{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T09:19:25Z","timestamp":1775121565900,"version":"3.50.1"},"reference-count":25,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T00:00:00Z","timestamp":1774569600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health Sciences University, Kayseri City Hospital","award":["17\/063"],"award-info":[{"award-number":["17\/063"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sciences"],"abstract":"<jats:p>Background: Contrast-induced encephalopathy (CIE) is an uncommon yet clinically significant complication associated with iodinated contrast media, with its mechanisms remaining unclear. Objective: The aims of this study are to examine the neurotoxic effects of contrast media and assess the neuroprotective roles of N-Acetylcysteine (NAC) and sildenafil with regard to HIF-1\u03b1 expression. Methods: Thirty-six female Wistar albino rats (n = 36) were allocated into four experimental groups (n = 9 each): control, contrast media + saline (CMA + Saline), contrast media + NAC (CMA + NAC), and contrast media + sildenafil (CMA + Sildenafil). NAC (150 mg\/kg) and sildenafil (50 mg\/kg\/day) were administered intragastrically for 48 h before exposure to contrast media. Biochemical, histopathological, and immunohistochemical evaluations were conducted 48 h post-contrast administration. Results: Exposure to contrast media resulted in neuronal death, vascular obstruction, and increased hypoxia-inducible factor-1 alpha (HIF-1\u03b1) immunoreactivity. The primary outcome measure, tissue HIF-1\u03b1 concentration by ELISA, did not differ significantly among groups (p = 0.119). Semi-quantitative immunohistochemical analysis revealed significant group differences in HIF-1\u03b1 immunoreactivity (p &lt; 0.001), with all injury\/treatment groups differing significantly from control. The difference between the contrast media group and the sildenafil-treated group approached but did not reach statistical significance after correction for multiple comparisons (Dunn\u2019s test, p = 0.050). Conclusions: The primary biochemical endpoint did not demonstrate significant group differences. Secondary IHC analysis suggests a potential attenuation of HIF-1\u03b1 immunoreactivity by sildenafil, though this did not reach statistical significance and requires confirmation in adequately powered studies. HIF-1\u03b1 immunoreactivity warrants further investigation as a potential biomarker for contrast-induced neural injury.<\/jats:p>","DOI":"10.3390\/brainsci16040362","type":"journal-article","created":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T14:33:33Z","timestamp":1774622013000},"page":"362","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigation of Contrast-Induced Neurotoxicity and the Effects of Sildenafil and N-Acetylcysteine on HIF-1\u03b1 Levels in Wistar Rats"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9043-7369","authenticated-orcid":false,"given":"Ismail","family":"Altintop","sequence":"first","affiliation":[{"name":"Department of Emergency Medicine, Kayseri City Medical Faculty, Health Science University, Kayseri 38090, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5907-9161","authenticated-orcid":false,"given":"Mehmet","family":"Tatli","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Van Training and Research Hospital, Health Science University, Van 65100, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8134-5139","authenticated-orcid":false,"given":"Zeynep Soyer","family":"Sarica","sequence":"additional","affiliation":[{"name":"Central Research Laboratory Application and Research Center, Gebze Technical University, Kocaeli 41400, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arzu Han\u0131m","family":"Yay","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, School of Medicine, Erciyes University, Kayseri 38280, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9858-3272","authenticated-orcid":false,"given":"\u00c7i\u011fdem","family":"Karakukcu","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Erciyes University, Kayseri 38280, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1007\/s00059-013-3871-6","article-title":"Contrast-induced neurotoxicity after coronary angiography","volume":"39","author":"Kocabay","year":"2014","journal-title":"Herz"},{"key":"ref_2","first-page":"317","article-title":"Contrast-induced encephalopathy in patients with advanced chronic kidney disease","volume":"44","author":"Romani","year":"2024","journal-title":"Nefrol. (Engl. Ed.)"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"331","DOI":"10.2217\/fca-2016-0075","article-title":"Case report and literature review on contrast-induced encephalopathy","volume":"13","author":"Hamra","year":"2017","journal-title":"Future Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"00368504251377944","DOI":"10.1177\/00368504251377944","article-title":"Contrast-induced encephalopathy following endovascular treatment of intracranial aneurysms","volume":"108","author":"Balasubramanian","year":"2025","journal-title":"Sci. Prog."},{"key":"ref_5","first-page":"197","article-title":"Contrast-Induced Encephalopathy following Coronary Angiography with No Radiological Features","volume":"2018","author":"Dattani","year":"2018","journal-title":"Case Rep. Neurol. Med."},{"key":"ref_6","first-page":"184","article-title":"A Case of Unusual Presentation of Contrast-induced Encephalopathy after Cerebral Angiography Using Iodixanol","volume":"60","author":"Park","year":"2017","journal-title":"J. Korean Neurosurg. Soc."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/cns.12162","article-title":"Neuroprotection by sildenafil: Neuronal networks potentiation in acute experimental stroke","volume":"20","author":"Chen","year":"2014","journal-title":"CNS Neurosci. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"850","DOI":"10.1161\/STROKEAHA.113.003606","article-title":"Sildenafil mediates blood-flow redistribution and neuroprotection after neonatal hypoxia-ischemia","volume":"45","author":"Nguyen","year":"2014","journal-title":"Stroke"},{"key":"ref_9","first-page":"1660","article-title":"Phosphodiesterase-5 inhibition potentiates cerebrovascular reactivity in traumatic brain injury","volume":"32","author":"Kenney","year":"2018","journal-title":"Brain Inj."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1165\/rcmb.2012-0043OC","article-title":"Sildenafil alleviates bronchopulmonary dysplasia in neonatal rats by activating the hypoxia-inducible factor signaling pathway","volume":"48","author":"Park","year":"2013","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"940207","DOI":"10.1155\/2015\/940207","article-title":"Phosphodiesterase-5 inhibitors: Action on the signaling pathways of neuroinflammation, neurodegeneration, and cognition","volume":"2015","author":"Peixoto","year":"2015","journal-title":"Mediat. Inflamm."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.brainresbull.2012.08.010","article-title":"Sildenafil provides sustained neuroprotection in the absence of learning recovery following the 4-vessel occlusion model in middle-aged rats","volume":"90","author":"Ferreira","year":"2013","journal-title":"Brain Res. Bull."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Zinni, M., Pansiot, J., L\u00e9ger, P.L., El Kamouh, M., and Baud, O. (2021). Sildenafil-Mediated Neuroprotection from Adult to Neonatal Brain Injury: Evidence, Mechanisms, and Future Translation. Cells, 10.","DOI":"10.3390\/cells10102766"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Da Silva, R., De Moura, M., De Paula, L., Arantes, K.C., da Silva, M., de Amorim, J., Miguel, M.P., Martins, D.B., Silva, D.d.M.e., and Melo, M.M. (2023). Effects of coenzyme Q10 and N-Acetylcysteine on experimental poisoning by paracetamol in Wistar rats. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0290268"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1705","DOI":"10.1016\/j.biopha.2018.07.125","article-title":"A comparison of the effects of thymoquinone, silymarin and N-Acetylcysteine in an experimental hepatotoxicity","volume":"106","author":"Demiroren","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Lei, X., Teng, W., Fan, Y., Zhu, Y., Yao, L., Li, Y., and Zhu, S. (2022). The protective effects of HIF-1\u03b1 activation on sepsis induced intestinal mucosal barrier injury in rats model of sepsis. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0268445"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1007\/s12272-020-01237-y","article-title":"Empagliflozin alleviates neuronal apoptosis induced by cerebral ischemia\/reperfusion injury through HIF-1\u03b1\/VEGF signaling pathway","volume":"43","author":"Amin","year":"2020","journal-title":"Arch. Pharm. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/sj.ki.5002567","article-title":"Adaptation to hypoxia in the diabetic rat kidney","volume":"73","author":"Rosenberger","year":"2008","journal-title":"Kidney Int."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1704","DOI":"10.4049\/jimmunol.1801166","article-title":"Glycine Exhibits Neuroprotective Effects in Ischemic Stroke in rats through the Inhibition of M1 Microglial Polarization via the NF-\u03baB p65\/HIF-1\u03b1 Signaling Pathway","volume":"202","author":"Liu","year":"2019","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Chen, Y., Fu, Y., and Wu, M. (2019). Does Resveratrol Play a Role in Decreasing the Inflammation Associated with Contrast Induced Nephropathy in Rat Model?. J. Clin. Med., 8.","DOI":"10.3390\/jcm8020147"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/0720-048X(94)00599-8","article-title":"Neurotoxicity of non-ionic X-ray contrast media after intracisternal administration in rats","volume":"19","author":"Wible","year":"1995","journal-title":"Eur. J. Radiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1148\/radiology.206.1.9423675","article-title":"Are iodinated contrast agents detrimental in acute cerebral ischemia? An experimental study in rats","volume":"206","author":"Doerfler","year":"1998","journal-title":"Radiology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/j.cell.2012.01.021","article-title":"Hypoxia-Inducible Factors in Physiology and Medicine","volume":"148","author":"Semenza","year":"2012","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.molcel.2008.04.009","article-title":"Oxygen Sensing by Metazoans: The Central Role of the HIF Hydroxylase Pathway","volume":"30","author":"Kaelin","year":"2008","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s000180300001","article-title":"Molecular Mechanisms of N-Acetylcysteine Actions","volume":"60","author":"Zafarullah","year":"2003","journal-title":"Cell. Mol. Life Sci."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/4\/362\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T08:15:14Z","timestamp":1775117714000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/4\/362"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,27]]},"references-count":25,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["brainsci16040362"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16040362","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,27]]}}}