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| Prof. Stephen Hawking. Image Credits: Getty Images |
Who can forget the sight of Professor Stephen Hawking hunched in his wheel chair with hands on his lap and speaking through a speech-generating device? Professor Hawking suffered from a type of Motor Neuron Disease (MND) called the Amyotrophic Lateral Schlerosis (ALS), also known as the Lou Gehrig’s disease. It is a progressive disease resulting from the loss of neurons controlling voluntary muscles that produce movement such as talking, moving, and eating. Currently, there is no cure for ALS or treatment for halting the progression of the disease. The patient has 3-4 years at most from the time of diagnosis (Stephen Hawking was an exception). Approximately fifteen thousand Americans die each year from the disease. More men are afflicted than women and the incidence of ALS increases after the age of 55.
What we know about ALS? Unfortunately, not much
There are a number of studies, clinical and non-clinical, on ALS to find a cure and to help the patients have a better quality of life. Most of these efforts are hampered because the pathways leading to development of ALS are still unclear. Few genes have been shown to be associated with the disease-C9ORF72, SOD1, FUS, etc. However, 90% of the cases are sporadic with no known cases of the disease in the family. There is no cure for the disease and the drugs approved by the FDA, riluzole and edaravone, only prolong life by few months.
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| Effect of ALS on nerve cells and muscles |
Mechanism of ALS and current study
Cells maintain a fine balance of various cations and anions such as Na+, Cl-, Ca2+, through involvement of various organelles, ion pumps and channels on the cell membrane as well as organelle membranes. Evidence for involvement of Ca2+dysregulation and organelle dysfunction in various neurological and neuro-degenerative diseases is increasing. However, exact mechanisms leading to the death of motor neurons in ALS and other neuro-degenerative diseases remain elusive.
A recent study published in the Frontiers in Cellular Neuroscience, focuses on involvement of Ca2+ in motor neuron degeneration and how riluzole, but not melatonin, ameliorates MN degeneration in the model systems studied.
Riluzole, a FDA approved neuro-protective drug for ALS, is known to preferentially block sodium channels and also, accelerate glutamate clearance from synapse and prevent glutamate release from presynaptic terminals. Another molecule that has gained recent fame is Melatonin; it’s an antioxidant known to scavenge free radicals and reactive oxygen species (ROS). Melatonin has been shown to be neuro-protective in Alzheimer’s disease, another neuro-degenerative disease with no known cures.
This research, conducted on human cell lines and mice, elegantly shows how the drugs alleviate Ca2+-induced toxicity in the cells and in mitochondria, in particular. Moreover, it establishes a method to screen drug targets individually or together (similar to a multi-drug therapy regime) and fast track drug screening at the pre-clinical level.
resYear if research discovered a mutation in a key gene, SOD1 is involved in the pathogenicity of ALS. The current research investigated how two drugs, riluzole and melatonin, might prevent the mitochondrial SOD1 mediated cell death. They used the chemical, sodium azide, a known inhibitor of elctron transport chain IV, to induce excito-toxicity and eventual cell death in control and SOD1 mutant cells. They then observe how this toxicity is reduced when riluzole and melatonin are used. Intracellular calcium levels were measured using fluorescence-based assays. They go on to show how the function of mitochondria is affected in sod-1mutant human cells and mice leading to motor neuron degeneration and that riluzole, but not melatonin, moderately ameliorates motor neuron degeneration by inhibiting calcium toxicity.
The project leader and lead author of the paper, Dr. Manoj Kumar Jaiswal, when asked how this work is significant, answered, “Many ALS clinical trials investigating the efficacy of a new drug have failed due to the vast heterogeneity of the ALS patient population, resulting in drugs benefitting a small patient subgroup. We have done the groundwork and tested the efficacy of these two drugs (riluzole and melatonin) on mutant SOD1 neuronal cell lines and control cells. Different patient cell types react differently to the same antioxidant drugs and therefore our study can be extended in the future to either motor neurons co-cultured with astrocytes, microglia, oligo dendrocytes and several other cell types or cell types specific iPSC (induced Pluripotent Stem Cells) derived from ALS patients”.
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| Mechanism of action of Riluzole |
This work has shown the importance of gaining exact knowledge of mechanism of drug action and goes on to show how riluzole can prevent cell death by restoring Ca2+homeostasis. Dr. Jaiswal concludes, “Molecules targeting the protection of mitochondrial function and Ca2+ homeostasis could be useful in both sporadic and familial ALS and most likely prolong survival of ALS patients". His experiments promise a potentially effective and methodological way to test the multiple drugs and their targets most likely tested with different drug cocktails to check the efficacy of multi-drug therapy.
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