Cisplatin Toxicity in Dorsal Root Ganglion Neurons Is Relieved by Meclizine via Diminution of Mitochondrial Compromise and Improved Clearance of DNA Damage

Murat F. Gorgun, Ming Zhuo, Ella Englander

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8 Citations (Scopus)

Abstract

Chemotherapy-induced neurotoxicity of peripheral nervous system (PNS) hinders efficacy of cancer treatments. Mechanisms initiating PNS injury by anticancer drugs are incompletely understood delaying development of effective management strategies. To understand events triggered in PNS by cancer drugs, we exposed dorsal root ganglion (DRG) neurons to cisplatin, a drug from platinum-based class of chemotherapeutics frequently implicated in peripheral neuropathies. While cisplatin enters cancer cells and forms cisplatin/DNA crosslinks that block cell proliferation, circulating cisplatin can also reach the PNS and produce crosslinks that impede critical DNA transactions in postmitotic neurons. Cisplatin forms crosslinks with both, nuclear and mitochondrial DNA (mtDNA). Crosslinks are repairable primarily via the nucleotide excision repair (NER) pathway, which is present in nuclei but absent from mitochondrial compartment. Hence, high mitochondrial content and limited shielding by blood nerve barrier make DRG neurons particularly vulnerable to mitochondrial injury by cisplatin. We report that in DRG neurons, cisplatin elevates reactive oxygen species, depletes mtDNA, and impairs mitochondrial respiration, whereas concomitant meclizine supplementation preserves redox balance, attenuates mitochondrial compromise, and augments DNA repair. Meclizine is an antihistamine drug recently implicated in neuroprotection via modulation of energy metabolism. Our data demonstrate that in the mitochondria-rich DRG neurons, meclizine mitigates cisplatin-induced mitochondrial compromise via enhancement of pentose phosphate pathway and repletion of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione stores. The findings suggest that meclizine-mediated preservation of redox balance sustains mitochondrial respiration and supports execution of cellular processes, including timely removal of cisplatin crosslinks from nuclear DNA, thereby attenuating cisplatin toxicity in DRG neurons. Collectively, the findings reveal potential for pharmacologic modulation of dorsal root ganglion neurons metabolism for protection against toxicity of chemotherapeutic drugs.

Original languageEnglish (US)
Pages (from-to)1-13
Number of pages13
JournalMolecular Neurobiology
DOIs
StateAccepted/In press - Nov 17 2016

Fingerprint

Meclizine
Spinal Ganglia
Cisplatin
DNA Damage
Neurons
Peripheral Nervous System
Mitochondrial DNA
DNA Repair
Peripheral Nervous System Agents
Oxidation-Reduction
DNA
Respiration
Blood-Nerve Barrier
Pharmaceutical Preparations
Nervous System Trauma
Pentose Phosphate Pathway
Neoplasms
Histamine Antagonists
Peripheral Nervous System Diseases
Platinum

Keywords

  • Cisplatin
  • DNA damage
  • DNA repair
  • Dorsal root ganglion neurons
  • Meclizine
  • Mitochondrial respiration
  • mtDNA
  • Pentose phosphate pathway
  • ROS

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

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title = "Cisplatin Toxicity in Dorsal Root Ganglion Neurons Is Relieved by Meclizine via Diminution of Mitochondrial Compromise and Improved Clearance of DNA Damage",
abstract = "Chemotherapy-induced neurotoxicity of peripheral nervous system (PNS) hinders efficacy of cancer treatments. Mechanisms initiating PNS injury by anticancer drugs are incompletely understood delaying development of effective management strategies. To understand events triggered in PNS by cancer drugs, we exposed dorsal root ganglion (DRG) neurons to cisplatin, a drug from platinum-based class of chemotherapeutics frequently implicated in peripheral neuropathies. While cisplatin enters cancer cells and forms cisplatin/DNA crosslinks that block cell proliferation, circulating cisplatin can also reach the PNS and produce crosslinks that impede critical DNA transactions in postmitotic neurons. Cisplatin forms crosslinks with both, nuclear and mitochondrial DNA (mtDNA). Crosslinks are repairable primarily via the nucleotide excision repair (NER) pathway, which is present in nuclei but absent from mitochondrial compartment. Hence, high mitochondrial content and limited shielding by blood nerve barrier make DRG neurons particularly vulnerable to mitochondrial injury by cisplatin. We report that in DRG neurons, cisplatin elevates reactive oxygen species, depletes mtDNA, and impairs mitochondrial respiration, whereas concomitant meclizine supplementation preserves redox balance, attenuates mitochondrial compromise, and augments DNA repair. Meclizine is an antihistamine drug recently implicated in neuroprotection via modulation of energy metabolism. Our data demonstrate that in the mitochondria-rich DRG neurons, meclizine mitigates cisplatin-induced mitochondrial compromise via enhancement of pentose phosphate pathway and repletion of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione stores. The findings suggest that meclizine-mediated preservation of redox balance sustains mitochondrial respiration and supports execution of cellular processes, including timely removal of cisplatin crosslinks from nuclear DNA, thereby attenuating cisplatin toxicity in DRG neurons. Collectively, the findings reveal potential for pharmacologic modulation of dorsal root ganglion neurons metabolism for protection against toxicity of chemotherapeutic drugs.",
keywords = "Cisplatin, DNA damage, DNA repair, Dorsal root ganglion neurons, Meclizine, Mitochondrial respiration, mtDNA, Pentose phosphate pathway, ROS",
author = "Gorgun, {Murat F.} and Ming Zhuo and Ella Englander",
year = "2016",
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T1 - Cisplatin Toxicity in Dorsal Root Ganglion Neurons Is Relieved by Meclizine via Diminution of Mitochondrial Compromise and Improved Clearance of DNA Damage

AU - Gorgun, Murat F.

AU - Zhuo, Ming

AU - Englander, Ella

PY - 2016/11/17

Y1 - 2016/11/17

N2 - Chemotherapy-induced neurotoxicity of peripheral nervous system (PNS) hinders efficacy of cancer treatments. Mechanisms initiating PNS injury by anticancer drugs are incompletely understood delaying development of effective management strategies. To understand events triggered in PNS by cancer drugs, we exposed dorsal root ganglion (DRG) neurons to cisplatin, a drug from platinum-based class of chemotherapeutics frequently implicated in peripheral neuropathies. While cisplatin enters cancer cells and forms cisplatin/DNA crosslinks that block cell proliferation, circulating cisplatin can also reach the PNS and produce crosslinks that impede critical DNA transactions in postmitotic neurons. Cisplatin forms crosslinks with both, nuclear and mitochondrial DNA (mtDNA). Crosslinks are repairable primarily via the nucleotide excision repair (NER) pathway, which is present in nuclei but absent from mitochondrial compartment. Hence, high mitochondrial content and limited shielding by blood nerve barrier make DRG neurons particularly vulnerable to mitochondrial injury by cisplatin. We report that in DRG neurons, cisplatin elevates reactive oxygen species, depletes mtDNA, and impairs mitochondrial respiration, whereas concomitant meclizine supplementation preserves redox balance, attenuates mitochondrial compromise, and augments DNA repair. Meclizine is an antihistamine drug recently implicated in neuroprotection via modulation of energy metabolism. Our data demonstrate that in the mitochondria-rich DRG neurons, meclizine mitigates cisplatin-induced mitochondrial compromise via enhancement of pentose phosphate pathway and repletion of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione stores. The findings suggest that meclizine-mediated preservation of redox balance sustains mitochondrial respiration and supports execution of cellular processes, including timely removal of cisplatin crosslinks from nuclear DNA, thereby attenuating cisplatin toxicity in DRG neurons. Collectively, the findings reveal potential for pharmacologic modulation of dorsal root ganglion neurons metabolism for protection against toxicity of chemotherapeutic drugs.

AB - Chemotherapy-induced neurotoxicity of peripheral nervous system (PNS) hinders efficacy of cancer treatments. Mechanisms initiating PNS injury by anticancer drugs are incompletely understood delaying development of effective management strategies. To understand events triggered in PNS by cancer drugs, we exposed dorsal root ganglion (DRG) neurons to cisplatin, a drug from platinum-based class of chemotherapeutics frequently implicated in peripheral neuropathies. While cisplatin enters cancer cells and forms cisplatin/DNA crosslinks that block cell proliferation, circulating cisplatin can also reach the PNS and produce crosslinks that impede critical DNA transactions in postmitotic neurons. Cisplatin forms crosslinks with both, nuclear and mitochondrial DNA (mtDNA). Crosslinks are repairable primarily via the nucleotide excision repair (NER) pathway, which is present in nuclei but absent from mitochondrial compartment. Hence, high mitochondrial content and limited shielding by blood nerve barrier make DRG neurons particularly vulnerable to mitochondrial injury by cisplatin. We report that in DRG neurons, cisplatin elevates reactive oxygen species, depletes mtDNA, and impairs mitochondrial respiration, whereas concomitant meclizine supplementation preserves redox balance, attenuates mitochondrial compromise, and augments DNA repair. Meclizine is an antihistamine drug recently implicated in neuroprotection via modulation of energy metabolism. Our data demonstrate that in the mitochondria-rich DRG neurons, meclizine mitigates cisplatin-induced mitochondrial compromise via enhancement of pentose phosphate pathway and repletion of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione stores. The findings suggest that meclizine-mediated preservation of redox balance sustains mitochondrial respiration and supports execution of cellular processes, including timely removal of cisplatin crosslinks from nuclear DNA, thereby attenuating cisplatin toxicity in DRG neurons. Collectively, the findings reveal potential for pharmacologic modulation of dorsal root ganglion neurons metabolism for protection against toxicity of chemotherapeutic drugs.

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KW - Mitochondrial respiration

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KW - ROS

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