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SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease.
Neuropharmacology. 2011 Dec; 61(8):1441-51.N

Abstract

We have recently shown that the Na(+)/Ca(2+) exchanger (NCX) is involved in nitric oxide (NO)-induced cytotoxicity in cultured astrocytes and neurons. However, there is no in vivo evidence suggesting the role of NCX in neurodegenerative disorders associated with NO. NO is implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease. This study examined the effect of SEA0400, the specific NCX inhibitor, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a model of Parkinson's disease, in C57BL/6J mice. MPTP treatment (10 mg/kg, four times at 2-h intervals) decreased dopamine levels in the midbrain and impaired motor coordination, and these effects were counteracted by S-methylthiocitrulline, a selective neuronal NO synthase inhibitor. SEA0400 protected against the dopaminergic neurotoxicity (determined by dopamine levels in the midbrain and striatum, tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum, striatal dopamine release, and motor deficits) in MPTP-treated mice. SEA0400 had no radical-scavenging activity. SEA0400 did not affect MPTP metabolism and MPTP-induced NO production and microglial activation, while it attenuated MPTP-induced increases in extracellular signal-regulated kinase (ERK) phosphorylation and lipid peroxidation product, thiobarbituric acid reactive substance. These findings suggest that SEA0400 protects against MPTP-induced neurotoxicity probably by blocking ERK phosphorylation and lipid peroxidation which are downstream of NCX-mediated Ca(2+) influx.

Authors+Show Affiliations

Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21903118

Citation

Ago, Yukio, et al. "SEA0400, a Specific Na+/Ca2+ Exchange Inhibitor, Prevents Dopaminergic Neurotoxicity in an MPTP Mouse Model of Parkinson's Disease." Neuropharmacology, vol. 61, no. 8, 2011, pp. 1441-51.
Ago Y, Kawasaki T, Nashida T, et al. SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease. Neuropharmacology. 2011;61(8):1441-51.
Ago, Y., Kawasaki, T., Nashida, T., Ota, Y., Cong, Y., Kitamoto, M., Takahashi, T., Takuma, K., & Matsuda, T. (2011). SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease. Neuropharmacology, 61(8), 1441-51. https://doi.org/10.1016/j.neuropharm.2011.08.041
Ago Y, et al. SEA0400, a Specific Na+/Ca2+ Exchange Inhibitor, Prevents Dopaminergic Neurotoxicity in an MPTP Mouse Model of Parkinson's Disease. Neuropharmacology. 2011;61(8):1441-51. PubMed PMID: 21903118.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson's disease. AU - Ago,Yukio, AU - Kawasaki,Toshiyuki, AU - Nashida,Tetsuaki, AU - Ota,Yuki, AU - Cong,Yana, AU - Kitamoto,Mari, AU - Takahashi,Teisuke, AU - Takuma,Kazuhiro, AU - Matsuda,Toshio, Y1 - 2011/09/02/ PY - 2011/05/18/received PY - 2011/08/24/revised PY - 2011/08/26/accepted PY - 2011/9/10/entrez PY - 2011/9/10/pubmed PY - 2012/8/2/medline SP - 1441 EP - 51 JF - Neuropharmacology JO - Neuropharmacology VL - 61 IS - 8 N2 - We have recently shown that the Na(+)/Ca(2+) exchanger (NCX) is involved in nitric oxide (NO)-induced cytotoxicity in cultured astrocytes and neurons. However, there is no in vivo evidence suggesting the role of NCX in neurodegenerative disorders associated with NO. NO is implicated in the pathogenesis of neurodegenerative disorders such as Parkinson's disease. This study examined the effect of SEA0400, the specific NCX inhibitor, on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity, a model of Parkinson's disease, in C57BL/6J mice. MPTP treatment (10 mg/kg, four times at 2-h intervals) decreased dopamine levels in the midbrain and impaired motor coordination, and these effects were counteracted by S-methylthiocitrulline, a selective neuronal NO synthase inhibitor. SEA0400 protected against the dopaminergic neurotoxicity (determined by dopamine levels in the midbrain and striatum, tyrosine hydroxylase immunoreactivity in the substantia nigra and striatum, striatal dopamine release, and motor deficits) in MPTP-treated mice. SEA0400 had no radical-scavenging activity. SEA0400 did not affect MPTP metabolism and MPTP-induced NO production and microglial activation, while it attenuated MPTP-induced increases in extracellular signal-regulated kinase (ERK) phosphorylation and lipid peroxidation product, thiobarbituric acid reactive substance. These findings suggest that SEA0400 protects against MPTP-induced neurotoxicity probably by blocking ERK phosphorylation and lipid peroxidation which are downstream of NCX-mediated Ca(2+) influx. SN - 1873-7064 UR - https://www.unboundmedicine.com/medline/citation/21903118/SEA0400_a_specific_Na+/Ca2+_exchange_inhibitor_prevents_dopaminergic_neurotoxicity_in_an_MPTP_mouse_model_of_Parkinson's_disease_ DB - PRIME DP - Unbound Medicine ER -