Neuronal alarmin IL-1α evokes astrocyte-mediated protective signals: Effectiveness in chemotherapy-induced neuropathic pain.

Abstract

The distinction between glial painful and protective pathways is unclear and the possibility to finely modulate the system is lacking. Focusing on painful neuropathies, we studied the role of interleukin 1α (IL-1α), an alarmin belonging to the larger family of damage-associated molecular patterns endogenously secreted to restore homeostasis. The treatment of rat primary neurons with increasing doses of the neurotoxic anticancer drug oxaliplatin (0.3-100μM, 48 h) induced the release of IL-1α. The knockdown of the alarmin in neurons leads to their higher mortality when co-cultured with astrocytes. This toxicity was related to increased extracellular ATP and decreased release of transforming growth factor β1, mostly produced by astrocytes. In a rat model of neuropathy induced by oxaliplatin, the intrathecal treatment with IL-1α was able to reduce mechanical and thermal hypersensitivity both after acute injection (100 ng and 300 ng) and continuous infusion (100 and 300 ng/die-1). Ex vivo analysis on spinal purified astrocyte processes (gliosomes) and nerve terminals (synaptosomes) revealed the property of IL-1α to reduce the endogenous glutamate release induced by oxaliplatin. This protective effect paralleled with an increased number of GFAP-positive cells in the spinal cord, suggesting the ability of IL-1α to evoke a positive, conservative astrocyte phenotype. Endogenous IL-1α induced protective signals in the cross-talk between neurons and astrocytes. Exogenously administered in rats, IL-1α prevented neuropathic pain in the presence of spinal glutamate decrease and astrocyte activation.

• Authors: Lorenzo Di Cesare Mannelli, Laura Micheli, Chiara Cervetto, Alessandra Toti, Elena Lucarini, Carmen Parisio, Manuela Marcoli, Carla Ghelardini
• Journal: Neurobiology of disease (Neurobiol Dis) Vol. 168 Pg. 105716 (06 15 2022) ISSN: 1095-953X [Electronic] United States
• PMID: 35367629 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Alarmins
• Antineoplastic Agents
• Interleukin-1alpha
• Oxaliplatin
• Glutamic Acid

Topics

• Alarmins (adverse effects, metabolism)
• Animals
• Antineoplastic Agents (adverse effects)
• Astrocytes (metabolism)
• Glutamic Acid (metabolism)
• Hyperalgesia (metabolism)
• Interleukin-1alpha (adverse effects, metabolism)
• Neuralgia (metabolism)
• Neurons (metabolism)
• Oxaliplatin (toxicity)
• Rats
• Rats, Sprague-Dawley
• Spinal Cord (metabolism)