SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson’s disease

Ago, Yukio; Kawasaki, Toshiyuki; Nashida, Tetsuaki; Ota, Yuki; Cong, Yana; Kitamoto, Mari; Takahashi, Teisuke; Takuma, Kazuhiro; Matsuda, Takehisa

doi:10.1016/j.neuropharm.2011.08.041

Cited by 24 publications

(13 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ago et al recently suggested that NCX inhibitor, SEA0400, ameliorated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor deficits and reduced the decline in DA levels and tyrosine hydroxylase (TH) immunoreactivity in the midbrain and striatum of MPTP treated mice (Ago et al, 2011). This study implied that NCX is a novel molecular target for PD therapy (Ago, 2011).…”

Section: Introductionmentioning

confidence: 99%

Involvement of the sodium–calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity

et al. 2014

View full text Add to dashboard Cite

Ziram is a dimethyldithiocarbamate fungicide which can cause intraneuronal calcium (Ca2+) dysregulation and subsequently neuronal death. The signaling mechanisms underlying ziram-induced Ca2+ dyshomeostasis and neurotoxicity are not fully understood. NCX3 is the third isoform of the sodium-calcium exchanger (NCX) family and plays an important role in regulating Ca2+ homeostasis in excitable cells. We previously generated a mouse model deficient for the sodium-calcium exchanger 3 and showed that NCX3 is protective against ischemic damage. In the present study, we aim to examine whether NCX3 exerts a similar role against toxicological injury caused by the pesticide ziram. Our data show baby hamster kidney (BHK) cells stably transfected with NCX3 (BHK-NCX3) are more susceptible to ziram toxicity than cells transfected with the empty vector (BHK-WT). Increased toxicity in BHK-NCX3 was associated with a rapid rise in cytosolic Ca2+ concentration [Ca2+i] induced by ziram. Profound mitochondrial dysfunction and ATP depletion were also observed in BHK-NCX3 cells following treatment with ziram. Lastly, primary dopaminergic neurons lacking NCX3 (NCX3−/−) were less sensitive to ziram neurotoxicity than wildtype control dopaminergic neurons. These results demonstrate that NCX3 genetic deletion protects against ziram-induced neurotoxicity and suggest NCX3 and its downstream molecular pathways as key factors involved in ziram toxicity. Our study identifies new molecular events through which pesticides (e.g. ziram) can lead to pathological features of degenerative diseases such as Parkinson’s disease and indicates new targets to slow down neuronal degeneration.

show abstract

Section: Introductionmentioning

confidence: 99%

Involvement of the sodium–calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Three different isoforms of the NCX (NCX1, NCX2 and NCX3) have been characterized, cloned and detected in various tissues, including the central nervous system (Philipson and Nicoll, 1997; Quednau et al, 1997; Papa et al, 2003; Lytton, 2007). The NCX has been implicated in the pathophysiology of various neurological conditions, including Alzheimer’s disease (Bi et al, 2012; Sokolow et al, 2011), ischemia (Pignataro et al, 2004; Lee et al, 2005; Boscia et al, 2006), hypoxia (Secondo et al, 2007) and Parkinson’s disease (Ago et al, 2011). Although the role of the NCX in the pathogenesis of seizures and epilepsy remains poorly understood, we have reported that inhibition of Ca 2+ influx via NCX activity in the reverse mode reduced the incidence of pilocarpine-induced limbic seizures and status epilepticus (Martinez and N’Gouemo, 2010).…”

Section: Introductionmentioning

confidence: 99%

Probing the role of the sodium/calcium exchanger in pentylenetetrazole-induced generalized seizures in rats

N’Gouemo¹

2013

Brain Research Bulletin

View full text Add to dashboard Cite

The Na+/Ca2+ exchanger (NCX) is thought to play an important role in the pathogenesis of pentylenetetrazole (PTZ)-induced tonic flexion in mice. Here, I investigated the expression of PTZ-induced generalized clonic and tonic-clonic seizures in rats, using two potent NCX reverse mode inhibitors, KB-R7943 and SN-6 for NCX subtypes 3 (NCX3) and 1 (NCX1), respectively. Pretreatment with KB-R7943 (3, 10, 30 mg/kg; p.o.) significantly reduced the expression of PTZ-induced generalized seizures with clonic and tonic-clonic components in 12–62% and 25–62% of the treated animals, respectively. In the remaining animals that exhibited seizures, KB-R7943 (3 mg/kg; p.o.) pretreatment significantly delayed the onset of the first seizure episode and reduced the seizure severity. Following pretreatment with SN-6 (0.3, 1, 3, 10, 30 mg/kg; p.o.), clonic and tonic-clonic PTZ-induced generalized seizures were reduced in 25–50% and 38–63% of treated animals, respectively. SN-6 (0.3, 1, 3, mg/kg; p.o.) also significantly reduced PTZinduced seizure severity scores, but did not alter seizure latencies. KB-R7943 (3, 30 mg/kg; p.o.) or SN-6 (3, 30 mg/kg; p.o.) administration potentiated the sub-anticonvulsant dose of diazepam (2.5 mg/kg; i.p.) that suppresses clonic and tonic-clonic PTZ-induced seizures. These findings suggested that Ca2+ influx via the NCX in reverse mode contributes to a neuronal hyperexcitability that leads to clonic and tonic-clonic generalized seizures and that the NCX1 and NCX3 isoforms may serve as novel molecular targets for seizure suppression.

show abstract

“…NCX could be involved in the degeneration of dopaminergic neurons following MPTP administration given the important role of calcium homeostasis in this model [31–33] and the involvement of NCX in a variety of disease states [34]. Indeed, SEA0400, a specific NCX inhibitor was recently shown to reduce dopaminergic neurotoxicity in the MPTP model [35]. Yet, the inhibition of NCX by amiloride cannot explain the protection of dopaminergic neurons in the 6-hydroxydopamine model by psalmotoxin-1, a specific inhibitor of ASIC1a homomers [22].…”

Section: Resultsmentioning

confidence: 99%

ASIC1a Deficient Mice Show Unaltered Neurodegeneration in the Subacute MPTP Model of Parkinson Disease

et al. 2016

View full text Add to dashboard Cite

Inflammation contributes to the death of dopaminergic neurons in Parkinson disease and can be accompanied by acidification of extracellular pH, which may activate acid-sensing ion channels (ASIC). Accordingly, amiloride, a non-selective inhibitor of ASIC, was protective in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson disease. To complement these findings we determined MPTP toxicity in mice deficient for ASIC1a, the most common ASIC isoform in neurons. MPTP was applied i.p. in doses of 30 mg per kg on five consecutive days. We determined the number of dopaminergic neurons in the substantia nigra, assayed by stereological counting 14 days after the last MPTP injection, the number of Nissl positive neurons in the substantia nigra, and the concentration of catecholamines in the striatum. There was no difference between ASIC1a-deficient mice and wildtype controls. We are therefore not able to confirm that ASIC1a are involved in MPTP toxicity. The difference might relate to the subacute MPTP model we used, which more closely resembles the pathogenesis of Parkinson disease, or to further targets of amiloride.

show abstract

SEA0400, a specific Na+/Ca2+ exchange inhibitor, prevents dopaminergic neurotoxicity in an MPTP mouse model of Parkinson’s disease

Cited by 24 publications

References 49 publications

Involvement of the sodium–calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity

Involvement of the sodium–calcium exchanger 3 (NCX3) in ziram-induced calcium dysregulation and toxicity

Probing the role of the sodium/calcium exchanger in pentylenetetrazole-induced generalized seizures in rats

ASIC1a Deficient Mice Show Unaltered Neurodegeneration in the Subacute MPTP Model of Parkinson Disease

Contact Info

Product

Resources

About