The Impact of the Antipsychotic Medication Chlorpromazine on Cytotoxicity through Ca2+ Signaling Pathway in Glial Cell Models

Chu, Che‐Sheng; Lin, Yung-Shang; Liang, Wei-Zhe

doi:10.1007/s12640-022-00507-5

Cited by 7 publications

(7 citation statements)

References 56 publications

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“…Our results showing the negative change in astrocyte activity with chlorpromazine treatment suggested that the transfer of calcium ions might have been inhibited by chlorpromazine. Furthermore, Chu et al (2022) reported that when human primary astrocytes were treated with chlorpromazine at concentrations from 10 to 50 μM for 24 h, cell death was observed at 50 μM, but [Ca 2+ ]i measurements using a spectrophotometer with Fura-2-AM showed no change at 10–30 μM. Our MEA measurements successfully captured astrocyte responses at concentrations (0.1–10 μM) even lower than those concentrations.…”

Section: Discussionmentioning

confidence: 69%

Detection of astrocytic slow oscillatory activity and response to seizurogenic compounds using planar microelectrode array

Kuroda

Matsuda²,

Ishibashi³

et al. 2023

Front. Neurosci.

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Since the development of the planar microelectrode array (MEA), it has become popular to evaluate compounds based on the electrical activity of rodent and human induced pluripotent stem cell (iPSC)-derived neurons. However, there are no reports recording spontaneous human astrocyte activity from astrocyte-only culture sample by MEA. It is becoming clear that astrocytes play an important role in various neurological diseases, and astrocytes are expected to be excellent candidates for targeted therapeutics for the treatment of neurological diseases. Therefore, measuring astrocyte activity is very important for drug development for astrocytes. Recently, astrocyte activity has been found to be reflected in the low-frequency band < 1 Hz, which is much lower than the frequency band for recording neural activity. Here, we separated the signals obtained from human primary astrocytes cultured on MEA into seven frequency bands and successfully recorded the extracellular electrical activity of human astrocytes. The slow waveforms of spontaneous astrocyte activity were observed most clearly in direct current potentials < 1 Hz. We established nine parameters to assess astrocyte activity and evaluated five seizurogenic drug responses in human primary astrocytes and human iPSC-derived astrocytes. Astrocytes demonstrated the most significant dose-dependent changes in pilocarpine. Furthermore, in a principal component analysis using those parameter sets, the drug responses to each seizurogenic compound were separated. In this paper, we report the spontaneous electrical activity measurement of astrocytes alone using MEA for the first time and propose that the MEA measurement focusing on the low-frequency band could be useful as one of the methods to assess drug response in vitro.

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Section: Discussionmentioning

confidence: 69%

Detection of astrocytic slow oscillatory activity and response to seizurogenic compounds using planar microelectrode array

Kuroda

Matsuda²,

Ishibashi³

et al. 2023

Front. Neurosci.

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“… 31 , 32 Moreover, the induction of cytotoxicity in glial cells via the Ca 2+ signaling pathway by chlorpromazine suggests the need for further mechanistic inquiries into the context of the trigeminal nerve. 33 Furthermore, extending the exploration of the chlorpromazine-induced corneal trigeminal denervation model to other species, such as rats, guinea pigs, and rabbits, appears both feasible and worthwhile.…”

Section: Discussionmentioning

confidence: 99%

Establishing a Mouse Model of Chlorpromazine-Induced Corneal Trigeminal Denervation

Lin,

Xu,

Tian

et al. 2023

Trans. Vis. Sci. Tech.

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Purpose This study aimed to establish a mouse model of chlorpromazine-induced corneal trigeminal denervation (CCTD). Methods Retrobulbar chlorpromazine injections were administered to 6- to 8-week-old C57BL/6j mice to induce corneal denervation. Additionally, apoptosis was assessed in isolated primary trigeminal ganglion cells after culturing in a conditioned medium containing chlorpromazine. Finally, the success rate of model generation, mortality and complication rates, and model-preparation learning curves were compared between the CCTD model and the electrocoagulation and axotomy models. Results Chlorpromazine retrobulbar injections resulted in trigeminal denervation, leading to a reduced blink reflex, corneal nerve density, and corneal epithelium thickness. Furthermore, 90% (9/10) of the mice developed epithelial defects, accompanied by increased apoptosis and inhibited proliferation of corneal epithelial cells. In vitro, trigeminal ganglion cell apoptosis increased after culturing in a conditioned medium containing chlorpromazine. Moreover, the CCTD model exhibited a higher success rate, longer survival rate, and lower complication rate compared to the electrocoagulation and axotomy models. Crucially, the learning curve demonstrated that the method used to generate the CCTD model was easy to learn. Conclusions The CCTD model is a user-friendly mouse model for studying corneal trigeminal denervation that offers a less invasive alternative to existing models. Translational Relevance The CCTD model serves as a valuable tool for investigating the functional mechanisms of corneal trigeminal nerves and their interactions with corneal cells.

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“…STATs are transcription factors, and STAT signalling has a role in inflammation (Morris et al, 2018), and therefore this could represent a mechanism by which MβCD caused increased cytokine release. In addition, chlorpromazine has been shown to effect calcium homeostasis in human glial cell models in vitro (Chu et al, 2022), which could have a myriad of effects on intracellular signalling pathways. It should also be noted that WTCM is media collected from cultured wild type neurons and therefore, although WTCM contains negligible levels of Aβ, it may contain other factors released from neurons.…”

Section: Discussionmentioning

confidence: 99%

Investigating the role that astrocytes play in mediating changes in synaptic health in Alzheimer’s disease

Johnson

Noble

Perez‐Nievas

2020

Alzheimer's & Dementia

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Background Previous results from our group showed that abeta‐stimulated astrocytes release factors that are detrimental to neurons. Our aim is to investigate and validate those factors. One cytokine in particular is shown to be increased after treatment with low concentrations of oligomeric abeta and has been associated with abnormal tau cleavage. We analysed the effect of the cytokine on neuronal health and complexity and on localisation of tau. We also investigated whether the change in phenotype of astrocytes in response to abeta depends on abeta internalisation, and which pathways are involved. Method Primary astrocytic and neuronal cultures were prepared from CD1 mice following standard protocols. Neurons were treated with the cytokine and/or its receptor antagonist and transfected with GFP to allow measurement of dendritic spine density and neurite complexity. Localisation of tau was examined in similarly treated neurons by immunocytochemistry. To investigate abeta internalisation, transgenic conditioned media containing abeta was collected from Tg2576 neurons, with medium from littermate wild type neurons as a control. Astrocytes were treated with conditioned media in the presence or absence of Dynasore, a small molecule inhibitor of dynamin GTPases, and abeta uptake assessed by immunocytochemistry. Result Exposure of neurons to the cytokine results in a reduction of dendritic spine density and neuronal complexity which is rescued when its receptor is blocked by a specific inhibitor. Exposure to the cytokine also seems to affect tau localisation in neurons, causing mislocalisation of tau from the axonal to the somatodendritic compartment. Preliminary data shows that astrocytes internalise abeta quite quickly following addition to the medium, at least in part through endocytosis. Conclusion The phenotype of astrocytes is altered in response to abeta, causing their secretion of molecules, including cytokines. Exposure of neurons to one of these cytokines causes reduced neuronal health and complexity, further confirming that factors released by astrocytes are synaptotoxic.

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The Impact of the Antipsychotic Medication Chlorpromazine on Cytotoxicity through Ca2+ Signaling Pathway in Glial Cell Models

Cited by 7 publications

References 56 publications

Detection of astrocytic slow oscillatory activity and response to seizurogenic compounds using planar microelectrode array

Detection of astrocytic slow oscillatory activity and response to seizurogenic compounds using planar microelectrode array

Establishing a Mouse Model of Chlorpromazine-Induced Corneal Trigeminal Denervation

Investigating the role that astrocytes play in mediating changes in synaptic health in Alzheimer’s disease

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