Neurotoxicity of propofol on rat hypoglossal motoneurons in vitro

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

doi:10.1016/j.neulet.2017.06.040

Cited by 6 publications

(8 citation statements)

References 35 publications

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“…The neurotoxicity of propofol have been reported in several types of neurons, including human stem cell-derived neurons, rat prefrontal cortical neurons and hypoglossal motoneurons, as well as rodent developing hippocampal astrocytes [22][23][24][25]. Consistently, we found that propofol had markedly inhibited the growth and stimulated the apoptosis of rat hippocampal neurons.…”

Section: Discussionsupporting

confidence: 84%

Dexmedetomidine reduces propofol-induced apoptosis of neonatal rat hippocampal neurons via up-regulating Bcl-2 expression

Li¹,

Zeng²,

Wang³

et al. 2018

biomedicalresearch

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Background: The use of anesthetics propofol in certain pediatric age groups remains off-label, but it may cause neuronal apoptosis, long-term cognitive and neurological abnormalities during early postnatal period. Dexmedetomidine (Dex) can exert neuroprotective effects in rats. This study aimed to evaluate the effects of Dex and propofol on the apoptosis of neonatal rat hippocampal neurons. Methods: Primary hippocampal neurons of neonatal rats were isolated and identified by immunofluorescence. Neurons were then divided into normal control, propofol (12 μg/ml propofol), and propofol+Dex group (12 μg/ml propofol+0.25 μg/ml Dex). The cell morphology was detected by Hematoxylin-Eosin (HE) staining. The cell apoptosis was analysed by flow cytometry and Hoechst assay. The expression of Bcl-2 mRNA and protein was determined by quantitative reverse transcription PCR and Western blot. Results: The apoptosis rate and proportion of Hoechst-positive cells in propofol group was significantly higher compared with control group (p=0.023 and 0.036, respectively). Propofol+Dex group exhibited significantly lower apoptosis and Hoechst-positive rate compared with propofol group (p=0.016 and 0.028, respectively). The expression of Bcl-2 mRNA and protein in propofol group was significantly decreased compared with control group (p=0.012 and 0.043, respectively). The Bcl-2 mRNA and protein expression in propofol+Dex group was significantly higher than those in propofol group (p=0.033 and 0.026, respectively). Conclusion: Propofol inhibited the growth and induced apoptosis of neonatal rat hippocampal neurons, whereas Dex suppressed the propofol-induced apoptosis via increasing the expression of Bcl-2. Our findings indicate that Dex in conjunction with propofol might reduce the propofol-induced neurotoxicity in pediatric patients who undergo general anesthetics, and therefore might provide an effective clinical measure against neural damages associated with general anesthetics.

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Section: Discussionsupporting

confidence: 84%

Dexmedetomidine reduces propofol-induced apoptosis of neonatal rat hippocampal neurons via up-regulating Bcl-2 expression

Li¹,

Zeng²,

Wang³

et al. 2018

biomedicalresearch

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“…DEA was demonstrated to increase cytosolic free Ca 2+ concentration [ 19 , 20 ], which, in turn, can trigger apoptosis, by upregulating among other mechanisms AIF translocation to the nucleus [ 21 ]. Accordingly, we treated T24 cells with increasing concentrations of DEA for 24 hours, isolated the nuclei and assessed AIF nuclear translocation by immunoblotting from the nuclear fraction ( Fig 7 ).…”

Section: Resultsmentioning

confidence: 99%

Desethylamiodarone—A metabolite of amiodarone—Induces apoptosis on T24 human bladder cancer cells via multiple pathways

et al. 2017

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Bladder cancer (BC) is a common malignancy of the urinary tract that has a higher frequency in men than in women. Cytostatic resistance and metastasis formation are significant risk factors in BC therapy; therefore, there is great interest in overcoming drug resistance and in initiating research for novel chemotherapeutic approaches. Here, we suggest that desethylamiodarone (DEA)–a metabolite of amiodarone—may have cytostatic potential. DEA activates the collapse of mitochondrial membrane potential (detected by JC-1 fluorescence), and induces cell death in T24 human transitional-cell bladder carcinoma cell line at physiologically achievable concentrations. DEA induces cell cycle arrest in the G0/G1 phase, which may contribute to the inhibition of cell proliferation, and shifts the Bax/Bcl-2 ratio to initiate apoptosis, induce AIF nuclear translocation, and activate PARP-1 cleavage and caspase-3 activation. The major cytoprotective kinases—ERK and Akt—are inhibited by DEA, which may contribute to its cell death-inducing effects. DEA also inhibits the expression of B-cell-specific Moloney murine leukemia virus integration site 1 (BMI1) and reduces colony formation of T24 bladder carcinoma cells, indicating its possible inhibitory effect on metastatic potential. These data show that DEA is a novel anti-cancer candidate of multiple cell death-inducing effects and metastatic potential. Our findings recommend further evaluation of its effects in clinical studies.

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“…), whereas AIF immunostaining was employed as a biomarker of cell damage (Monni et al . ). Representative images of brainstem slices are shown in Figs and , whereas HM number and AIF intensity signal quantification are shown in Fig.…”

Section: Resultsmentioning

confidence: 97%

“…; Monni et al . ). It is not possible to understand the fate of surviving HMs because of the time‐limited survival of the in vitro preparation (Corsini et al .…”

Section: Discussionmentioning

confidence: 97%

“…) was used as biomarker of neurotoxicity (Monni et al . ). For the detection of Kv7 channel subunits, the primary antibodies employed were: anti‐Kv7.2 (KCNQ2, rabbit polyclonal, dilution 1:400; Alomone, Jerusalem, Israel) (Devaux, ), anti‐Kv7.3 (KCNQ3, rabbit polyclonal, dilution 1:100; Alomone) and anti‐Kv7.5 (KCNQ5, rabbit polyclonal, dilution 1:400; Alomone).…”

Section: Methodsmentioning

confidence: 97%

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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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Neurotoxicity of propofol on rat hypoglossal motoneurons in vitro

Cited by 6 publications

References 35 publications

Dexmedetomidine reduces propofol-induced apoptosis of neonatal rat hippocampal neurons via up-regulating Bcl-2 expression

Dexmedetomidine reduces propofol-induced apoptosis of neonatal rat hippocampal neurons via up-regulating Bcl-2 expression

Desethylamiodarone—A metabolite of amiodarone—Induces apoptosis on T24 human bladder cancer cells via multiple pathways

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

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