Evaluation of neuroprotective effects of Sigma 1 receptor ligands on motoneuron degeneration models.

Student thesis: Doctoral thesis


Motor neuron diseases (MND) include a wide type of sporadic and hereditary neurological disorders characterized by degeneration of motor neurons (MNs), and are highly debilitating and severe conditions for which only limited therapeutic options are available. Amyotrophic lateral sclerosis (ALS), the most frequent MND in adults, is a fatal neurodegenerative disease with degeneration of MNs in the spinal cord and the brain. Currently, available treatments have modest effects on patient survival. Thus, there is an urgent need to understand the molecular mechanisms involved in the MN degeneration to discover new therapeutic targets and develop effective therapies protecting and restoring neuronal integrity. Among the putative targets for neuroprotection, recently the Sigma-1 receptor (Sig-1R) has gained attention. The aim of the present thesis was to assess the therapeutic potential of several Sig-1R ligands for promoting MN survival and maintenance of neuromuscular function. For this purpose, we first used an in vitro model of spinal cord organotypic culture subjected to chronic excitotoxicity, and then, two murine models, the spinal nerve injury and the transgenic SOD1G93A mice. Our in vitro results revealed that the Sig-1R ligands tested (PRE-084, BD1063, SA4503, EST79232 and EST79376) increased MN survival under chronic excitotoxicity. On the other hand, in vivo studies showed that the neuroprotective effects observed differed between the Sig-1R ligands tested. In the SOD1G93A mouse treatment with several Sig-1R ligands was effective to preserve neuromuscular function and junctions of the hindlimbs, to increase the number of surviving MNs and to modulate glial reactivity in the spinal cord. These Sig-1R ligands were also able to increase MN survival and modulate glial reactivity after a spinal nerve injury. Altogether, the results of this thesis provide clear evidence that Sig-1R is an interesting target for the treatment of MND.
Date of Award26 Nov 2021
Original languageEnglish
SupervisorMireia Herrando Grabulosa (Co-director) & Xavier Navarro Acebes (Co-director)

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