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Article

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

1
In Vitro Toxicology and Biomedicine, Dept Inaugurated by the Doerenkamp-Zbinden Foundation, University of Konstanz, 78457 Konstanz, Germany
2
Konstanz Research School Chemical Biology (KoRS-CB), University of Konstanz, 78457 Konstanz, Germany
3
CAAT-Europe, University of Konstanz, 78457 Konstanz, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Ralf Hausmann
Int. J. Mol. Sci. 2022, 23(7), 3734; https://doi.org/10.3390/ijms23073734
Received: 20 February 2022 / Revised: 22 March 2022 / Accepted: 24 March 2022 / Published: 29 March 2022
(This article belongs to the Special Issue The Role of P2X Receptors in Nociception, Pain and Neuronal Toxicity)
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 (Ca2+-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 Ca2+ concentration but signaling through transient receptor potential V1 (TRPV1) receptors or depolarization-triggered Ca2+ 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. View Full-Text
Keywords: nociceptors; purinergic receptor P2X3; peripheral nervous system diseases; bortezomib; proteasome inhibitors nociceptors; purinergic receptor P2X3; peripheral nervous system diseases; bortezomib; proteasome inhibitors
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MDPI and ACS Style

Holzer, A.-K.; Suciu, I.; Karreman, C.; Goj, T.; Leist, M. Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro. Int. J. Mol. Sci. 2022, 23, 3734. https://doi.org/10.3390/ijms23073734

AMA Style

Holzer A-K, Suciu I, Karreman C, Goj T, Leist M. Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro. International Journal of Molecular Sciences. 2022; 23(7):3734. https://doi.org/10.3390/ijms23073734

Chicago/Turabian Style

Holzer, Anna-Katharina, Ilinca Suciu, Christiaan Karreman, Thomas Goj, and Marcel Leist. 2022. "Specific Attenuation of Purinergic Signaling during Bortezomib-Induced Peripheral Neuropathy In Vitro" International Journal of Molecular Sciences 23, no. 7: 3734. https://doi.org/10.3390/ijms23073734

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