N
 ‐methyl‐
 <scp>D</scp>
 ‐aspartate receptor‐mediated mitochondrial Ca
 2+
 overload in acute excitotoxic motor neuron death: A mechanism distinct from chronic neurotoxicity after Ca
 2+
 influx

Urushitani, Makoto; Tomoki,; Nakamizo, Tomoki; Inoue, Rikako; Sawada, Hideyuki; Kihara, Takeshi; Honda, Kazuo; Akaike, Akinori; Shimohama, Shun

doi:10.1002/1097-4547(20010301)63:5<377::aid-jnr1032>3.0.co;2-#

Cited by 110 publications

(58 citation statements)

References 51 publications

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“…For instance, hypoxic preconditioning-induced generation of reactive oxygen species, as well as subsequent hypoxic tolerance, is suppressed by DIDS but not by NOS inhibitors in cardiac myocytes (68). In neuron cultures for which NOS inhibitors are ineffective, FCCP, DNP, and MnTBAP suppress NMDA-mediated generation of reactive oxygen species and toxicity (14,60,67). Taken together, these findings show that OGD preconditioning can induce dramatically different cellular signaling to achieve OGD-resistant phenotypes in cortical neurons.…”

Section: Nitric Oxide-independent Preconditioningmentioning

confidence: 84%

Preconditioning of cortical neurons by oxygen-glucose deprivation: tolerance induction through abbreviated neurotoxic signaling

Tauskela

Brunette

Monette

et al. 2003

American Journal of Physiology-Cell Physiology

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Transient exposure of rat cortical cultures to nonlethal oxygen-glucose deprivation (OGD preconditioning) induces tolerance to otherwise lethal oxygen-glucose deprivation (OGD) or N-methyl-d-aspartate 24 h later. This study evaluates the role of cytosolic and mitochondrial Ca2+-dependent cellular signaling. Mechanistic findings are placed in context with other models of ischemic preconditioning or known neurotoxic pathways within cortical neurons. Tolerance to otherwise lethal OGD is suppressed by performing OGD preconditioning in the presence of the broad-scope catalytic antioxidants Mn(III)tetra(4-carboxyphenyl)porphyrin (MnTBAP) or Zn(II)tetra(4-carboxyphenyl)porphyrin [Zn(II)TBAP], but not by a less active analog, Mn(III)tetra(4-sulfonatophenyl)porphyrin, or a potent superoxide scavenger, Mn(III)tetra( N-ethyl-2-pyridyl)porphyrin chloride. Inhibitors of adenosine A1 receptors, nitric oxide synthase, mitogen-activated protein kinase, and poly(ADP-ribose) polymerase fail to suppress OGD preconditioning despite possible links with reactive oxygen species in other models of ischemic preconditioning. Preconditioning is suppressed by 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS), which has been ascribed elsewhere to inhibition of superoxide transport to the cytosol through mitochondrial anion channels. However, although it induces mitochondrial Ca2+ uptake, neuronal preconditioning is largely insensitive to mitochondrial uncoupling with carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone or 2,4-dinitrophenol. Un-couplers will prevent production of mitochondrial reactive oxygen species, implying nonmitochondrial targets by MnTBAP, Zn(II)TBAP, and DIDS. Emphasizing the importance of an increase in cytosolic Ca2+ during preconditioning, a Ca2+/calmodulin-dependent protein kinase II inhibitor, KN-62, suppresses development of subsequent tolerance. Summarizing, only those cellular transduction pathways that have the potential to be neurotoxic may be activated by preconditioning in cortical neurons. Finally, a marked decrease in extracellular glutamate is observed during otherwise lethal OGD in preconditioned cultures, suggesting that this end effector may represent a point of convergence across different preconditioning models.

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Section: Nitric Oxide-independent Preconditioningmentioning

confidence: 84%

Preconditioning of cortical neurons by oxygen-glucose deprivation: tolerance induction through abbreviated neurotoxic signaling

Tauskela

Brunette

Monette

et al. 2003

American Journal of Physiology-Cell Physiology

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“…2). Glutamate also is known to compromise the respiratory function of mitochondria (i.e., inducing Ca 2ϩ accumulation and increasing reactive oxygen species (ROS) (Urushitani et al, 2001) and inhibiting proton generation for aspartate transport which leads to excitotoxicity. Thus, when the MNLS fails to shuttle lactate due to a lack of ATP, lactate and glutamate accumulation would lead to degeneration of the nerve endings (Vijayvergiya et al, 2005), dysfunction of the NMJ, and axonal toxicity.…”

Section: The Molecular Modelmentioning

confidence: 99%

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

Meethal

Atwood

2012

Neurobiology of Aging

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Amyotrophic lateral sclerosis (ALS; Lou Gehrig's disease) is a progressive debilitating neurodegenerative disease with no cure. We propose a novel molecular model for the pathogenesis of ALS that involves an adenosine triphosphate (ATP)-dependent muscle neuronal lactate shuttle (MNLS) at the neuromuscular junction (NMJ) to regulate the flow of lactate from muscle to neurons and vice versa. Failure of the MNLS due to respiratory chain dysfunction is proposed to result in lactate toxicity and degeneration of nerve endings at the NMJ leading to nerve terminus dysjunction from the muscle cell. At a critical threshold where denervation outpaces reinnervation, a vicious cycle is established where the remaining innervated muscle fibers are required to work harder to compensate for normal function, and in so doing produce toxic lactate concentrations which induces further denervation and neuronal death. This mechanism explains the exponential progression of ALS leading to paralysis. The molecular events leading to the dysregulation of the MNLS and the dismantling of NMJ are explained in the context of known ALS familial mutations and age-related endocrine dyscrasia. Combination drug therapies that inhibit lactate accumulation at the NMJ, enhance respiratory chain function, and/or promote reinnervation are predicted to be effective therapeutic strategies for ALS. Published by Elsevier Inc.

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“…In a separate study, the co-application of FCCP (1μM) with glutamate (0.5 mM) to spinal cord motor and nonmotor neurons blocked Ca 2+ uptake into mitochondria. FCCP was also shown to directly prevent the increase in ROS generated by glutamate exposure as indicated by a decrease in dihydrorhodamine-123 (DHR123) fluorescence (Urushitani et al, 2001). Unlike CCCP, FCCP may also act on non-mitochondrial Ca 2+ stores (Jensen and Rehder, 1991;Ruben et al, 1991).…”

Section: Mitochondrial Uncoupling By Protonophoresmentioning

confidence: 99%

Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration

Foster

Galeffi

Gerich

et al. 2006

Progress in Neurobiology

166

135

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Mitochondria are critical for cellular ATP production; however, recent studies suggest that these organelles fulfill a much broader range of tasks. For example, they are involved in the regulation of cytosolic Ca 2+ levels, intracellular pH and apoptosis, and are the major source of reactive oxygen species (ROS). Various reactive molecules that originate from mitochondria, such as ROS, are critical in pathological events, such as ischemia, as well as in physiological events such as long-term potentiation, neuronal-vascular coupling and neuronal-glial interactions. Due to their key roles in the regulation of several cellular functions, the dysfunction of mitochondria may be critical in various brain disorders. There has been increasing interest in the development of tools that modulate mitochondrial function, and the refinement of techniques that allow for real time monitoring of mitochondria, particularly within their intact cellular environment. Innovative imaging techniques are especially powerful since they allow for mitochondrial visualization at high resolution, tracking of mitochondrial structures and optical real time monitoring of parameters of mitochondrial function. Among the techniques discussed are the uses of classic imaging techniques such as rhodamine-123, the highly advanced semi-conductor nanoparticles (quantum dots), and wide field microscopy as well as high-resolution multi-photon imaging. We have highlighted the use of these techniques to study mitochondrial function in brain tissue and have included studies from our laboratories in which these techniques have been successfully applied.

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N ‐methyl‐ D ‐aspartate receptor‐mediated mitochondrial Ca ²⁺ overload in acute excitotoxic motor neuron death: A mechanism distinct from chronic neurotoxicity after Ca ²⁺ influx

Cited by 110 publications

References 51 publications

Preconditioning of cortical neurons by oxygen-glucose deprivation: tolerance induction through abbreviated neurotoxic signaling

Preconditioning of cortical neurons by oxygen-glucose deprivation: tolerance induction through abbreviated neurotoxic signaling

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration

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N ‐methyl‐ D ‐aspartate receptor‐mediated mitochondrial Ca 2+ overload in acute excitotoxic motor neuron death: A mechanism distinct from chronic neurotoxicity after Ca 2+ influx

Cited by 110 publications

References 51 publications

Preconditioning of cortical neurons by oxygen-glucose deprivation: tolerance induction through abbreviated neurotoxic signaling

Preconditioning of cortical neurons by oxygen-glucose deprivation: tolerance induction through abbreviated neurotoxic signaling

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration

Contact Info

Product

Resources

About

N ‐methyl‐ D ‐aspartate receptor‐mediated mitochondrial Ca ²⁺ overload in acute excitotoxic motor neuron death: A mechanism distinct from chronic neurotoxicity after Ca ²⁺ influx