ATP Mediates Neuroprotective and Neuroproliferative Effects in Mouse Olfactory Epithelium following Exposure to Satratoxin G In Vitro and In Vivo

Abstract

Intranasal aspiration of satratoxin G (SG), a mycotoxin produced by the black mold Stachybotrys chartarum, selectively induces apoptosis in olfactory sensory neurons (OSNs) in mouse olfactory epithelium (OE) through unknown mechanisms. Here, we show a dose-dependent induction of apoptosis 24 h post-SG exposure in vitro as measured by increased activated caspases in the OP6 olfactory placodal cell line and increased propidium iodide staining in primary OE cell cultures. Intranasal aspiration of SG increased TUNEL (Terminal dUTP Nick End Labeling) staining in the neuronal layer of the OE and significantly increased the latency to find a buried food pellet, confirming that SG selectively induces neuronal apoptosis and demonstrating that SG impairs the sense of smell. Next, we investigated whether ATP can prevent SG-induced OE toxicity. ATP did not decrease apoptosis under physiological conditions but significantly reduced SG-induced OSN apoptosis in vivo and in vitro. Furthermore, purinergic receptor inhibition significantly increased apoptosis in OE primary cell culture and in vivo. These data indicate that ATP is neuroprotective against SG-induced OE toxicity. The number of cells that incorporated 5'-bromodeoxyuridine, a measure of proliferation, was significantly increased 3 and 6 days post-SG aspiration. Treatment with purinergic receptor antagonists significantly reduced SG-induced cell proliferation, whereas post-treatment with ATP significantly potentiated SG-induced cell proliferation. These data indicate that ATP is released and promotes cell proliferation via activation of purinergic receptors in SG-induced OE injury. Thus, the purinergic system is a therapeutic target to alleviate or restore the loss of OSNs.

Olfactory mucosal microstructural changes in a rat model of acute rhinosinusitis with dysosmia

“…Under physiological conditions, a large number of neuron-pathogenic microorganisms exist in the nasal cavity, and when the body resistance decreases or during dysbacteriosis, neuronal damage and apoptosis can be induced by inflammatory responses (Jia et al, 2011). In our study, S. pneumoniae, which is the common cause of rhinosinusitis, was selected for establishing a model that is close to the development of human rhinosinusitis.…”

Effect of IP3R3 and NPY on age-related declines in olfactory stem cell proliferation

“…We used 2 methods to cause injury: (1) administration of satratoxin G that causes ATP-induced IP3R3-dependent NPY release (Jia et al, 2011) and (2) bulbectomy that does not cause ATP-activated IP3R3-mediated NPY release (Jia et al, 2013, Jia et al, 2010). IP3R3 +/− and IP3R3 −/− mice at 2, 6, 12 and 24 months old intranasally aspirated vehicle or satratoxin G (100 µg/kg) or underwent a unilateral bulbectomy, and BrdU-incorporation was quantified in the OE at 6 days post-aspiration or surgery.…”

Neuropeptide Y and extracellular signal-regulated kinase mediate injury-induced neuroregeneration in mouse olfactory epithelium

“…Our previous reports demonstrate that ATP is neuroprotective in the OE. Over a period of hours to days, ATP initiates a heat shock protein-mediated stress signaling cascade that facilitates cell survival (Hegg and Lucero, 2006), and blockade of P2 purinergic receptors increases DNA fragmentation in the OE (Jia et al, 2011b), indicating that activation of P2 purinergic receptors is involved in cell protection. Inhibition of p44/42 ERK with the MEK inhibitor PD98059, leads to a reduction of cells that are double-labeled with TUNEL and mature OSN marker olfactory marker protein (OMP) in primary OSN culture, indicating ERK inhibition decreases OSN apoptosis (Simpson et al, 2003) and is neuroprotective.…”

“…In the OE, injury by toxic compounds such as nickel sulfate, satratoxin G or high concentrations of odorants induces ATP release and ATP promotes basal cell proliferation via activation of P2 purinergic receptors (Hegg and Lucero, 2006; Jia et al, 2010; Jia et al, 2011b). P2 purinergic receptors, including P2X and P2Y, are expressed in the OE (Hegg et al, 2003).…”