Dipentylammonium Binds to the Sigma-1 Receptor and Protects Against Glutamate Toxicity, Attenuates Dopamine Toxicity and Potentiates Neurite Outgrowth in Various Cultured Cell Lines

• Published in: Neurotoxicity research 2018-08, Vol.34 (2), p.263-272
• Main Authors: Brimson, James M., Safrany, Stephen T., Qassam, Heider, Tencomnao, Tewin
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Boronic Acids - pharmacology; Cell Biology; Cell Line; Dopamine - pharmacology; Dose-Response Relationship, Drug; Excitatory Amino Acid Agonists - pharmacology; Glutamic Acid - pharmacology; Humans; Imidazoles - pharmacology; L-Lactate Dehydrogenase - metabolism; Neurobiology; Neuroblastoma - pathology; Neurochemistry; Neurology; Neuronal Outgrowth - drug effects; Neuroprotective Agents - pharmacology; Neurosciences; NF-kappa B - metabolism; Original Article; Pentazocine - pharmacology; Pharmacology/Toxicology; Protein Transport - drug effects; Radioligand Assay; Receptors, sigma - metabolism; Sigma-1 Receptor; Tritium - pharmacokinetics
• ISSN: 1029-8428; 1476-3524
• DOI: 10.1007/s12640-018-9883-5

Alzheimer’s disease is a neurodegenerative disease that affects 44 million people worldwide, costing the world $605 billion to care for those affected not taking into account the physical and psychological costs for those who care for Alzheimer’s patients. Dipentylammonium is a simple amine, which is structurally similar to a number of other identified sigma-1 receptor ligands with high affinities such as (2R-trans)-2butyl-5-heptylpyrrolidine, stearylamine and dodecylamine. This study investigates whether dipentylammonium is able to provide neuroprotective effects similar to those of sigma-1 receptor agonists such as PRE-084. Here we identify dipentylammonium as a sigma-1 receptor ligand with nanomolar affinity. We have found that micromolar concentrations of dipentylammonium protect from glutamate toxicity and prevent NFκB activation in HT-22 cells. Micromolar concentrations of dipentylammonium also protect stably expressing amyloid precursor protein Swedish mutant (APP/Swe) Neuro2A cells from toxicity induced by 150 μM dopamine, suggesting that dipentylammonium may be useful for the treatment of Parkinsonian symptoms in Alzheimer’s patients which are often associated with a more rapid deterioration of cognitive and physical ability. Finally, we found that low micromolar concentrations of dipentylammonium could out preform known sigma-1 receptor agonist PRE-084 in potentiating neurite outgrowth in Neuro2A cells, further suggesting that dipentylammonium has a potential use in the treatment of neurodegenerative diseases and could be acting through the sigma-1 receptor.