Dipentylammonium Binds to the Sigma-1 Receptor and Protects Against Glutamate Toxicity, Attenuates Dopamine Toxicity and Potentiates Neurite Outgrowth in Various Cultured Cell Lines
- 122 Downloads
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.
KeywordsAlzheimer’s disease Sigma-1 receptor Parkinson’s disease Neuroprotection Neurotoxicity
This work was supported by The National Research University Project, Office of Higher Education Commission. NRU-59-057-AS Dr. James M. Brimson was supported by the Rachadapisek Sompote Fund for Postdoctoral Fellowship, Chulalongkorn University, Thailand.
- Brimson JM, Brimson SJ, Brimson CA, Rakkhitawatthana V, Tencomnao T (2012) Rhinacanthus nasutus extracts prevent glutamate and amyloid-β neurotoxicity in HT-22 mouse hippocampal cells: possible active compounds include lupeol, stigmasterol and β-sitosterol. Int J Mol Sci 13:5074–5097. https://doi.org/10.3390/ijms13045074 CrossRefPubMedPubMedCentralGoogle Scholar
- Cagnin M, Ozzano M, Bellio N, Fiorentino I, Follo C, Isidoro C (2012) Dopamine induces apoptosis in APPswe-expressing Neuro2A cells following Pepstatin-sensitive proteolysis of APP in acid compartments. Brain Res 1471:102–117. https://doi.org/10.1016/j.brainres.2012.06.025 CrossRefPubMedGoogle Scholar
- Cherng J, Lin H, Hung M, Lin YR, Chan MH, Lin JC (2006) Inhibition of nuclear factor κ B is associated with neuroprotective effects of glycyrrhizic acid on glutamate-induced excitotoxicity in primary neurons. Eur J Pharmacol 547:10–21. https://doi.org/10.1016/j.ejphar.2006.06.080 CrossRefPubMedGoogle Scholar
- Guerchet M, Prina M, Prince M (2013) Policy brief for heads of government: the global impact of dementia 2013–2050. Policy Br Heads Gov Glob Impact Dement 2013–2050 Publ by Alzheimer’s Dis Int (ADI), London December 2013 1–8Google Scholar
- Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kempner E, Glossmann H (1996) Purification, molecular cloning and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci 93:8072-8077Google Scholar
- Hayashi T, Su T (2007) Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell 131:596-610Google Scholar
- Meunier J, Ieni J, Maurice T (2006) The anti-amnesic and neuroprotective effects of donepezil against amyloid beta25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor. Br J Pharmacol 149:998–1012. https://doi.org/10.1038/sj.bjp.0706927 CrossRefPubMedPubMedCentralGoogle Scholar
- Navarro X, Casas C (2009) Selective sigma receptor agonist 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE084) promotes neuroprotection and neurite elongation through protein kinase C (PKC) signaling on motoneurons. Neuroscience 162:31–38. https://doi.org/10.1016/j.neuroscience.2009.03.067 CrossRefPubMedGoogle Scholar
- Ramachandran S, Lu H, Prabhu U, Ruoho AE (2010) Purification and characterization of guinea pig sigma-1 receptor functionally expressed in Escherichia coli. Protein Expr Purif 51:283–292. https://doi.org/10.1016/j.pep.2006.07.019.PURIFICATION CrossRefGoogle Scholar
- Sánchez-blázquez P, Rodríguez-muñoz M, Herrero-labrador R (2014) The calcium-sensitive Sigma-1 receptor prevents cannabinoids from provoking glutamate NMDA receptor hypofunction: implications in antinociception and psychotic diseases. Int J Neurosychopharmacol 17:1943–1955. https://doi.org/10.1017/S1461145714000029 CrossRefGoogle Scholar
- Urani A, Romieu P, Roman FJ, Yamada K, Noda Y, Kamei H, Tran HM, Nagai T, Nabeshima T, Maurice T (2004) Enhanced antidepressant efficacy of σ 1 receptor agonists in rats after chronic intracerebroventricular infusion of β-amyloid-(1–40) protein. Eur J Pharmacol 486:151–161CrossRefPubMedGoogle Scholar