piperidines and Motor-Neuron-Disease

Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of the CAG triplet repeat within the androgen receptor (AR) gene. Here, we demonstrated that pathogenic AR upregulates the gene encoding calcitonin gene-related peptide α (CGRP1). In neuronal cells, overexpression of CGRP1 induced cellular damage via the activation of the c-Jun N-terminal kinase (JNK) pathway, whereas pharmacological suppression of CGRP1 or JNK attenuated the neurotoxic effects of pathogenic AR. The depletion of CGRP1 inactivated JNK and suppressed neurodegeneration in a mouse model of SBMA. Naratriptan, a serotonin 1B/1D (5-hydroxytryptamine 1B/1D, or 5-HT1B/1D) receptor agonist, decreased CGRP1 expression via the induction of dual-specificity protein phosphatase 1 (DUSP1), attenuated JNK activity and mitigated pathogenic AR-mediated neuronal damage in cellular and mouse SBMA models. These observations suggest that pharmacological activation of the 5-HT1B/1D receptor may be used therapeutically to treat SBMA and other polyglutamine-related neurodegenerative diseases.

Topics: Animals; Calcitonin; Calcitonin Gene-Related Peptide; Cell Survival; Cells, Cultured; Dual Specificity Phosphatase 1; JNK Mitogen-Activated Protein Kinases; Male; Mice; Mice, Transgenic; Motor Neuron Disease; Muscular Disorders, Atrophic; Peptides; Piperidines; Protein Precursors; Receptors, Androgen; RNA Interference; RNA, Small Interfering; Serotonin 5-HT1 Receptor Agonists; Spinal Cord; Trinucleotide Repeat Expansion; Tryptamines

To evaluate if increased metabolic demand in remaining motor neurons in ALS spinal cord sections can be visualized by 3H-vesamicol binding.. As a presumed marker of the vesicular acetylcholine transporter, 3H-vesamicol was applied in quantitative autoradiography in cervical spinal cord sections from 11 ALS patients and 4 control cases. The regional binding was compared to that of the muscarinic ligand 3H-QNB.. Our results demonstrate the same magnitude of H-vesamicol binding in the ventral horn of ALS spinal cord as compared to controls, despite the profound loss of motor neurons in that specific area in ALS. The specificity of 3H-vesamicol binding for the cholinergic transporter is high in the motor neuron area, and sigma-sites constitute a minor proportion.. The lack of decrease in 3H-vesamicol binding in postmortem ALS spinal cord sections probably reflects an upregulated synthesis of vesicular membranes in remaining and hyperactive motor neurons in vivo.

Topics: Autoradiography; Carrier Proteins; Energy Metabolism; Humans; Membrane Transport Proteins; Motor Neuron Disease; Motor Neurons; Neuromuscular Depolarizing Agents; Piperidines; Reference Values; Spinal Cord; Tritium; Vesicular Acetylcholine Transport Proteins; Vesicular Transport Proteins