title: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824, USA.
authors.forename: Cuihong
authors.initials: C
authors.lastname: Jia
authors.forename: Sutheera
authors.initials: S
authors.lastname: Sangsiri
authors.forename: Bethany
authors.initials: B
authors.lastname: Belock
authors.forename: Tania R
authors.initials: TR
authors.lastname: Iqbal
authors.forename: James J
authors.initials: JJ
authors.lastname: Pestka
authors.forename: Colleen C
authors.initials: CC
authors.lastname: Hegg
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D000281:Administration, Intranasal; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D018929:Cell Culture Techniques; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D009831:Olfactory Mucosa / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018034:Olfactory Receptor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012903:Smell / Q000187:drug effects; D014255:Trichothecenes / Q000633:toxicity*
chemical_list: D014255:Trichothecenes; C028268:satratoxin G; D000255:Adenosine Triphosphate