Kinetic changes and modulation by carbamazepine on voltage-gated sodium channels in rat CA1 neurons after epilepsy

Sun, Guangchun; Werkman, T.R.; Wadman, Wytse J.

doi:10.1111/j.1745-7254.2006.00452.x

Cited by 15 publications

(11 citation statements)

References 29 publications

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“…What appears to be irreversible Nav-CLS arising from metabolic (not mechanical) injury has been reported for the Nav channels of hippocampal neuronal somata subjected to prolonged epileptic discharge: the somatic Nav channels (presumably Nav1.2) show a measurably left-shifted I window associated with left-shifted (fast-mode) activation and availability (Sun et al, 2006). Presumably these overworked neurons are ATP-depleted and their plasma membranes are beset by the usual chemical insults of ischemia.…”

Section: The Problem: Nav Channels Get Leaky In Sick Excitable Cellsmentioning

confidence: 94%

Left-Shifted Nav Channels in Injured Bilayer: Primary Targets for Neuroprotective Nav Antagonists?

Morris¹,

Boucher²,

Joós³

2012

Front. Pharmacol.

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Mechanical, ischemic, and inflammatory injuries to voltage-gated sodium channel (Nav)-rich membranes of axon initial segments and nodes of Ranvier render Nav channels dangerously leaky. By what means? The behavior of recombinant Nav1.6 (Wang et al., 2009) leads us to postulate that, in neuropathologic conditions, structural degradation of axolemmal bilayer fosters chronically left-shifted Nav channel operation, resulting in ENa rundown. This “sick excitable cell Nav-leak” would encompass left-shifted fast- and slow-mode based persistent INa (i.e., Iwindow and slow-inactivating INa). Bilayer-damage-induced electrophysiological dysfunctions of native-Nav channels, and effects on inhibitors on those channels, should, we suggest, be studied in myelinated axons, exploiting INa(V,t) hysteresis data from sawtooth ramp clamp. We hypothesize that (like dihydropyridines for Ca channels), protective lipophilic Nav antagonists would partition more avidly into disorderly bilayers than into the well-packed bilayers characteristic of undamaged, healthy plasma membrane. Whereas inhibitors using aqueous routes would access all Navs equally, differential partitioning into “sick bilayer” would co-localize lipophilic antagonists with “sick-Nav channels,” allowing for more specific targeting of impaired cells. Molecular fine-tuning of Nav antagonists to favor more avid partitioning into damaged than into intact bilayers could reduce side effects. In potentially salvageable neurons of traumatic and/or ischemic penumbras, in inflammatory neuropathies, in muscular dystrophy, in myocytes of cardiac infarct borders, Nav-leak driven excitotoxicity overwhelms cellular repair mechanisms. Precision-tuning of a lipophilic Nav antagonist for greatest efficacy in mildly damaged membranes could render it suitable for the prolonged continuous administration needed to allow for the remodeling of the excitable membranes, and thus functional recovery.

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Section: The Problem: Nav Channels Get Leaky In Sick Excitable Cellsmentioning

confidence: 94%

Left-Shifted Nav Channels in Injured Bilayer: Primary Targets for Neuroprotective Nav Antagonists?

Morris¹,

Boucher²,

Joós³

2012

Front. Pharmacol.

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“…Resveratrol inhibited pro-MMP-9 production at 25 or 50 μM concentrations in colon cancer cells (Kimura et al, 2008). Also expression and activity of MMP-2 and MMP-9 were downregulated in MCF-7 cells, mouse mammary tumors, and multiple myeloma cells (Banerjee et al, 2002; Sun et al, 2006; Tang et al, 2008). …”

Section: Resveratrol In Cancermentioning

confidence: 99%

Resveratrol: French Paradox Revisited

et al. 2012

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Resveratrol is a polyphenol that plays a potentially important role in many disorders and has been studied in different diseases. The research on this chemical started through the “French paradox,” which describes improved cardiovascular outcomes despite a high-fat diet in French people. Since then, resveratrol has been broadly studied and shown to have antioxidant, anti-inflammatory, anti-proliferative, and anti-angiogenic effects, with those on oxidative stress possibly being most important and underlying some of the others, but many signaling pathways are among the molecular targets of resveratrol. In concert they may be beneficial in many disorders, particularly in diseases where oxidative stress plays an important role. The main focus of this review will be the pathways affected by resveratrol. Based on these mechanistic considerations, the involvement of resveratrol especially in cardiovascular diseases, cancer, neurodegenerative diseases, and possibly in longevity will be is addressed.

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“…In hippocampal neurons, a Nav-CLS based window current left-shift occurs following metabolic insult from prolonged epilepsy-like stimulation [15]. Hippocampal neurons exposed to the industrial compound, melamine, also show Nav-CLS and exhibit hyperexcitability [16].…”

Section: Introductionmentioning

confidence: 99%

Spontaneous Excitation Patterns Computed for Axons with Injury-like Impairments of Sodium Channels and Na/K Pumps

Morris

Joós

et al. 2012

PLoS Comput Biol

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In injured neurons, “leaky” voltage-gated sodium channels (Nav) underlie dysfunctional excitability that ranges from spontaneous subthreshold oscillations (STO), to ectopic (sometimes paroxysmal) excitation, to depolarizing block. In recombinant systems, mechanical injury to Nav1.6-rich membranes causes cytoplasmic Na+-loading and “Nav-CLS”, i.e., coupled left-(hyperpolarizing)-shift of Nav activation and availability. Metabolic injury of hippocampal neurons (epileptic discharge) results in comparable impairment: left-shifted activation and availability and hence left-shifted INa-window. A recent computation study revealed that CLS-based INa-window left-shift dissipates ion gradients and impairs excitability. Here, via dynamical analyses, we focus on sustained excitability patterns in mildly damaged nodes, in particular with more realistic Gaussian-distributed Nav-CLS to mimic “smeared” injury intensity. Since our interest is axons that might survive injury, pumps (sine qua non for live axons) are included. In some simulations, pump efficacy and system volumes are varied. Impacts of current noise inputs are also characterized. The diverse modes of spontaneous rhythmic activity evident in these scenarios are studied using bifurcation analysis. For “mild CLS injury”, a prominent feature is slow pump/leak-mediated EIon oscillations. These slow oscillations yield dynamic firing thresholds that underlie complex voltage STO and bursting behaviors. Thus, Nav-CLS, a biophysically justified mode of injury, in parallel with functioning pumps, robustly engenders an emergent slow process that triggers a plethora of pathological excitability patterns. This minimalist “device” could have physiological analogs. At first nodes of Ranvier and at nociceptors, e.g., localized lipid-tuning that modulated Nav midpoints could produce Nav-CLS, as could co-expression of appropriately differing Nav isoforms.

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Kinetic changes and modulation by carbamazepine on voltage-gated sodium channels in rat CA1 neurons after epilepsy

Cited by 15 publications

References 29 publications

Left-Shifted Nav Channels in Injured Bilayer: Primary Targets for Neuroprotective Nav Antagonists?

Left-Shifted Nav Channels in Injured Bilayer: Primary Targets for Neuroprotective Nav Antagonists?

Resveratrol: French Paradox Revisited

Spontaneous Excitation Patterns Computed for Axons with Injury-like Impairments of Sodium Channels and Na/K Pumps

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