Ambroxol may slow the progression of Parkinson’s disease


Ambroxol, a medication originally designed to clear phlegm and ease coughing for people with respiratory diseases such as bronchitis, is being tested to see if it can slow down the progression of Parkinson’s disease by keeping cells healthier for longer.

A research team led by Professor Tony Schapira (UCL Queen Square Institute of Neurology) reported in January that ambroxol was safe and well-tolerated in 17 study participants with Parkinson’s disease.

According to the findings published in JAMA Neurology, the drug also effectively crossed the blood-brain barrier and increased levels of the glucocerebrosidase (GCase) protein in the participants’ brain cells.

This protein allows cells to remove waste more effectively, a function which evidence suggests is deficient in some people with Parkinson’s.

Increasing levels of the protein may have the potential to keep cells healthier for longer and, therefore, slow Parkinson’s progression.

This week, The Cure Parkinson’s Trust (CPT), the Van Andel Institute (VAI) and the John Black Charitable Foundation announced £522,126 of funding for the next stage of the research, which will seek to determine the optimal dosage of ambroxol.

The trial will be run this year at the Leonard Wolfson Experimental Neurology Centre at UCL and led by Professor Schapira, with the aim of leading to a larger clinical trial later on.

“By increasing levels of GCase, ambroxol allows cells to remove waste, which would ideally keep cells healthier for longer and could slow down the progression of Parkinson’s,” explained Professor Schapira.

The announcement comes as part of a USD $4.5 million co-funding agreement with the Van Andel Institute (VAI) to support the International Linked Clinical Trials (iLCT) initiative. iLCT is a thriving global programme that aims to develop new, potentially disease-modifying Parkinson’s therapies, many of which are repurposed medications originally designed or approved to treat other diseases.

A research team led by Professor Tony Schapira (UCL Queen Square Institute of Neurology) reported in January that ambroxol was safe and well-tolerated in 17 study participants with Parkinson’s disease.

Candidate drugs are evaluated and prioritised annually by a committee of world-leading Parkinson’s experts, who select which drugs should enter clinical trials in people with the condition.

These drugs have the potential to get to the clinic much faster as they have already passed crucial safety tests.

The iLCT committee had prioritised ambroxol in 2014.

Professor Patrik Brundin, Chair of the Linked Clinical Trials committee and Director of the Center for Neurodegenerative Science at the VAI said:

“We are thrilled to continue our long-standing collaboration with The Cure Parkinson’s Trust on the International Linked Clinical Trials initiative and look forward to expanding our program to evaluate additional promising medications in the coming years. We are especially grateful to the trial participants, without whom this critical work would not be possible.”

Will Cook, CEO of CPT said: “This will enable the launch of many more clinical trials of potentially disease-modifying repurposed and novel drugs that have been identified through the diligent iLCT process, and thereby bringing us closer to our goal: a cure for the 10 million people living with Parkinson’s globally.”

Amyotrophic lateral sclerosis (ALS) is a multifactorial and fatal neurodegenerative disease. Growing evidence connects sphingolipid metabolism to the pathophysiology of ALS.

In particular, levels of ceramides, glucosylceramides, and gangliosides are dysregulated in the central nervous system and at the neuromuscular junctions of both animal models and patients.

Glucosylceramide is the main precursor of complex glycosphingolipids that is degraded by lysosomal (GBA1) or non-lysosomal (GBA2) glucocerebrosidase.

Here, we report that GBA2, but not GBA1, activity is markedly increased in the spinal cord, of SOD1G86R mice, an animal model of familial ALS, even before disease onset. We therefore investigated the effects of ambroxol hydrochloride, a known GBA2 inhibitor, in SOD1G86R mice.

A presymptomatic administration of ambroxol hydrochloride, in the drinking water, delayed disease onset, protecting neuromuscular junctions, and the number of functional spinal motor neurons. When administered at disease onset, ambroxol hydrochloride delayed motor function decline, protected neuromuscular junctions, and extended overall survival of the SOD1G86R mice.

In addition, ambroxol hydrochloride improved motor recovery and muscle re-innervation after transient sciatic nerve injury in non-transgenic mice and promoted axonal elongation in an in vitro model of motor unit.

Our study suggests that ambroxol hydrochloride promotes and protects motor units and improves axonal plasticity, and that this generic compound is a promising drug candidate for ALS.


myotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a loss of cortical motor neurons in the motor cortex and spinal motor neurons located in the brainstem and in the spinal cord with denervation.

Considered to be the most common motor neuron disease in adults, ALS leads to progressive paralysis, muscle atrophy, fasciculation, and spasticity and affects the central nervous system and peripheral organs (Schmitt et al., 2014).

ALS is associated with sporadic forms (90%) and familial form (10%). Mutations on genes encoding superoxide dismutase 1 (SOD1), TAR DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS), and repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) (Lattante et al., 2015) are now documented.

It is reported that lipid metabolism in ALS patient has a major impact on the disease severity. A high incidence of dyslipidemia and hypermetabolism is present in ALS patients (Desport et al., 2001Funalot et al., 2009) and hypermetabolism and high low-density lipoprotein (LDL)/high-density lipoprotein (HDL) ratios or high body mass index are associated with better prognosis and slower disease progression (Dupuis et al., 2008Paganoni et al., 2011Jésus et al., 2018).

The causes of the metabolic dysfunctions in ALS remain unknown and could result from central pathologies combined with peripheral alterations.

Metabolomic studies have now shown that recent human evolution has marked changes in lipid metabolism in muscle and brain to support increased metabolic activity (Noakes and Spedding, 2012Bozek et al., 2014).

Beyond their role in energy metabolism, lipids and particularly sphingolipids are modulators of cellular signaling pathways and participate in the maintenance and repair of the various components of the motor axis such as neurons and muscles.

Our transcriptomic studies on muscle biopsies in ALS patients showed a significant increase in the expression of the UGCG gene (UDP-glucose ceramide glucosyltransferase), encoding the sphingolipid metabolism enzyme that synthesizes glucosylceramide (GlcCer) (Henriques et al., 2015Dodge, 2017Henriques et al., 2017).

It has been shown in ALS that GlcCer and ceramide levels are deregulated (Cutler et al., 2002Dodge et al., 2015Henriques et al., 2015Henriques et al., 2018).

These data suggest that GlcCer plays a key role in the pathophysiology of ALS. We performed a lipidomic analysis of different tissues of SOD1G86R mice, an animal model of ALS, and we observed a complete rearrangement of the main lipid classes, including sphingolipids like GlcCer and ceramides in the muscles and spinal cords of SOD1G86R mice, before the onset of the disease.

Inhibition of GlcCer synthesis by administration of a UGCG inhibitor (AMP-DMN) significantly delays functional recovery after sciatic nerve injury (Henriques et al., 2015Henriques et al., 2018). GlcCer is the precursor of gangliosides, and this hydrolysis is performed by GBA1 and GBA2, two beta-glucocerebrosidases (GCases).

Our previous results have shown a beneficial effect for SOD1G86Rmice after inhibition of GlcCer degradation (Henriques et al., 2017). Partial inhibition of GlcCer degradation with a low dose of conduritol B epoxide (CBE) (10 mg/kg/d) delays disease onset and improves motor functions in presymptomatic and in symptomatic SOD1G86R mice.

Pharmacological inhibition of GCase by CBE preserves motor neuron number and the neuromuscular junctions (NMJs) in SOD1G86R mice. Furthermore, CBE promotes recovery after sciatic nerve injury in vivo (Henriques et al., 2017).

Conversely, a high dose CBE (100 mg/kg/d) induced neuronal toxicity and can be used to inhibit the lysosomal GCase to induce a chemical model of Gaucher’s diseases (Kanfer et al., 1975Vardi et al., 2016).

Indeed, CBE is an inhibitor of lysosomal GCase (GBA1) and, less potently, of the non-lysosomal GCase (GBA2) (Ridley et al., 2013). Moreover, loss-of-function mutations of GBA1 are a major cause of hereditary Parkinson’s Disease (PD), while the activation of beta-GCase increases alpha-synuclein clearance and lysosomal function in dopaminergic neurons (Schapira, 2015Mazzulli et al., 2016Stojkovska et al., 2018); thus, there may be a risk of PD with GBA1 inhibitors.

GBA2 is localized at the plasma membrane and as a membrane-associated protein at the Golgi apparatus and at the endoplasmic reticulum (Woeste and Wachten, 2017).

Loss of function of GBA2 is associated with hereditary spastic paraplegia suggesting that the regulation of GlcCer at the plasma membrane and/or at intracellular organelles is important for the maintenance of motor functions, even if the role of GBA2 in the central nervous system remains poorly understood.

Our approach was therefore to inhibit the non-lysosomal GBA2 without inhibiting GBA1. Among the safe molecules able to cross the blood–brain barrier (BBB), ambroxol hydrochloride (AMB) has been extensively studied (Albin and Dauer, 2014McNeill et al., 2014Ambrosi et al., 2015Migdalska‐Richards et al., 2016bMigdalska‐Richards et al., 2017O’Regan et al., 2017). In our study, we confirmed that AMB inhibited GBA2 activity.

We have then investigated the effects of AMB in vivo, in a transgenic model of ALS and on non-transgenic mice to determine whether it could improve the lifespan of SOD1G86R mice and stimulate the plasticity of the neuromuscular junctions (NMJs).



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