A new study led by Prs. Yehezkel Ben-Ari & Constance Hammond (Neurochlore and B&A Therapeutics, Marseille, France) demonstrates that bumetanide, an antagonist of the NKCC1 chloride importer, normalizes the activity of neurons in the striatum and alleviates motor impairment in a mouse model of Parkinson’s disease. These findings corroborate the results of a pilot clinical study previously conducted in collaboration with Pr. Philippe Damier (CHU Nantes, France), and set solid foundations for a phase 2 clinical trial in this indication. The work is published in Nature Communications on 12th april, 2018.
Parkinson’s disease (PD) is a degenerative disorder of the central nervous system that progressively leads to motor impairments including movement difficulties (akinesia), tremors, rigidity and often the development of a distinctive gait characterized by a stooped position, diminished or absent arm swings and freezing episodes (a temporary inability to move). Most cases of Parkinson’s disease are sporadic, and their origin remains unknown. PD is due to loss of neurons that produce dopamine leading to a loss of this chemical messenger notably in the striatum, which is instrumental to the control of movements. Current therapies for PD are all designed to restore dopamine transmission in the brain (by increasing the amount of brain dopamine or acting directly on dopamine receptors). These treatments are efficient but associated with side effects like involuntary movements (dyskinesias) and their efficiency usually decreases over time raising the need for other non dopaminergic treatments.
This new study published in Nature Communications results from the convergence of 2 series of observations: studies by the group of Pr. Hammond showing that loss of dopaminergic neurons severly impacts GABAergic signals in the striatum and investigations by Pr. Ben-Ari’s teams showing that GABAergic dysfunction in many pathological conditons is due to an accumulation of chloride in neurons that suppresses the inhibitory action of GABA. Hence the idea to reduce these levels with bumetanide, a blocker of chloride import in cells.
In this new study, they have first discovered that, unlike most neurons which typically release a single neurotransmitter, a subpopulation of striatal neurons actually releases two different chemical agents: acetylcholine and GABA, which respectively activate and inhibit neuronal activity to ensure proper motor control. In a mouse model of Parkinson’s disease produced by chemical destruction of dopamine cells, chloride accumulates in these neurons, leading to a loss of GABAergic inhibition and an unbalanced excitatory drive and motor disturbance. Bumetanide restores GABAergic inhibition, normalizes neuronal activity and spectacularly improves motor skills.
“We now provide mechanistic insight into the effects of bumetanide on striatal neurons to improve motor function in Parkinson’s disease”, stresses Pr. Yehezkel Ben-Ari, President and co-founder of Neurochlore and B&A Therapeutics. “Our results also confirm our hypothesis that the pathological state arises as a result of a chronic defect in the mechanisms that control the concentration of intracellular chloride to regulate neuron excitability. It raises the possibility of a novel treatment for Parkinson’s that is not based on the restoration of dopaminergic signals. ”
In keeping with this, Pr. Damier conducted in 2016 a pilot open study on 4 parkinsonian patients and demonstrated that bumetanide treatment, associated with levodopa treatment, reduced the severity of some motor symptoms, in particular freezing and falls. “Current treatments for Parkinson’s all seek to restore dopamine transmission in the brain. Our work over the past years has identified bumetanide as an alternative that we now know acts by a different mechanism”, explains Pr. Philippe Damier, Professor of neurology at Nantes University Hospital “In addition, bumetanide has been used for its diuretic properties for several decades to treat hypertension, broncho-pulmonary dysplasia, nephritic syndromes or heart congestions and is known to cause mild and manageable side-effects (diuresis, hypokalemia and dehydration). It could therefore represent a breakthrough in the treatment of the disease and may lead to a real gain in quality of life for our patients.”
This convergence of experimental research and pilot clinical trials open the way to a phase 2 clinical trial in this indication.
About B&A Therapeutics
B&A Therapeutics has been created 4 years ago (primarily) by Y Ben-Ari, P Damier and C Hammond to gain better understanding on the pathogenesis of Parkinson Disease and develop novel treatments. It relies on the expertise of Prof Hammond and Damier on the experimental and clinical features of the disease, respectively, and Prof Ben-Ari on chloride regulation and the usefulness of Bumetanide in restoring low levels of chloride in neurons. It is accompanied by experts in drug development and patent issues. In parallel to its experimental research, B&A Therapeutics sponsors clinical trials on Parkinson Disease.
Neurochlore is developing an innovative therapeutic strategy to ameliorate developmental brain pathologies. Located within the biotech district of Grand Luminy campus (Marseille) and founded by Pr. Ben-Ari, the company has formed close links with internationally recognized scientific experts in some fields of developmental neurobiology and neurological disorders, favoring interactions between basic and applied research. 21 researchers and ingeneers have been recruited by the company. Neurochlore has also established extensive collaborations with drug developers and clinical experts in neuro-pediatrics and psychiatry to accelerate the development and clinical evaluation of its therapeutic agent and extend its application field. The company has an international patent in the use of bumetanide in the treatment of Autism Spectrum Disorders (ASD) and Fragile X. In parallel to its extensive research on brain development in health and disease, Neurochlore sponsors clinical trials on developmental disorders.
About Nantes University Hospital
Nantes is a University Hospital with out and in-patients facilities to provide diagnosis and treatment for most diseases. In close collaboration with Nantes University and INSERM, the hospital develops several programs in basic and clinical research. Through a medical school, it is in charge of general and specialized medical training. The department of neurology has specific expertise in stroke, Parkinson’s and Alzheimer’s disease, and multiple sclerosis. The clinical research center has a 15-year experience in phase 2 drug/device trials and pathophysiological studies in these fields. It has close links with two basic research labs: one dedicates to the enteric nervous system (with a focus on its dysfunction and lesion in PD and other degenerative diseases) and one to neuro-immunology (with a focus on multiple sclerosis alteration).