title: Varying butyric acid amounts induce different stress- and cell death-related signals in nerve growth factor-treated PC12 cells: implications in neuropathic pain absence during periodontal disease progression.
abstract: Neuropathic pain is absent from the early stages of periodontal disease possibly due to neurite retraction. Butyric acid (BA) is a periodontopathic metabolite that activates several stress-related signals and, likewise, induce neurite retraction. Neuronal cell death is associated to neurite retraction which would suggest that BA-induced neurite retraction is ascribable to neuronal cell death. However, the underlying mechanism of BA-related cell death signaling remains unknown. In this study, we exposed NGF-treated PC12 cells to varying BA concentrations [0 (control), 0.5, 1.0, 5.0 mM] and determined selected stress-related (H2O2, glutathione reductase, calcium (Ca(2+)), plasma membrane Ca(2+) ATPase (PMCA), and GADD153/CHOPS) and cell death-associated (extrinsic: FasL, TNF-α, TWEAK, and TRAIL; intrinsic: cytochrome C (CytC), NF-kB, CASP8, CASP9, CASP10, and CASP3) signals. Similarly, we confirmed cell death execution by chromatin condensation. Our results showed that low (0.5 mM) and high (1.0 and 5.0 mM) BA levels differ in stress and cell death signaling. Moreover, at periodontal disease-level BA concentration (5 mM), we observed that only FasL amounts were affected and occurred concurrently with chromatin condensation insinuating that cells have fully committed to neurodegeneration. Thus, we believe that both stress and cell death signaling in NGF-treated PC12 cells are affected differently depending on BA concentration. In a periodontal disease scenario, we hypothesize that during the early stages, low BA amounts accumulate resulting to both stress- and cell death-related signals that favor neurite non-proliferation, whereas, during the later stages, high BA amounts accumulate resulting to both stress- and cell death-related signals that favor neurodegeneration. More importantly, we propose that neuropathic pain absence at any stage of periodontal disease progression is ascribable to BA accumulation regardless of amount.
authors.affiliation: Department of Microbiology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan.|Department of Comprehensive Dentistry and Clinical Education, Nihon University School of Dentistry, Tokyo, 101-8310, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Seki
authors.affiliation: Department of Microbiology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan. marni.cueno@nihon-u.ac.jp.
authors.forename: Marni E
authors.identifier: 0000-0002-6275-2676
authors.initials: ME
authors.lastname: Cueno
authors.affiliation: Department of Microbiology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Kamio
authors.affiliation: Department of Microbiology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Department of Comprehensive Dentistry and Clinical Education, Nihon University School of Dentistry, Tokyo, 101-8310, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kamimoto
authors.affiliation: Department of Microbiology and Immunology, Nihon University School of Dentistry at Matsudo, Chiba, 271-8587, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kurita-Ochiai
authors.affiliation: Department of Microbiology, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-8310, Japan. ochiai.kuniyasu@nihon-u.ac.jp.
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Ochiai
mesh_terms: D000818:Animals; D017209:Apoptosis; D020148:Butyric Acid / Q000378:metabolism*; D018450:Disease Progression; D020932:Nerve Growth Factor / Q000378:metabolism; D009437:Neuralgia / Q000378:metabolism / Q000473:pathology*; D016501:Neurites / Q000378:metabolism; D018384:Oxidative Stress; D016716:PC12 Cells; D010510:Periodontal Diseases / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D020148:Butyric Acid; D051742:Transcription Factor CHOP; D020932:Nerve Growth Factor
keywords: Butyric acid; Cell death signals; Neurodegeneration; Pheochromocytoma PC12; Stress signals