Propofol Protects Rat Hypoglossal Motoneurons in an In Vitro Model of Excitotoxicity by Boosting GABAergic Inhibition and Reducing Oxidative Stress

Ghezzi, Filippo; Monni, Laura; Corsini, Silvia; Rauti, Rossana; Nistri, Andrea

doi:10.1016/j.neuroscience.2017.10.019

Cited by 6 publications

(7 citation statements)

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“…; Ghezzi et al . ), treatment with TBOA (50 μ m ) led to a significant reduction in HM number (Fig. , second row, green pseudocolor, and Fig.…”

Section: Resultsmentioning

confidence: 85%

“…; Ghezzi et al . ). A representative current trace ( V h = –70 mV) of a bursting HM is shown in Fig.…”

Section: Resultsmentioning

confidence: 97%

“…, ) and propofol (Ghezzi et al . ), acting on different molecular targets, share the ability to contrast bursting and thus prevent cell death. The retigabine‐dependent reduction in network excitability affecting both HMs (Ghezzi et al .…”

Section: Discussionmentioning

confidence: 99%

“…; Ghezzi et al . ), Ca 2+ overload (Sharifullina & Nistri, ; Corsini et al . ), oxidative stress, mitochondrial damage (Tortora et al .…”

Section: Introductionmentioning

confidence: 99%

“…, ) and propofol (Ghezzi et al . ), which, although acting on different molecular targets, share the ability to reduce HM hyperexcitability and inhibit bursting.…”

Section: Introductionmentioning

confidence: 99%

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Functional up‐regulation of the M‐current by retigabine contrasts hyperexcitability and excitotoxicity on rat hypoglossal motoneurons

Ghezzi

Monni

Nistri

2018

The Journal of Physiology

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Neuronal hyperexcitability is a symptom characterizing several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). In the ALS bulbar form, hypoglossal motoneurons (HMs) are an early target for neurodegeneration because of their high vulnerability to metabolic insults. In recent years, our laboratory has developed an in vitro model of a brainstem slice comprising the hypoglossal nucleus in which HM neurodegeneration is achieved by blocking glutamate clearance with dl-threo-β-benzyloxyaspartate (TBOA), thus leading to delayed excitotoxicity. During this process, HMs display a set of hallmarks such as hyperexcitability (and network bursting), reactive oxygen species (ROS) generation and, finally, cell death. The present study aimed to investigate whether blocking early hyperexcitability and bursting with the anti-convulsant drug retigabine was sufficient to achieve neuroprotection against excitotoxicity. Retigabine is a selective positive allosteric modulator of the M-current (I ), an endogenous mechanism that neurons (comprising HMs) express to dampen excitability. Retigabine (10 μm; co-applied with TBOA) contrasted ROS generation, release of endogenous toxic factors into the HM cytoplasm and excitotoxicity-induced HM death. Electrophysiological experiments showed that retigabine readily contrasted and arrested bursting evoked by TBOA administration. Because neuronal I subunits (Kv7.2, Kv7.3 and Kv7.5) were expressed in the hypoglossal nucleus and in functionally connected medullary nuclei, we suggest that they were responsible for the strong reduction in network excitability, a potent phenomenon for achieving neuroprotection against TBOA-induced excitotoxicity. The results of the present study may have translational value for testing novel positive pharmacological modulators of the I under pathological conditions (including neurodegenerative disorders) characterized by excessive neuronal excitability.

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“…; Ghezzi et al . ), treatment with TBOA (50 μ m ) led to a significant reduction in HM number (Fig. , second row, green pseudocolor, and Fig.…”

Section: Resultsmentioning

confidence: 85%

“…; Ghezzi et al . ). A representative current trace ( V h = –70 mV) of a bursting HM is shown in Fig.…”

Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

“…; Ghezzi et al . ), Ca 2+ overload (Sharifullina & Nistri, ; Corsini et al . ), oxidative stress, mitochondrial damage (Tortora et al .…”

Section: Introductionmentioning

confidence: 99%

“…, ) and propofol (Ghezzi et al . ), which, although acting on different molecular targets, share the ability to reduce HM hyperexcitability and inhibit bursting.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations