his colleagues began looking for ways to interrupt it.
"One of the key strategies that worked in our experiments is to treat dopamine neurons early in the toxic cascade with specific antioxidants that improve mitochondrial oxidant stress and lower oxidized dopamine," Krainc said. "With this approach, we found that we can attenuate or prevent the downstream toxic effects in human dopaminergic neurons."
This approach to interrupting the toxic cascade of oxidized dopamine may provide a target for the development of future therapies. However, identifying patients or subjects with early-stage neurodegeneration can be difficult, because damage has often occurred far before any symptoms are apparent, according to Krainc.
Consequently, genetic testing will be central to future diagnostic efforts. Causative genes are prime candidates for screening, while risk genes such as GBA1 are less conclusive but still important markers, Krainc said. Early detection will also rely on brain imaging and other clinical signifiers.
Interestingly, when compared to human cellular models, mouse models of PD did not demonstrate the same toxic cascade, according to the study. Krainc and his colleagues showed this is due to differences in metabolism of dopamine between species, and underscored the importance of studying human neurons to discover new targets for drug development.