KOPS - The Institutional Repository of the University of Konstanz

Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro

Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro

Cite This

Files in this item

Checksum: MD5:c7d7a62a5d969dfb78437f1d2c0f6c24

HOLZER, Anna-Katharina, Ilinca SUCIU, Christiaan KARREMAN, Thomas GOJ, Marcel LEIST, 2022. Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro. In: International Journal of Molecular Sciences. MDPI. 23(7), 3734. ISSN 1661-6596. eISSN 1422-0067. Available under: doi: 10.3390/ijms23073734

@article{Holzer2022-04Speci-57242, title={Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro}, year={2022}, doi={10.3390/ijms23073734}, number={7}, volume={23}, issn={1661-6596}, journal={International Journal of Molecular Sciences}, author={Holzer, Anna-Katharina and Suciu, Ilinca and Karreman, Christiaan and Goj, Thomas and Leist, Marcel}, note={Article Number: 3734} }

Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro Leist, Marcel Suciu, Ilinca eng Attribution 4.0 International Leist, Marcel Suciu, Ilinca 2022-04-08T13:18:11Z 2022-04-08T13:18:11Z 2022-04 Holzer, Anna-Katharina Goj, Thomas Holzer, Anna-Katharina Goj, Thomas Human peripheral neuropathies are poorly understood, and the availability of experimental models limits further research. The PeriTox test uses immature dorsal root ganglia (DRG)-like neurons, derived from induced pluripotent stem cells (iPSC), to assess cell death and neurite damage. Here, we explored the suitability of matured peripheral neuron cultures for the detection of sub-cytotoxic endpoints, such as altered responses of pain-related P2X receptors. A two-step differentiation protocol, involving the transient expression of ectopic neurogenin-1 (NGN1) allowed for the generation of homogeneous cultures of sensory neurons. After >38 days of differentiation, they showed a robust response (Ca<sup>2+</sup>-signaling) to the P2X3 ligand α,β-methylene ATP. The clinical proteasome inhibitor bortezomib abolished the P2X3 signal at ≥5 nM, while 50–200 nM was required in the PeriTox test to identify neurite damage and cell death. A 24 h treatment with low nM concentrations of bortezomib led to moderate increases in resting cell intracellular Ca<sup>2+</sup> concentration but signaling through transient receptor potential V1 (TRPV1) receptors or depolarization-triggered Ca<sup>2+</sup> influx remained unaffected. We interpreted the specific attenuation of purinergic signaling as a functional cell stress response. A reorganization of tubulin to form dense structures around the cell somata confirmed a mild, non-cytotoxic stress triggered by low concentrations of bortezomib. The proteasome inhibitors carfilzomib, delanzomib, epoxomicin, and MG-132 showed similar stress responses. Thus, the model presented here may be used for the profiling of new proteasome inhibitors in regard to their side effect (neuropathy) potential, or for pharmacological studies on the attenuation of their neurotoxicity. P2X3 signaling proved useful as endpoint to assess potential neurotoxicants in peripheral neurons. Karreman, Christiaan Karreman, Christiaan

Downloads since Apr 8, 2022 (Information about access statistics)

Holzer_2-1d8cr5x5k5vr32.pdf 61

This item appears in the following Collection(s)

Attribution 4.0 International Except where otherwise noted, this item's license is described as Attribution 4.0 International

Search KOPS


Browse

My Account