Hypoxia enhances high-voltage-activated calcium currents in rat primary cortical neurons via calcineurin

Kong, Xiang; Earl, Damien E.; Dwyer, Trisha; Behrle, Brian L; Tietz, Elizabeth I.; Greenfield, Lazar J.

doi:10.1016/j.eplepsyres.2011.12.011

Cited by 7 publications

(5 citation statements)

References 67 publications

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“…While Nav channels themselves pass essentially no Ca ++ [50], Nav channel activity would activate any voltage-dependent Ca ++ channels [51]. With this in mind we also investigated the effect of the Nav channel agonist, veratridine, on neurotoxicity and the mechanical properties of neurons, selecting initial concentrations based on previous studies [52].…”

Section: Resultsmentioning

confidence: 99%

Force Spectroscopy Measurements Show That Cortical Neurons Exposed to Excitotoxic Agonists Stiffen before Showing Evidence of Bleb Damage

et al. 2013

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In ischemic and traumatic brain injury, hyperactivated glutamate (N-methyl-D-aspartic acid, NMDA) and sodium (Nav) channels trigger excitotoxic neuron death. Na+, Ca++ and H2O influx into affected neurons elicits swelling (increased cell volume) and pathological blebbing (disassociation of the plasma membrane’s bilayer from its spectrin-actomyosin matrix). Though usually conflated in injured tissue, cell swelling and blebbing are distinct processes. Around an injury core, salvageable neurons could be mildly swollen without yet having suffered the bleb-type membrane damage that, by rendering channels leaky and pumps dysfunctional, exacerbates the excitotoxic positive feedback spiral. Recognizing when neuronal inflation signifies non-lethal osmotic swelling versus blebbing should further efforts to salvage injury-penumbra neurons. To assess whether the mechanical properties of osmotically-swollen versus excitotoxically-blebbing neurons might be cytomechanically distinguishable, we measured cortical neuron elasticity (gauged via atomic force microscopy (AFM)-based force spectroscopy) upon brief exposure to hypotonicity or to excitotoxic agonists (glutamate and Nav channel activators, NMDA and veratridine). Though unperturbed by solution exchange per se, elasticity increased abruptly with hypotonicity, with NMDA and with veratridine. Neurons then invariably softened towards or below the pre-treatment level, sometimes starting before the washout. The initial channel-mediated stiffening bespeaks an abrupt elevation of hydrostatic pressure linked to NMDA or Nav channel-mediated ion/H2O fluxes, together with increased [Ca++]int-mediated submembrane actomyosin contractility. The subsequent softening to below-control levels is consistent with the onset of a lethal level of bleb damage. These findings indicate that dissection/identification of molecular events during the excitotoxic transition from stiff/swollen to soft/blebbing is warranted and should be feasible.

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Section: Resultsmentioning

confidence: 99%

Force Spectroscopy Measurements Show That Cortical Neurons Exposed to Excitotoxic Agonists Stiffen before Showing Evidence of Bleb Damage

et al. 2013

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“…) and cortical neurons (Xiang et al . ). Administration of nimodipine attenuated cytosolic calcineurin activity in the hippocampus of aged rats (Foster et al .…”

Section: Discussionmentioning

confidence: 97%

Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis

Ingwersen

Santi

Wingerath

et al. 2018

Journal of Neurochemistry

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Multiple sclerosis is characterised by inflammatory neurodegeneration, with axonal injury and neuronal cell death occurring in parallel to demyelination. Regarding the molecular mechanisms responsible for demyelination and axonopathy, energy failure, aberrant expression of ion channels and excitotoxicity have been suggested to lead to Ca overload and subsequent activation of calcium-dependent damage pathways. Thus, the inhibition of Ca influx by pharmacological modulation of Ca channels may represent a novel neuroprotective strategy in the treatment of secondary axonopathy. We therefore investigated the effects of the L-type voltage-gated calcium channel blocker nimodipine in two different models of mouse experimental autoimmune encephalomyelitis (EAE), an established experimental paradigm for multiple sclerosis. We show that preventive application of nimodipine (10 mg/kg per day) starting on the day of induction had ameliorating effects on EAE in SJL/J mice immunised with encephalitic myelin peptide PLP , specifically in late-stage disease. Furthermore, supporting these data, administration of nimodipine to MOG -immunised C57BL/6 mice starting at the peak of pre-established disease, also led to a significant decrease in disease score, indicating a protective effect on secondary CNS damage. Histological analysis confirmed that nimodipine attenuated demyelination, axonal loss and pathological axonal β-amyloid precursor protein accumulation in the cerebellum and spinal cord in the chronic phase of disease. Of note, we observed no effects of nimodipine on the peripheral immune response in EAE mice with regard to distribution, antigen-specific proliferation or activation patterns of lymphocytes. Taken together, our data suggest a CNS-specific effect of L-type voltage-gated calcium channel blockade to inflammation-induced neurodegeneration.

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“…A c c e p t e d M a n u s c r i p t 13 demonstrated there were no differences in behavioral seizures between rats that did or did not receive FK506 after termination of SE. However, we found that FK506 markedly inhibited brain focal edema, brain water content and astrogliosis, indicating that SE induced CaN activity and CaN concentration increase and CaN further participated in a series of pathological process after SE [13,14,15].…”

Section: S T a C C E P T E Dmentioning

confidence: 85%

“…However, we found that FK506 markedly inhibited brain focal edema, brain water content and astrogliosis, indicating that SE induced CaN activity and CaN concentration increase and CaN further participated in a series of pathological process after SE [13,14,15].…”

Section: S T a C C E P T E Dmentioning

confidence: 90%

Increased calcineurin expression after pilocarpine-induced status epilepticus is associated with brain focal edema and astrogliosis

Liu

Chen³

et al. 2015

International Journal of Neuroscience

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Calcineurin plays an important role in the development of neuronal excitability, modulation of receptor's function and induction of apoptosis in neurons. It has been established in kindling models that status epilepticus induces brain focal edema and astrocyte activation. However, the role of calcineurin in brain focal edema and astrocyte activation in status epilepticus has not been fully understood. In this study, we employed a model of lithium-pilocarpine-induced status epilepticus and detected calcineurin expression in hippocampus by immunoblotting, brain focal edema by non-invasive magnetic resonance imaging (MRI-7T) and astrocyte expression by immunohistochemistry. We found that the brain focal edema was seen at 24 h after status epilepticus, and astrocyte expression was obviously seen at 7 d after status epilepticus. Meanwhile, calcineurin expression was seen at24 h and retained to 7 d after status epilepticus. A FK506, a calcineurin inhibitor, remarkably suppressed the status epilepticus-induced brain focal edema and astrocyte expression. Our data suggested that calcineurin overexpression plays a very important role in brain focal edema and astrocyte expression. Therefore, calcineurin may be a novel candidate for brain focal edema occurring and intracellular trigger of astrogliosis in status epilepticus.

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Hypoxia enhances high-voltage-activated calcium currents in rat primary cortical neurons via calcineurin

Cited by 7 publications

References 67 publications

Force Spectroscopy Measurements Show That Cortical Neurons Exposed to Excitotoxic Agonists Stiffen before Showing Evidence of Bleb Damage

Force Spectroscopy Measurements Show That Cortical Neurons Exposed to Excitotoxic Agonists Stiffen before Showing Evidence of Bleb Damage

Nimodipine confers clinical improvement in two models of experimental autoimmune encephalomyelitis

Increased calcineurin expression after pilocarpine-induced status epilepticus is associated with brain focal edema and astrogliosis

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