NCX3 knockout mice exhibit increased hippocampal CA1 and CA2 neuronal damage compared to wild-type mice following global cerebral ischemia

Jeffs, Graham Joseph; Meloni, Bruno P.; Sokolow, Sophie; Herchuelz, André; Schurmans, Stéphane; Knuckey, Neville W.

doi:10.1016/j.expneurol.2007.10.013

Cited by 30 publications

(13 citation statements)

References 26 publications

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“…For example, NCX3 is neuroprotective against ischemia-induced injuries (Jeffs et al, 2008, Molinaro et al, 2008). The protective role of NCX3 in ischemic lesions depends on the overload of intracellular [Na + ] which forces NCX3 to work on reverse mode.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in NCX2 deficient mice implied that NCX2 is important for cognitive function (Jeon, 2003). We produced NCX3 knockout mice and showed that NCX3 plays a significant role in cognition (Molinaro et al, 2011), in oligodendrocyte differentiation (Boscia et al, 2013), in amyloid-beta pathology (Pannaccione et al, 2012, Sokolow et al, 2011) and is protective against ischemic damage (Cross et al, 2009, Jeffs et al, 2008, Molinaro et al, 2013, Molinaro et al, 2008). …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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“…Bilateral common carotid artery occlusions were performed with 3‐month‐old male C57/Bl6 wild‐type and p47 phox−/− mice 26, 27. The mice were anesthetized with 2% isoflurane and a 75:25 mixture of nitrous oxide/oxygen, and core temperature was kept at 36.5 to 37.5°C with a homeothermic blanket control unit (Harvard Apparatus, Holliston, MA).…”

Section: Methodsmentioning

confidence: 99%

Glucose and NADPH oxidase drive neuronal superoxide formation in stroke

Suh

Shin

et al. 2008

Annals of Neurology

255

200

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Objective Hyperglycemia has been recognized for decades to be an exacerbating factor in ischemic stroke, but the mechanism of this effect remains unresolved. Here we evaluated superoxide production by neuronal NADPH oxidase as a link between glucose metabolism and neuronal death in ischemia-reperfusion. Methods Superoxide production was measured by the ethidium method in cultured neurons treated with oxygen-glucose deprivation and in mice treated with forebrain ischemia-reperfusion. The role of NADPH oxidase was examined using genetic disruption of its p47phox subunit and with the pharmacological inhibitor, apocynin. Results In neuron cultures, post-ischemic superoxide production and cell death were completely prevented by removing glucose from the medium, by inactivating NADPH oxidase, or by inhibiting the hexose monophosphate shunt which generates NADPH from glucose. In murine stroke, neuronal superoxide production and death were decreased by the glucose anti-metabolite, 2-deoxyglucose, and increased by high blood glucose concentrations. Inactivating NADPH oxidase with either apocynin or deletion of the p47phox subunit blocked neuronal superoxide production and negated the deleterious effects of hyperglycemia. Interpretation These findings identify glucose as the requisite electron donor for reperfusion-induced neuronal superoxide production and establish a previously unrecognized mechanism by which hyperglycemia can exacerbate ischemic brain injury.

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“…Furthermore, a number of studies have shown that NCX inhibitors produce larger infarcts following cerebral ischemia, and increasing the activity of this transporter reduces infarct volume under the same conditions (Pignataro et al 2004a;. In addition, NCX3 knockout mice exhibit greater neural damage following cerebral ischemia than control mice (Jeffs et al 2008), which confirms the neuroprotective effect of this transporter, even though some other studies have shown a role of the Ca 2? entry mode NCX in cellular death (Araujo et al 2007;Shono et al 2010).…”

Section: Discussionmentioning

confidence: 81%

Effects of Estradiol and IGF-1 on the Sodium Calcium Exchanger in Rat Cultured Cortical Neurons

et al. 2011

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The Na(+)/Ca(2+) exchanger (NCX) is an important bidirectional transporter of calcium in neurons and has been shown to be involved in neuroprotection. Calcium can activate a number of cascades that can result in apoptosis and cell death, and NCX is a key factor in regulating the cytoplasmic concentration of this ion. 17-β-estradiol and insulin-like growth factor 1 (IGF-1) are known neuroprotective hormones with interacting mechanisms and effects on intracellular calcium; however, their relationship with the NCX has not been explored. In this article, the effects of these two hormones on neuronal NCX were tested using the whole-cell patch clamp technique on rat primary culture neurons. Both 17-β-estradiol and IGF-1 produced an increase in the NCX-mediated inward current and a decrease in the NCX-mediated outward current. However, the IGF-1 effect was lower than that of 17-β-estradiol, and the effect of both agents together was greater than the sum of each agent alone. Neither of the agents affected the pattern of regulation by extracellular or intrapipette calcium. Inhibitors of the IGF-1 and 17-β-estradiol receptors and inhibitors of the main signaling pathways failed to change the observed effects, indicating that these actions were not mediated by the classical receptors of these hormones. These effects on the NCX could be a mechanism explaining the neuroprotective actions of 17-β-estradiol and IGF-1, and these findings could help researchers to understand the role of the NCX in neuroprotection.

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NCX3 knockout mice exhibit increased hippocampal CA1 and CA2 neuronal damage compared to wild-type mice following global cerebral ischemia

Cited by 30 publications

References 26 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

Glucose and NADPH oxidase drive neuronal superoxide formation in stroke

Effects of Estradiol and IGF-1 on the Sodium Calcium Exchanger in Rat Cultured Cortical Neurons

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