α7 Nicotinic Receptor Promotes the Neuroprotective Functions of Astrocytes against Oxaliplatin Neurotoxicity.

Lorenzo Di Cesare Mannelli,Paola Failli,Matteo Zanardelli,Carla Ghelardini,Barbara Tenci

doi:10.1155/2015/396908

Lorenzo Di Cesare Mannelli, Paola Failli + Show 3 more

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https://doi.org/10.1155/2015/396908

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Journal: Neural plasticity	Publication Date: Jan 1, 2015
Citations: 75	License type: CC BY 3.0

Affiliation: University of Florence

Abstract

Neuropathies are characterized by a complex response of the central nervous system to injuries. Glial cells are recruited to maintain neuronal homeostasis but dysregulated activation leads to pain signaling amplification and reduces the glial neuroprotective power. Recently, we highlighted the property of α7 nicotinic-acetylcholine-receptor (nAChR) agonists to relieve pain and induce neuroprotection simultaneously with a strong increase in astrocyte density. Aimed to study the role of α7 nAChR in the neuron-glia cross-talk, we treated primary rat neurons and astrocytes with the neurotoxic anticancer drug oxaliplatin evaluating the effect of the α7 nAChR agonist PNU-282987 (PNU). Oxaliplatin (1 μM, 48 h) reduced cell viability and increased caspase-3 activity of neuron monocultures without damaging astrocytes. In cocultures, astrocytes were not able to protect neurons by oxaliplatin even if glial cell metabolism was stimulated (pyruvate increase). On the contrary, the coculture incubation with 10 μM PNU improved neuron viability and inhibited apoptosis. In the absence of astrocytes, the protection disappeared. Furthermore, PNU promoted the release of the anti-inflammatory cytokine TGF-β1 and the expression of the glutamate-detoxifying enzyme glutamine synthetase. The α7 nAChR stimulation protects neurons from oxaliplatin toxicity through an astrocyte-mediated mechanism. α7 nAChR is suggested for recovering the homeostatic role of astrocytes.

Highlights

The development of painful neuropathies is a dose limiting side effect of commonly used chemotherapeutic agents, including platinum drugs [1,2,3]
Astrocytes appeared more resistant to oxaliplatin toxicity since cell viability was decreased by about 40% and 55% after treatment with 10 μM and 100 μM oxaliplatin, respectively (Figure 1(a), astrocyte monoculture)
As compared to neuron monoculture, the presence of astrocytes did not significantly modify oxaliplatin toxicity evaluated as cell viability as well as caspase-3 activity

Summary

Introduction

The development of painful neuropathies is a dose limiting side effect of commonly used chemotherapeutic agents, including platinum drugs [1,2,3]. In particular astrocytes, is strictly related to oxaliplatindependent pain since glial inhibitors reduce mechanical and thermal hypersensitivity [12]. The stimulation of the α7 subtype of the nicotinic receptors (α7 nAChR; see [15, 16] for review) has emerged as effective in reducing oxaliplatin-dependent pain and preventing damage to the nervous tissue.

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