Preventive Measures For AMPA Found To Induce Excitotoxicity In ALS Patients

Previous research has revealed the importance of mitochondrial metabolism in Amyotropic Lateral Sclerosis (ALS). ALS neurodegenerative disorder is characterized by death of motor neurons (MN) in the upper motor cortex of the brain and in the lower stem and spinal cord (comprising the Central Nervous System). As far as etiological analysis of the factors responsible for such a condition is concerned, around 10% are considered to be hereditary while the remaining 90% do not have any specific causes. A number of factors have been shown to contribute to such a condition like oxidative stress, mitochondrial dysfunction, glutamate receptor-mediated excitotoxicity, neuro-inflammation, aberrations in axonal transport and protein aggregation.

A recent report published in the May 14^th edition of Acta Neuropathologica Communications co-authored by Citlalli Netzahualcoyotzi and Ricardo Tapia has focussed on one of these probable reasons – excitotoxicity and possible its possible remedies.

The report suggests that excessive neurotransmission of Calcium (Ca²⁺) through glutamate receptors could lead to over excitation of neurones. This disturbs the balance in calcium levels in the CNS, causing release of lytic enzymes and overproduction of oxygen free radicals that ultimately causes mitochondrial dysfunction and leads to failure in energy production. This acts as a ‘shock’ to motor neurones causing motor neurones to get paralysed and ultimately die.

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Laboratory experiments with rats, having artificially infused α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) glutamate receptor type for several days via microdialysis or osmotic minipumps causing increased permeability of calcium ions in the lumbar spinal cord, caused paralysis of the rear limbs and progressive bilateral motor neurone degeneration. Apart from causing extensive motor neurone damage, overactivity of AMPA receptors caused increase in the number of astrocytes (astrogliosis) which was another indicator of neurological damage.

As a protective measure, researchers checked the effects of energy substrates pyruvate and β-hydroxybutyrate (βHB) and the antioxidants glutathione ethyl ester (GEE) and ascorbate in reducing the extent of damage caused by AMPA. It was seen that the energy substrates pyruvate and β-hydroxybutyrate (βHB) were successful in salvaging the mitochondrial energy deficit caused by exciotoxicity due to calcium influx, and reduced the death of motor neurones to as less as 25% of the total number of deaths caused previously. Moreover, astrogliosis was completely prevented. However, the antioxidants were ineffective in this case.