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Preventive action of benztropine on platinum-induced peripheral neuropathies and tumor growth.
Acta Neuropathol Commun. 2019 01 18; 7(1):9.AN

Abstract

The endogenous cholinergic system plays a key role in neuronal cells, by suppressing neurite outgrowth and myelination and, in some cancer cells, favoring tumor growth. Platinum compounds are widely used as part of first line conventional cancer chemotherapy; their efficacy is however limited by peripheral neuropathy as a major side-effect. In a multiple sclerosis mouse model, benztropine, that also acts as an anti-histamine and a dopamine re-uptake inhibitor, induced the differentiation of oligodendrocytes through M1 and M3 muscarinic receptors and enhanced re-myelination. We have evaluated whether benztropine can increase anti-tumoral efficacy of oxaliplatin, while preventing its neurotoxicity.We showed that benztropine improves acute and chronic clinical symptoms of oxaliplatin-induced peripheral neuropathies in mice. Sensory alterations detected by electrophysiology in oxaliplatin-treated mice were consistent with a decreased nerve conduction velocity and membrane hyperexcitability due to alterations in the density and/or functioning of both sodium and potassium channels, confirmed by action potential analysis from ex-vivo cultures of mouse dorsal root ganglion sensory neurons using whole-cell patch-clamp. These alterations were all prevented by benztropine. In oxaliplatin-treated mice, MBP expression, confocal and electronic microscopy of the sciatic nerves revealed a demyelination and confirmed the alteration of the myelinated axons morphology when compared to animals injected with oxaliplatin plus benztropine. Benztropine also prevented the decrease in neuronal density in the paws of mice injected with oxaliplatin. The neuroprotection conferred by benztropine against chemotherapeutic drugs was associated with a lower expression of inflammatory cytokines and extended to diabetic-induced peripheral neuropathy in mice.Mice receiving benztropine alone presented a lower tumor growth when compared to untreated animals and synergized the anti-tumoral effect of oxaliplatin, a phenomenon explained at least in part by benztropine-induced ROS imbalance in tumor cells.This report shows that blocking muscarinic receptors with benztropine prevents peripheral neuropathies and increases the therapeutic index of oxaliplatin. These results can be rapidly transposable to patients as benztropine is currently indicated in Parkinson's disease in the United States.

Authors+Show Affiliations

Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris City, INSERM U1016, Paris, France.Molecular engineering of proteins unit (SIMOPRO), CEA of Saclay, and Paris-Saclay Institute of Neuroscience (Neuro-PSI), UMR CNRS 9197, Paris-Saclay University, Gif-sur-Yvette, France. Sanofi R & D, Integrated Drug Discovery - High Content Biology, Vitry-sur-Seine, France.Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris City, INSERM U1016, Paris, France.Molecular engineering of proteins unit (SIMOPRO), CEA of Saclay, and Paris-Saclay Institute of Neuroscience (Neuro-PSI), UMR CNRS 9197, Paris-Saclay University, Gif-sur-Yvette, France.Plateforme imagerie : microscopie électronique, Institut Cochin, INSERM U1016, Paris, France.Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris City, INSERM U1016, Paris, France.Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris City, INSERM U1016, Paris, France. Department of Immunology, Cochin Teaching Hospital, AP-HP, 27, rue du faubourg Saint-Jacques, F75014, Paris, France.Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris City, INSERM U1016, Paris, France.Service de diagnostic biologique automatisé, Cochin Teaching Hospital, Paris, France.Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris City, INSERM U1016, Paris, France. Department of Immunology, Cochin Teaching Hospital, AP-HP, 27, rue du faubourg Saint-Jacques, F75014, Paris, France.Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris City, INSERM U1016, Paris, France. Department of Gastroenterology, Cochin Teaching Hospital, Paris Descartes University, Paris, France.Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris City, INSERM U1016, Paris, France.Department "Development, Reproduction and Cancer", Institut Cochin, Paris Descartes University, Sorbonne Paris City, INSERM U1016, Paris, France. frederic.batteux@cch.aphp.fr. Department of Immunology, Cochin Teaching Hospital, AP-HP, 27, rue du faubourg Saint-Jacques, F75014, Paris, France. frederic.batteux@cch.aphp.fr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

30657060

Citation

Cerles, Olivier, et al. "Preventive Action of Benztropine On Platinum-induced Peripheral Neuropathies and Tumor Growth." Acta Neuropathologica Communications, vol. 7, no. 1, 2019, p. 9.
Cerles O, Gonçalves TC, Chouzenoux S, et al. Preventive action of benztropine on platinum-induced peripheral neuropathies and tumor growth. Acta Neuropathol Commun. 2019;7(1):9.
Cerles, O., Gonçalves, T. C., Chouzenoux, S., Benoit, E., Schmitt, A., Bennett Saidu, N. E., Kavian, N., Chéreau, C., Gobeaux, C., Weill, B., Coriat, R., Nicco, C., & Batteux, F. (2019). Preventive action of benztropine on platinum-induced peripheral neuropathies and tumor growth. Acta Neuropathologica Communications, 7(1), 9. https://doi.org/10.1186/s40478-019-0657-y
Cerles O, et al. Preventive Action of Benztropine On Platinum-induced Peripheral Neuropathies and Tumor Growth. Acta Neuropathol Commun. 2019 01 18;7(1):9. PubMed PMID: 30657060.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Preventive action of benztropine on platinum-induced peripheral neuropathies and tumor growth. AU - Cerles,Olivier, AU - Gonçalves,Tânia Cristina, AU - Chouzenoux,Sandrine, AU - Benoit,Evelyne, AU - Schmitt,Alain, AU - Bennett Saidu,Nathaniel Edward, AU - Kavian,Niloufar, AU - Chéreau,Christiane, AU - Gobeaux,Camille, AU - Weill,Bernard, AU - Coriat,Romain, AU - Nicco,Carole, AU - Batteux,Frédéric, Y1 - 2019/01/18/ PY - 2018/11/14/received PY - 2019/01/04/accepted PY - 2019/1/19/entrez PY - 2019/1/19/pubmed PY - 2020/4/3/medline KW - Benztropine KW - Muscarinic receptors KW - Myelin KW - Oxaliplatin KW - Peripheral neuropathies SP - 9 EP - 9 JF - Acta neuropathologica communications JO - Acta Neuropathol Commun VL - 7 IS - 1 N2 - The endogenous cholinergic system plays a key role in neuronal cells, by suppressing neurite outgrowth and myelination and, in some cancer cells, favoring tumor growth. Platinum compounds are widely used as part of first line conventional cancer chemotherapy; their efficacy is however limited by peripheral neuropathy as a major side-effect. In a multiple sclerosis mouse model, benztropine, that also acts as an anti-histamine and a dopamine re-uptake inhibitor, induced the differentiation of oligodendrocytes through M1 and M3 muscarinic receptors and enhanced re-myelination. We have evaluated whether benztropine can increase anti-tumoral efficacy of oxaliplatin, while preventing its neurotoxicity.We showed that benztropine improves acute and chronic clinical symptoms of oxaliplatin-induced peripheral neuropathies in mice. Sensory alterations detected by electrophysiology in oxaliplatin-treated mice were consistent with a decreased nerve conduction velocity and membrane hyperexcitability due to alterations in the density and/or functioning of both sodium and potassium channels, confirmed by action potential analysis from ex-vivo cultures of mouse dorsal root ganglion sensory neurons using whole-cell patch-clamp. These alterations were all prevented by benztropine. In oxaliplatin-treated mice, MBP expression, confocal and electronic microscopy of the sciatic nerves revealed a demyelination and confirmed the alteration of the myelinated axons morphology when compared to animals injected with oxaliplatin plus benztropine. Benztropine also prevented the decrease in neuronal density in the paws of mice injected with oxaliplatin. The neuroprotection conferred by benztropine against chemotherapeutic drugs was associated with a lower expression of inflammatory cytokines and extended to diabetic-induced peripheral neuropathy in mice.Mice receiving benztropine alone presented a lower tumor growth when compared to untreated animals and synergized the anti-tumoral effect of oxaliplatin, a phenomenon explained at least in part by benztropine-induced ROS imbalance in tumor cells.This report shows that blocking muscarinic receptors with benztropine prevents peripheral neuropathies and increases the therapeutic index of oxaliplatin. These results can be rapidly transposable to patients as benztropine is currently indicated in Parkinson's disease in the United States. SN - 2051-5960 UR - https://www.unboundmedicine.com/medline/citation/30657060/Preventive_action_of_benztropine_on_platinum-induced_peripheral_neuropathies_and_tumor_growth L2 - https://actaneurocomms.biomedcentral.com/articles/10.1186/s40478-019-0657-y DB - PRIME DP - Unbound Medicine ER -