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

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.

The interaction between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α represents a new antinociceptive signaling pathway in mice

“…Additionally, it has been demonstrated that the selective activation of α7 nAChR subtype may be involved in a rat model of oxaliplatin-induced neuropathy (Di Cesare Mannelli et al, 2014), and induce neuroprotection associated with an increase in astrocyte density (Di Cesare Mannelli et al, 2015). As we mentioned in the introduction, several possible mechanisms were proposed to mediate these disparate pharmacological and behavioral responses (Bagdas et al, 2016; Damaj et al, 2000; Egea et al, 2015; Feuerbach et al, 2009; Liu et al, 2012; Wang et al, 2005).…”

The α7 nicotinic receptor dual allosteric agonist and positive allosteric modulator GAT107 reverses nociception in mouse models of inflammatory and neuropathic pain

“…Previous studies report that the α7 nAChR is found within the CNS on astrocytes (Shen and Yakel, ), and modulation of astrocytic α7 nAChR leads to anti‐inflammatory signalling cascades, as well as decreases in astrocyte activation shown by the astrocyte‐specific glial fibrillary acidic protein (GFAP) (Liu et al ., ; Niranjan et al ., ; Di Cesare Mannelli et al ., ). It is now supported that glial activation, including astrocyte activation, within the dorsal horn of the spinal cord may also play a critical role in mediating pathological pain (Kim et al ., ; Wilkerson et al ., ).…”

SAK3-Induced Neuroprotection Is Mediated by Nicotinic Acetylcholine Receptors

“…Activated PI3K in turn promotes Akt activity and downstream survival signaling, including Nrf2/HO-1 signaling in neurons (Franke et al 1997;Kihara et al 2001;Navarro et al 2015;Niture and Jaiswal 2012;Shaw et al 2002). By contrast, α7 nAChR activation in microglia and/or astrocytes is neuroprotective by promoting release of anti-inflammatory cytokines and blocking release of inflammatory cytokines (Di Cesare et al 2015;Shin and Dixon 2015). The observation that both SAK3-induced ACh release and SAK3induced neuroprotection are blocked by α7 nAChR inhibitors supports the idea that SAK3 effects are in large part mediated by nAChRs.…”