{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:00:38Z","timestamp":1787029238447,"version":"build-2736575974"},"reference-count":35,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,4,9]],"date-time":"2022-04-09T00:00:00Z","timestamp":1649462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UO1 NS063555"],"award-info":[{"award-number":["UO1 NS063555"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HHSN271200623691C"],"award-info":[{"award-number":["HHSN271200623691C"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["G12-RR03035"],"award-info":[{"award-number":["G12-RR03035"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1U54NS083924-01"],"award-info":[{"award-number":["1U54NS083924-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["SC2NS119144"],"award-info":[{"award-number":["SC2NS119144"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P20GM103642"],"award-info":[{"award-number":["P20GM103642"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutraceuticals"],"abstract":"<jats:p>The tobacco cembranoid (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol (4R) interacts with nicotinic acetylcholine receptors, which results in neuroprotection against organophosphate toxicity, brain ischemia, and Parkinson\u2019s disease. The present study is a continuation of our previous research in which we applied a single dose of 4R 1 h before or 24 h after exposure to diisopropylfluorophosphate (DFP) (analog of the nerve agent sarin). The 4R dose robustly decreased neuroinflammation and neuronal death at both timepoints. Here, we investigated the toxicity of a single dose of 4R in male and female Sprague Dawley (SD) rats after a subcutaneous (s.c.) injection of 6, 24, or 98 mg\/kg. Body weight was not affected by 4R during the 7-day observation period. No histopathologic changes in the organs were attributed to 4R. Minor hematological and blood composition variations were detected on Day 3 in the mid- and the high-dose males, but these were resolved by Day 8. At the area of the s.c. injection site, alopecia and dry skin were detected in both the 4R-treated males and females and in the female controls.<\/jats:p>","DOI":"10.3390\/nutraceuticals2020005","type":"journal-article","created":{"date-parts":[[2022,4,10]],"date-time":"2022-04-10T06:02:54Z","timestamp":1649570574000},"page":"60-70","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["In Vivo Evaluation of the Acute Systemic Toxicity of (1S,2E,4R,6R,7E,11E)-Cembratriene-4,6-diol (4R) in Sprague Dawley Rats"],"prefix":"10.3390","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7714-4884","authenticated-orcid":false,"given":"Nadezhda","family":"Sabeva","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Medical of School, Universidad Central del Caribe, Bayam\u00f3n, PR 00956, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"On\u00e9 R.","family":"Pag\u00e1n","sequence":"additional","affiliation":[{"name":"Department of Biology, West Chester University, 750 S Church St., West Chester, PA 19383, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yancy","family":"Ferrer-Acosta","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Medical of School, Universidad Central del Caribe, Bayam\u00f3n, PR 00956, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vesna A.","family":"Eterovi\u0107","sequence":"additional","affiliation":[{"name":"Neuroprotection for Life, Carmel, IN 46032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter A.","family":"Ferchmin","sequence":"additional","affiliation":[{"name":"Neuroprotection for Life, Carmel, IN 46032, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1111\/j.1749-6632.1960.tb26438.x","article-title":"Chemistry of coelenterates. II. Occurrence of taurobetaine and creatine in gorgonians","volume":"90","author":"Ciereszko","year":"1960","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4571","DOI":"10.1016\/0040-4020(95)00216-U","article-title":"The natural products chemistry of West Indian gorgonian octocorals","volume":"51","author":"Rodriguez","year":"1995","journal-title":"Tetrahedron"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1016\/j.toxicon.2009.02.033","article-title":"Actions of octocoral and tobacco cembranoids on nicotinic receptors","volume":"54","author":"Ferchmin","year":"2009","journal-title":"Toxicon"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"367","DOI":"10.3891\/acta.chem.scand.46-0367","article-title":"Tobacco chemistry. 73. 4,6,8-trihydroxy-11-capnosene-2,10-dione, a new cembrane-derived bicyclic diterpenoid from tobacco","volume":"46","author":"Eklund","year":"1992","journal-title":"Acta Chem. Scand."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Yan, N., Du, Y., Liu, X., Zhang, H., Liu, Y., and Zhang, Z. (2019). A Review on Bioactivities of Tobacco Cembranoid Diterpenes. Biomolecules, 9.","DOI":"10.3390\/biom9010030"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"167","DOI":"10.3109\/01480545.2010.494669","article-title":"Antimicrobial, antioxidant, and antimutagenic activities of selected marine natural products and tobacco cembranoids","volume":"34","author":"Aqil","year":"2011","journal-title":"Drug Chem. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1517\/13543784.16.6.877","article-title":"Biocatalytic and semisynthetic studies of the anticancer tobacco cembranoids","volume":"16","author":"Sylvester","year":"2007","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"5748","DOI":"10.1016\/j.bmc.2016.09.032","article-title":"(1S,2E,4S,7E,11E)-2,7,11-Cembratriene-4,6-diol semisynthetic analogs as novel c-Met inhibitors for the control of c-Met-dependent breast malignancies","volume":"24","author":"Ebrahim","year":"2016","journal-title":"Bioorganic Med. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3911","DOI":"10.1016\/j.bmc.2017.05.028","article-title":"The tobacco cembranoid (1S,2E,4S,7E,11E)-2,7,11-cembratriene-4,6-diol as a novel angiogenesis inhibitory lead for the control of breast malignancies","volume":"25","author":"Hailat","year":"2017","journal-title":"Bioorganic Med. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2886","DOI":"10.1016\/j.bmc.2007.12.056","article-title":"Biocatalytic and semisynthetic optimization of the anti-invasive tobacco (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol","volume":"16","author":"Laphookhieo","year":"2008","journal-title":"Bioorganic Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.neuro.2012.03.011","article-title":"Organophosphate-induced brain damage: Mechanisms, neuropsychiatric and neurological consequences, and potential therapeutic strategies","volume":"33","author":"Chen","year":"2012","journal-title":"Neurotoxicology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1002\/jnr.1049","article-title":"Tobacco cembranoids block behavioral sensitization to nicotine and inhibit neuronal acetylcholine receptor function","volume":"64","author":"Ferchmin","year":"2001","journal-title":"J. Neurosci. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/jnr.20666","article-title":"Tobacco cembranoids protect the function of acute hippocampal slices against NMDA by a mechanism mediated by alpha4beta2 nicotinic receptors","volume":"82","author":"Ferchmin","year":"2005","journal-title":"J. Neurosci. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4678","DOI":"10.1016\/j.bmc.2013.05.018","article-title":"Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: Preliminary structure-activity relationship and pharmacophore modeling","volume":"21","author":"Eterovic","year":"2013","journal-title":"Bioorganic Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1002\/jnr.23155","article-title":"gamma-Aminobutyric acid type A receptor inhibition triggers a nicotinic neuroprotective mechanism","volume":"91","author":"Ferchmin","year":"2013","journal-title":"J. Neurosci. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"272","DOI":"10.3389\/fnins.2017.00272","article-title":"4R-Cembranoid Improves Outcomes after 6-Hydroxydopamine Challenge in Both In vitro and In vivo Models of Parkinson\u2019s Disease","volume":"11","author":"Hu","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.neuroscience.2015.02.001","article-title":"Neuroprotective activity of (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) in vitro and in vivo in rodent models of brain ischemia","volume":"291","author":"Martins","year":"2015","journal-title":"Neuroscience"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1016\/j.tiv.2011.04.021","article-title":"A cembranoid protects acute hippocampal slices against paraoxon neurotoxicity","volume":"25","author":"Eterovic","year":"2011","journal-title":"Toxicol. Vitr. Int. J. Publ. Assoc. BIBRA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.neuro.2014.06.001","article-title":"4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration","volume":"44","author":"Ferchmin","year":"2014","journal-title":"Neurotoxicology"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Velez-Carrasco, W., Green, C.E., Catz, P., Furimsky, A., O\u2019Loughlin, K., Eterovic, V.A., and Ferchmin, P.A. (2015). Pharmacokinetics and Metabolism of 4R-Cembranoid. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0121540"},{"key":"ref_21","unstructured":"(2022, February 09). Single Dose Acute Toxicity Testing for Pharmaceuticals, Guidance for Industry. In e Federal Register on August 26, 1996 (61 FR 43934), Available online: https:\/\/www.fda.gov\/regulatory-information\/search-fda-guidance-documents\/single-dose-acute-toxicity-testing-pharmaceuticals."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1007\/s40259-018-0295-0","article-title":"Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities","volume":"32","author":"Bittner","year":"2018","journal-title":"BioDrugs"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Dancygier, H., and Schirmacher, P. (2010). Liver Cell Degeneration and Cell Death. Clinical Hepatology, Springer.","DOI":"10.1007\/978-3-540-93842-2_23"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1097\/01.NPR.0000743328.87750.d7","article-title":"Organophosphate poisoning","volume":"46","author":"Richardson","year":"2021","journal-title":"Nurse Pr."},{"key":"ref_25","first-page":"989","article-title":"Anticholinesterase intoxication in man and its treatment","volume":"Volume XV","author":"Heffter","year":"1963","journal-title":"Handbuch der Experimentellen Pharmakologie"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1539\/joh.47.299","article-title":"Effects of sarin on the nervous system of subway workers seven years after the Tokyo subway sarin attack","volume":"47","author":"Miyaki","year":"2005","journal-title":"J. Occup. Health"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1097\/00043764-199801000-00006","article-title":"A preliminary study on delayed vestibulo-cerebellar effects of Tokyo Subway Sarin Poisoning in relation to gender difference: Frequency analysis of postural sway","volume":"40","author":"Yokoyama","year":"1998","journal-title":"J. Occup. Env. Med."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.bbi.2012.11.007","article-title":"Altered immune pathway activity under exercise challenge in Gulf War Illness: An exploratory analysis","volume":"28","author":"Broderick","year":"2013","journal-title":"Brain Behav. Immun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.bbi.2010.10.011","article-title":"A pilot study of immune network remodeling under challenge in Gulf War Illness","volume":"25","author":"Broderick","year":"2011","journal-title":"Brain Behav. Immun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"47","DOI":"10.2174\/138161211795049804","article-title":"Mean platelet volume: A link between thrombosis and inflammation?","volume":"17","author":"Gasparyan","year":"2011","journal-title":"Curr. Pharm. Des."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1161\/ATVBAHA.110.221788","article-title":"Mean platelet volume may represent a predictive parameter for overall vascular mortality and ischemic heart disease","volume":"31","author":"Slavka","year":"2011","journal-title":"Arter. Thromb Vasc. Biol."},{"key":"ref_32","unstructured":"Walker, H.K., Hall, W.D., and Hurst, J.W. (1990). BUN and Creatinine. Clinical Methods: The History, Physical, and Laboratory Examinations, Butterworths."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1007\/s00296-011-2096-3","article-title":"Injection-site reactions upon Kineret (anakinra) administration: Experiences and explanations","volume":"32","author":"Kaiser","year":"2012","journal-title":"Rheumatol. Int."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6288","DOI":"10.1002\/anie.200902672","article-title":"Poly(ethylene glycol) in drug delivery: Pros and cons as well as potential alternatives","volume":"49","author":"Knop","year":"2010","journal-title":"Angew. Chem. Int. Ed. Engl."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/jps.3030410112","article-title":"A study of the polyethylene glycols as vehicles for intramuscular and subcutaneous Injection","volume":"41","author":"Carpenter","year":"1952","journal-title":"J. Am. Pharm. Assoc. Am. Pharm. Assoc."}],"container-title":["Nutraceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1661-3821\/2\/2\/5\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:51:04Z","timestamp":1760136664000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1661-3821\/2\/2\/5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,9]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["nutraceuticals2020005"],"URL":"https:\/\/doi.org\/10.3390\/nutraceuticals2020005","relation":{},"ISSN":["1661-3821"],"issn-type":[{"value":"1661-3821","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,9]]}}}