Neuroprotective Strategies in Amyotrophic Lateral Sclerosis: Modulation of Neurotransmittory and Neurotrophic Input to Motor Neurons

Amyotrophic lateral sclerosis (ALS) is an adult-onset degenerative disease characterized by the selective progressive death of lower and upper motor neurons. Although its primary cause remains unknown, multiple pathogenic pathways have been identified. The major pathological event in ALS is the degeneration of lower motor neurons (LMNs), and it is thought to be the ultimate cause of death. Thus, neuroprotection of LMNs is assumed to be a reasonable target for P.-F. Pradat (*) Departement des Maladies du Systeme Nerveux, AP-HP, Groupe Hospitalier Pitie-Salpetriere, UMR-678, INSERM-UPMC, Paris, France e-mail: pierre-francois.pradat@psl.aphp.fr L. Dupuis INSERM, U1118, Faculte de Medecine, Mecanismes centraux et peripheriques de la neurodegenerescence, Universite de Strasbourg, Strasbourg, France e-mail: ldupuis@unistra.fr R.M. Kostrzewa (ed.), Handbook of Neurotoxicity, DOI 10.1007/978-1-4614-5836-4_173, # Springer Science+Business Media New York 2014 1417 treating ALS. This assumption guided most of research effort in the last 20 years to develop neuroprotective strategies able to preserve the remaining LMNs. Three major possibilities have been explored and are presented in this review. First, it is thought that LMN survival and degeneration are regulated by neurotransmittory inputs that LMN integrates. Several experimental and imaging studies have shown an impairment of multiple neuronal types innervating motor neurons, in particular glycinergic interneurons, glutamatergic input from proprioceptive type Ia fibers, and serotonergic neurons. The abnormalities in glutamatergic input proved especially fruitful since they led to the discovery of riluzole. A second potential neuroprotective strategy would be to modulate neurotrophic input to motor neurons. Indeed, studies of motor neuron development have shown that their survival is governed by neurotrophic input from its muscle target or from surrounding glia. Thus, modulating neurotrophic support to LMN might be a therapeutic strategy, although the multiple clinical trials based on this possibility were up to now unsuccessful. A last possibility to provide neuroprotection in ALS would be to indirectly modulate the motor neuron survival through action on events occurring outside this cell type, in particular inflammation or abnormal energy metabolism.