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Published on: June 9, 2017
Pretreatment with Zonisamide Mitigates Oxaliplatin-Induced Toxicity in Rat DRG Neurons and DRG Neuron-Schwann Cell
Shizuka Takaku1, Kazunori Sango1
1Diabetic Neuropathy Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
Abstract:
Oxaliplatin (OHP) is a platinum-based agent that can cause peripheral neuropathy, an adverse effect in which the dorsal root ganglion (DRG) neurons are targeted. Zonisamide has exhibited neuroprotective activities toward adult rat DRG neurons in vitro and therefore, we aimed to assess its potential efficacy against OHP-induced neurotoxicity. Pretreatment with zonisamide (100 μM) alleviated the DRG neuronal death caused by OHP (75 μM) and the protective effects were attenuated by a co-incubation with 25 μM of the mitogen-activated protein kinase (MAPK; MEK/ERK) inhibitor, U0126, or the phosphatidyl inositol-3'-phosphate-kinase (PI3K) inhibitor, LY294002. Pretreatment with zonisamide also suppressed the OHP-induced p38 MAPK phosphorylation in lined DRG neurons, ND7/23, while the OHP-induced DRG neuronal death was alleviated by pretreatment with the p38 MAPK inhibitor, SB239063 (25 μM). Although zonisamide failed to protect the immortalized rat Schwann cells IFRS1 from OHP-induced cell death, it prevented neurite degeneration and demyelination-like changes, as well as the reduction of the serine/threonine-specific protein kinase (AKT) phosphorylation in DRG neuron-IFRS1 co-cultures exposed to OHP. Zonisamide's neuroprotection against the OHP-induced peripheral sensory neuropathy is possibly mediated by a stimulation of the MEK/ERK and PI3K/AKT signaling pathways and suppression of the p38 MAPK pathway in DRG neurons. Future studies will allow us to solidify zonisamide as a promising remedy against the neurotoxic adverse effects of OHP.
Insights
Zonisamide protects against oxaliplatin-induced neurotoxicity by modulating key signaling pathways in dorsal root ganglion neurons. This study suggests zonisamide as a potential therapeutic agent for chemotherapy-induced peripheral neuropathy.
Area of Science:
- Neuroscience
- Pharmacology
- Oncology
Background:
- Oxaliplatin (OHP) is a chemotherapy agent known to cause peripheral neuropathy, damaging dorsal root ganglion (DRG) neurons.
- Zonisamide has demonstrated neuroprotective properties in previous studies.
Purpose of the Study:
- To evaluate the efficacy of zonisamide in preventing oxaliplatin-induced neurotoxicity in DRG neurons.
- To investigate the underlying molecular mechanisms of zonisamide's neuroprotective effects.
Main Methods:
- Primary DRG neurons and a neuronal cell line (ND7/23) were treated with OHP and zonisamide.
- Inhibitors of MEK/ERK (U0126) and PI3K (LY294002) pathways were used to assess zonisamide's mechanism.
- p38 MAPK phosphorylation and cell death were analyzed.
- Co-cultures with Schwann cells (IFRS1) were used to evaluate effects on neurites and myelination.
Main Results:
- Zonisamide pretreatment significantly reduced OHP-induced DRG neuronal death.
- The protective effect of zonisamide was diminished by MEK/ERK and PI3K inhibitors.
- Zonisamide suppressed OHP-induced p38 MAPK phosphorylation.
- Zonisamide prevented OHP-induced neurite degeneration and demyelination-like changes in co-cultures.
- Zonisamide prevented the reduction of AKT phosphorylation in co-cultures.
Conclusions:
- Zonisamide exhibits neuroprotective effects against oxaliplatin-induced neurotoxicity.
- These effects are mediated through the activation of MEK/ERK and PI3K/AKT pathways and the suppression of the p38 MAPK pathway in DRG neurons.
- Zonisamide shows promise as a therapeutic strategy to mitigate OHP-induced peripheral sensory neuropathy.
