{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T22:42:43Z","timestamp":1788043363844,"version":"build-2784847793"},"reference-count":63,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002386","name":"Cairo University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002386","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurochem Res"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Huntington\u2019s disease (HD) pathogenesis involves diverse cellular mechanisms, yet the contributions of pyroptosis and ferroptosis remain elusive. Roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor, has shown neuroprotective effects, but its precise mechanisms are yet to be elucidated. We evaluated the potential neuroprotective and therapeutic effects of roflumilast in 3-nitropropionic acid (3-NP)-induced HD-like neurodegeneration, focusing on pyroptotic and ferroptotic cell death signaling. Adult male Wistar rats were assigned to five groups: normal control (saline\u2009+\u20090.5% carboxymethyl cellulose), roflumilast-control (1\u00a0mg\/kg\/day, p.o. for 21 days), 3-NP (20\u00a0mg\/kg\/day, i.p. for seven days), roflumilast-prophylactic (1\u00a0mg\/kg\/day, p.o. for 21 days prior to 3-NP), and roflumilast-treatment (1\u00a0mg\/kg\/day, p.o. for 21 days post-3-NP). Behavioral outcomes of the open-field, rotarod, and grip strength tests were assessed. Striatal PDE-4, total and p-CREB, BDNF, interleukin-1\u03b2, and markers of pyroptosis (NLRP3, caspase-1, and gasdermin D) and ferroptosis (iron, GPx4, GSH, and malondialdehyde) were measured alongside histopathological alterations and GFAP and Iba-1 immunohistochemical staining. Bioinformatics was used to visualize the target genes\u2019 protein-protein interaction network. Behavioral assessments revealed impaired locomotion, motor coordination, and muscle strength in the 3-NP-injected rats. Biochemical analysis showed increased striatal PDE-4 expression and decreased p-CREB\/BDNF axis alongside NLRP3 inflammasome\/caspase-1\/gasdermin D activation and elevated interleukin-1\u03b2. In parallel, ferroptosis was evidenced by increased striatal iron and malondialdehyde levels, along with reduced GPx4 and GSH. Histopathological examination revealed pronounced striatal neurodegeneration, accompanied by enhanced GFAP and Iba-1 immunostaining, indicating astrogliosis and microglial activation. Roflumilast, administered prophylactically or therapeutically, significantly improved functional and behavioral abnormalities while ameliorating biochemical, histopathological, and immunohistochemical derangements induced by 3-NP. The therapeutic regimen exhibited superior efficacy relative to prophylaxis. Conclusively, roflumilast exerts therapeutic and neuroprotective effects in HD-like neurodegeneration by mitigating pyroptosis and ferroptosis, attenuating astrogliosis, microglial activation, and neuroinflammation, and restoring synaptic plasticity.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphical Abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>A graphical abstract illustrating the proposed mechanistic pathway underlying the neuroprotection of the PDE-4 inhibitor roflumilast through reducing striatal pyroptosis, ferroptosis, microglial and astrocyte activation, and neuroinflammation, while restoring synaptic plasticity in experimental Huntington\u2019s disease-like neurodegeneration induced by 3-NP.<\/jats:p>","DOI":"10.1007\/s11064-026-04682-1","type":"journal-article","created":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T07:58:44Z","timestamp":1772265524000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Roflumilast Elicits Therapeutic and Neuroprotective Effects in 3-Nitropropionic Acid-Induced Huntington\u2019s Disease-Like Neurodegeneration in Rats by Mitigating NLRP3 Inflammasome-Mediated Pyroptosis, Ferroptosis, and Glial Activation"],"prefix":"10.1007","volume":"51","author":[{"given":"Mohamed","family":"Taha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalia","family":"Salah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kareem","family":"Abdou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud A.","family":"Senousy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"issue":"12","key":"4682_CR1","doi-asserted-by":"publisher","first-page":"2327","DOI":"10.1002\/mds.29228","volume":"37","author":"A Medina","year":"2022","unstructured":"Medina A, Mahjoub Y, Shaver L, Pringsheim T (2022) Prevalence and incidence of Huntington\u2019s disease: an updated systematic review and meta-analysis. Mov Disord 37(12):2327\u20132335","journal-title":"Mov Disord"},{"key":"4682_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbr.2025.115475","volume":"483","author":"P Temgire","year":"2025","unstructured":"Temgire P, Arthur R, Upadhayay S, Arora S, Kapatia G, Kumar R et al (2025) Elucidating the neuroprotective potential of arbutin in 3-NPA induced HD-like pathology: insights from in silico, in vitro, and in vivo models. Behav Brain Res 483:115475","journal-title":"Behav Brain Res"},{"issue":"4","key":"4682_CR3","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1007\/s43440-024-00619-z","volume":"76","author":"S Upadhayay","year":"2024","unstructured":"Upadhayay S, Kumar P (2024) Mitochondrial targeted antioxidants as potential therapy for Huntington\u2019s disease. Pharmacol Rep 76(4):693\u2013713","journal-title":"Pharmacol Rep"},{"key":"4682_CR4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2024.176873","volume":"980","author":"K Singh","year":"2024","unstructured":"Singh K, Jain D, Sethi P, Gupta JK, Tripathi AK, Kumar S et al (2024) Emerging pharmacological approaches for Huntington\u2019s disease. Eur J Pharmacol 980:176873","journal-title":"Eur J Pharmacol"},{"issue":"6","key":"4682_CR5","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1007\/s11064-023-03868-1","volume":"48","author":"S Upadhayay","year":"2023","unstructured":"Upadhayay S, Yedke NG, Rahi V, Singh S, Kumar S, Arora A et al (2023) An overview of the pathophysiological mechanisms of 3-nitropropionic acid (3-NPA) as a neurotoxin in a Huntington\u2019s disease model and its relevance to drug discovery and development. Neurochem Res 48(6):1631\u20131647","journal-title":"Neurochem Res"},{"issue":"5\u20136","key":"4682_CR6","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1016\/j.pneurobio.2007.01.003","volume":"81","author":"C Zuccato","year":"2007","unstructured":"Zuccato C, Cattaneo E (2007) Role of brain-derived neurotrophic factor in Huntington\u2019s disease. Prog Neurobiol 81(5\u20136):294\u2013330","journal-title":"Prog Neurobiol"},{"key":"4682_CR7","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1007\/s10495-020-01645-x","volume":"26","author":"S Ahmed","year":"2021","unstructured":"Ahmed S, Kwatra M, Gawali B, Panda SR, Naidu VGM (2021) Potential role of TrkB agonist in neuronal survival by promoting CREB\/BDNF and PI3K\/Akt signaling in vitro and in vivo model of 3-nitropropionic acid (3-NP)-induced neuronal death. Apoptosis 26:52\u201370","journal-title":"Apoptosis"},{"issue":"2","key":"4682_CR8","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.nbd.2009.07.014","volume":"36","author":"Y-S Choi","year":"2009","unstructured":"Choi Y-S, Lee B, Cho H-Y, Reyes IB, Pu X-A, Saido TC et al (2009) CREB is a key regulator of striatal vulnerability in chemical and genetic models of Huntington\u2019s disease. Neurobiol Dis 36(2):259\u201368","journal-title":"Neurobiol Dis"},{"key":"4682_CR9","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2015.00046","volume":"8","author":"S Ortega-Mart\u00ednez","year":"2015","unstructured":"Ortega-Mart\u00ednez S (2015) A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis. Front Mol Neurosci 8:46","journal-title":"Front Mol Neurosci"},{"issue":"12","key":"4682_CR10","doi-asserted-by":"publisher","first-page":"1098","DOI":"10.1097\/WNR.0b013e32832e34ee","volume":"20","author":"A Silvestroni","year":"2009","unstructured":"Silvestroni A, Faull RLM, Strand AD, M\u00f6ller T (2009) Distinct neuroinflammatory profile in post-mortem human Huntington\u2019s disease. Neuroreport 20(12):1098\u20131103","journal-title":"Neuroreport"},{"issue":"16","key":"4682_CR11","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241613021","volume":"24","author":"A Jiang","year":"2023","unstructured":"Jiang A, Handley RR, Lehnert K, Snell RG (2023) From pathogenesis to therapeutics: a review of 150 years of Huntington\u2019s disease research. Int J Mol Sci 24(16):13021","journal-title":"Int J Mol Sci"},{"issue":"1","key":"4682_CR12","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1021\/acschemneuro.2c00656","volume":"14","author":"TK Motawi","year":"2022","unstructured":"Motawi TK, Al-Kady RH, Senousy MA, Abdelraouf SM (2022) Repaglinide elicits a neuroprotective effect in rotenone-induced Parkinson\u2019s disease in rats: emphasis on targeting the DREAM-ER stress BiP\/ATF6\/CHOP trajectory and activation of mitophagy. ACS Chem Neurosci 14(1):180\u2013194","journal-title":"ACS Chem Neurosci"},{"key":"4682_CR13","doi-asserted-by":"publisher","first-page":"1758","DOI":"10.1007\/s11064-015-1658-2","volume":"40","author":"S Singh","year":"2015","unstructured":"Singh S, Jamwal S, Kumar P (2015) Piperine enhances the protective effect of curcumin against 3-NP induced neurotoxicity: possible neurotransmitters modulation mechanism. Neurochem Res 40:1758\u20131766","journal-title":"Neurochem Res"},{"issue":"15","key":"4682_CR14","doi-asserted-by":"publisher","first-page":"8363","DOI":"10.3390\/ijms23158363","volume":"23","author":"E Paldino","year":"2022","unstructured":"Paldino E, Fusco FR (2022) Emerging role of NLRP3 inflammasome\/pyroptosis in Huntington\u2019s disease. Int J Mol Sci 23(15):8363","journal-title":"Int J Mol Sci"},{"key":"4682_CR15","doi-asserted-by":"publisher","first-page":"100207","DOI":"10.1016\/j.dscb.2025.100207","volume":"18","author":"MH Jamal","year":"2025","unstructured":"Jamal MH, Dhupar M, Aran KR (2025) Exploring the role of ferroptosis pathways in Huntington\u2019s disease: insight of pathophysiology to emerging treatment. Brain Disord 18:100207","journal-title":"Brain Disord"},{"issue":"2","key":"4682_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05634-1","volume":"14","author":"J Zhou","year":"2023","unstructured":"Zhou J, Qiu J, Song Y, Liang T, Liu S, Ren C et al (2023) Pyroptosis and degenerative diseases of the elderly. Cell Death Dis 14(2):94","journal-title":"Cell Death Dis"},{"issue":"1","key":"4682_CR17","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/s41420-025-02328-9","volume":"11","author":"G Eskander","year":"2025","unstructured":"Eskander G, Abdelhamid SG, Wahdan SA, Radwan SM (2025) Insights on the crosstalk among different cell death mechanisms. Cell Death Discov 11(1):56","journal-title":"Cell Death Discov"},{"key":"4682_CR18","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2022.922331","volume":"16","author":"X Wu","year":"2022","unstructured":"Wu X, Wan T, Gao X, Fu M, Duan Y, Shen X et al (2022) Microglia pyroptosis: a candidate target for neurological diseases treatment. Front Neurosci 16:922331","journal-title":"Front Neurosci"},{"issue":"22","key":"4682_CR19","doi-asserted-by":"publisher","first-page":"8765","DOI":"10.3390\/ijms21228765","volume":"21","author":"CO Reichert","year":"2020","unstructured":"Reichert CO, de Freitas FA, Sampaio-Silva J, Rokita-Rosa L, Barros PL, Levy D et al (2020) Ferroptosis mechanisms involved in neurodegenerative diseases. Int J Mol Sci 21(22):8765","journal-title":"Int J Mol Sci"},{"issue":"1","key":"4682_CR20","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/s41392-020-00428-9","volume":"6","author":"H-f Yan","year":"2021","unstructured":"Yan H-f, Zou T, Tuo Q-z, Xu S, Li H, Belaidi AA et al (2021) Ferroptosis: mechanisms and links with diseases. Signal Transduct Target Ther 6(1):49","journal-title":"Signal Transduct Target Ther"},{"issue":"7","key":"4682_CR21","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1001\/archneurol.2011.2945","volume":"69","author":"HD Rosas","year":"2012","unstructured":"Rosas HD, Chen YI, Doros G, Salat DH, Chen N-k, Kwong KK et al (2012) Alterations in brain transition metals in huntington disease: an evolving and intricate story. Arch Neurol 69(7):887\u2013893","journal-title":"Arch Neurol"},{"key":"4682_CR22","doi-asserted-by":"publisher","first-page":"147","DOI":"10.2147\/COPD.S7336","volume":"6","author":"SA Antoniu","year":"2011","unstructured":"Antoniu SA (2011) New therapeutic options in the management of COPD\u2013focus on roflumilast. Int J Chron Obstruct Pulmon Dis 6:147\u2013155","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"issue":"6","key":"4682_CR23","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.neuropharm.2010.05.004","volume":"59","author":"V Lakics","year":"2010","unstructured":"Lakics V, Karran EH, Boess FG (2010) Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 59(6):367\u2013374","journal-title":"Neuropharmacology"},{"issue":"1","key":"4682_CR24","doi-asserted-by":"publisher","first-page":"19737","DOI":"10.1038\/s41598-021-98743-w","volume":"11","author":"X-L Dong","year":"2021","unstructured":"Dong X-L, Wang Y-H, Xu J, Zhang N (2021) The protective effect of the PDE-4 inhibitor rolipram on intracerebral haemorrhage is associated with the cAMP\/AMPK\/SIRT1 pathway. Sci Rep 11(1):19737","journal-title":"Sci Rep"},{"key":"4682_CR25","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1007\/s11011-018-0374-4","volume":"34","author":"H Feng","year":"2019","unstructured":"Feng H, Wang C, He W, Wu X, Li S, Zeng Z et al (2019) Roflumilast ameliorates cognitive impairment in APP\/PS1 mice via cAMP\/CREB\/BDNF signaling and anti-neuroinflammatory effects. Metab Brain Dis 34:583\u201391","journal-title":"Metab Brain Dis"},{"key":"4682_CR26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2020.135281","volume":"736","author":"LJS Sugin","year":"2020","unstructured":"Sugin LJS, Murugesan A, Bindu M, Sunil KN (2020) Roflumilast: a potential drug for the treatment of cognitive impairment? Neurosci Lett 736:135281","journal-title":"Neurosci Lett"},{"key":"4682_CR27","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1007\/s10787-020-00787-3","volume":"29","author":"P Saroj","year":"2021","unstructured":"Saroj P, Bansal Y, Singh R, Akhtar A, Sodhi RK, Bishnoi M et al (2021) Neuroprotective effects of roflumilast against quinolinic acid-induced rat model of Huntington\u2019s disease through inhibition of NF-\u03baB mediated neuroinflammatory markers and activation of cAMP\/CREB\/BDNF signaling pathway. Inflammopharmacology 29:499\u2013511","journal-title":"Inflammopharmacology"},{"issue":"8","key":"4682_CR28","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1111\/1440-1681.13493","volume":"48","author":"H Keskin","year":"2021","unstructured":"Keskin H, Keskin F, Tavaci T, Halici H, Yuksel TN, Ozkaraca M et al (2021) Neuroprotective effect of roflumilast under cerebral ischaemia\/reperfusion injury in juvenile rats through NLRP-mediated inflammatory response inhibition. Clin Exp Pharmacol Physiol 48(8):1103\u201310","journal-title":"Clin Exp Pharmacol Physiol"},{"key":"4682_CR29","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2023.110491","volume":"379","author":"MA Desouky","year":"2023","unstructured":"Desouky MA, George MY, Michel HE, Elsherbiny DA (2023) Roflumilast escalates \u03b1-synuclein aggregate degradation in rotenone-induced Parkinson\u2019s disease in rats: modulation of the ubiquitin-proteasome system and endoplasmic reticulum stress. Chem Biol Interact 379:110491","journal-title":"Chem Biol Interact"},{"issue":"6","key":"4682_CR30","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1021\/acschemneuro.1c00523","volume":"13","author":"MA Senousy","year":"2022","unstructured":"Senousy MA, Hanafy ME, Shehata N, Rizk SM (2022) Erythropoietin and Bacillus calmette\u2013gu\u00e9rin vaccination mitigate 3-nitropropionic acid-induced Huntington-like disease in rats by modulating the PI3K\/Akt\/mTOR\/P70S6K pathway and enhancing the autophagy. ACS Chem Neurosci 13(6):721\u2013732","journal-title":"ACS Chem Neurosci"},{"key":"4682_CR31","doi-asserted-by":"publisher","first-page":"119904","DOI":"10.1016\/j.lfs.2021.119904","volume":"284","author":"D Fathi","year":"2021","unstructured":"Fathi D, Abulsoud AI, Saad MA, Nassar NN, Maksimos MM, Rizk SM et al (2021) Agomelatine attenuates alcohol craving and withdrawal symptoms by modulating the Notch1 signaling pathway in rats. Life Sci 284:119904","journal-title":"Life Sci"},{"issue":"4","key":"4682_CR32","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1111\/j.2042-7158.1968.tb09743.x","volume":"20","author":"BJ Jones","year":"1968","unstructured":"Jones BJ, Roberts DJ (1968) The quantitative measurement of motor inco-ordination in naive mice using an accelerating rotarod. J Pharm Pharmacol 20(4):302\u2013304","journal-title":"J Pharm Pharmacol"},{"issue":"1","key":"4682_CR33","first-page":"4032428","volume":"2019","author":"P Liu","year":"2019","unstructured":"Liu P, Li Y, Yang W, Liu D, Ji X, Chi T et al (2019) Prevention of Huntington\u2019s disease-like behavioral deficits in R6\/1 mouse by tolfenamic acid is associated with decreases in mutant Huntingtin and oxidative stress. Oxid Med Cell Longev 2019(1):4032428","journal-title":"Oxid Med Cell Longev"},{"issue":"1","key":"4682_CR34","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/0003-2697(78)90342-1","volume":"86","author":"M Uchiyama","year":"1978","unstructured":"Uchiyama M, Mihara M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86(1):271\u2013278","journal-title":"Anal Biochem"},{"key":"4682_CR35","first-page":"882","volume":"61","author":"E Beutler","year":"1963","unstructured":"Beutler E, Duron O, Kelly M (1963) Glutathione reagent and method-patent. J Lab Clin Med 61:882","journal-title":"J Lab Clin Med"},{"issue":"1\u20132","key":"4682_CR36","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/0003-2697(76)90527-3","volume":"72","author":"MM Bradford","year":"1976","unstructured":"Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72(1\u20132):248\u2013254","journal-title":"Anal Biochem"},{"issue":"9485","key":"4682_CR37","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1016\/S0140-6736(05)67100-0","volume":"366","author":"KF Rabe","year":"2005","unstructured":"Rabe KF, Bateman ED, O\u2019Donnell D, Witte S, Bredenbr\u00f6ker D, Bethke TD (2005) Roflumilast\u2014an oral anti-inflammatory treatment for chronic obstructive pulmonary disease: a randomised controlled trial. Lancet 366(9485):563\u2013571","journal-title":"Lancet"},{"key":"4682_CR38","doi-asserted-by":"publisher","first-page":"615","DOI":"10.1007\/s11307-018-1168-0","volume":"20","author":"A Takano","year":"2018","unstructured":"Takano A, Uz T, Garcia-Segovia J, Tsai M, Lahu G, Amini N et al (2018) A nonhuman primate PET study: measurement of brain PDE4 occupancy by roflumilast using (R)-[11 C] rolipram. Mol Imaging Biol 20:615\u201322","journal-title":"Mol Imaging Biol"},{"issue":"7","key":"4682_CR39","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-023-04804-w","volume":"80","author":"D Paes","year":"2023","unstructured":"Paes D, Schepers M, Willems E, Rombaut B, Tiane A, Solomina Y et al (2023) Ablation of specific long PDE4D isoforms increases neurite elongation and conveys protection against amyloid-\u03b2 pathology. Cell Mol Life Sci 80(7):178","journal-title":"Cell Mol Life Sci"},{"issue":"5","key":"4682_CR40","doi-asserted-by":"publisher","first-page":"1254","DOI":"10.3390\/cells9051254","volume":"9","author":"AJ Tibbo","year":"2020","unstructured":"Tibbo AJ, Baillie GS (2020) Phosphodiesterase 4B: master regulator of brain signaling. Cells 9(5):1254","journal-title":"Cells"},{"issue":"5","key":"4682_CR41","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1080\/17460441.2023.2201493","volume":"18","author":"S Upadhayay","year":"2023","unstructured":"Upadhayay S, Jamwal S, Kumar P (2023) Animal models of Huntington\u2019s disease and their applicability to novel drug discovery and development. Expert Opin Drug Discov 18(5):527\u2013538","journal-title":"Expert Opin Drug Discov"},{"key":"4682_CR42","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.mito.2023.05.007","volume":"71","author":"T Alqahtani","year":"2023","unstructured":"Alqahtani T, Deore SL, Kide AA, Shende BA, Sharma R, Chakole RD et al (2023) Mitochondrial dysfunction and oxidative stress in Alzheimer\u2019s disease, and Parkinson\u2019s disease, Huntington\u2019s disease and amyotrophic lateral sclerosis-an updated review. Mitochondrion 71:83\u201392","journal-title":"Mitochondrion"},{"issue":"12","key":"4682_CR43","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.tins.2008.09.004","volume":"31","author":"E Bossy-Wetzel","year":"2008","unstructured":"Bossy-Wetzel E, Petrilli A, Knott AB (2008) Mutant Huntingtin and mitochondrial dysfunction. Trends Neurosci 31(12):609\u2013616","journal-title":"Trends Neurosci"},{"issue":"1","key":"4682_CR44","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1186\/s10020-025-01172-y","volume":"31","author":"EM Elbaz","year":"2025","unstructured":"Elbaz EM, Sayed RH, Abdelkader AA, Fahim AT (2025) Neuroprotective role of Morin hydrate on 3-nitropropionic acid-elicited Huntington\u2019s disease: in vivo investigation of RIPK1\/RIPK3\/MLKL necroptosis signaling pathway. Mol Med 31(1):135","journal-title":"Mol Med"},{"issue":"11","key":"4682_CR45","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18112312","volume":"18","author":"T Numakawa","year":"2017","unstructured":"Numakawa T, Odaka H, Adachi N (2017) Actions of brain-derived neurotrophic factor and glucocorticoid stress in neurogenesis. Int J Mol Sci 18(11):2312","journal-title":"Int J Mol Sci"},{"key":"4682_CR46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12974-020-01965-4","volume":"17","author":"J Saba","year":"2020","unstructured":"Saba J, L\u00f3pez Couselo F, Turati J, Carniglia L, Durand D, de Laurentiis A et al (2020) Astrocytes from cortex and striatum show differential responses to mitochondrial toxin and BDNF: implications for protection of striatal neurons expressing mutant huntingtin. J Neuroinflammation 17:1\u201315","journal-title":"J Neuroinflammation"},{"issue":"24","key":"4682_CR47","doi-asserted-by":"publisher","first-page":"4405","DOI":"10.1021\/acschemneuro.0c00636","volume":"11","author":"A Bhat","year":"2020","unstructured":"Bhat A, Tan V, Heng B, Lovejoy DB, Sakharkar MK, Essa MM et al (2020) Roflumilast, a cAMP-specific phosphodiesterase-4 inhibitor, reduces oxidative stress and improves synapse functions in human cortical neurons exposed to the excitotoxin quinolinic acid. ACS Chem Neurosci 11(24):4405\u201315","journal-title":"ACS Chem Neurosci"},{"issue":"1","key":"4682_CR48","doi-asserted-by":"publisher","DOI":"10.1038\/s41420-020-00293-z","volume":"6","author":"E Paldino","year":"2020","unstructured":"Paldino E, D\u2019Angelo V, Sancesario G, Fusco FR (2020) Pyroptotic cell death in the R6\/2 mouse model of Huntington\u2019s disease: new insight on the inflammasome. Cell Death Discov 6(1):69","journal-title":"Cell Death Discov"},{"key":"4682_CR49","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuint.2021.105221","volume":"152","author":"M Cai","year":"2022","unstructured":"Cai M, Zhuang W, Lv E, Liu Z, Wang Y, Zhang W et al (2022) Kaemperfol alleviates pyroptosis and microglia-mediated neuroinflammation in Parkinson\u2019s disease via inhibiting p38MAPK\/NF-\u03baB signaling pathway. Neurochem Int 152:105221","journal-title":"Neurochem Int"},{"issue":"11","key":"4682_CR50","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1093\/ijnp\/pyaa060","volume":"23","author":"W Rui","year":"2020","unstructured":"Rui W, Li S, Xiao H, Xiao M, Shi J (2020) Baicalein attenuates neuroinflammation by inhibiting NLRP3\/caspase-1\/GSDMD pathway in MPTP-induced mice model of Parkinson\u2019s disease. Int J Neuropsychopharmacol 23(11):762\u2013773","journal-title":"Int J Neuropsychopharmacol"},{"key":"4682_CR51","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2025.123378","volume":"362","author":"G Eskander","year":"2025","unstructured":"Eskander G, Abdelhamid SG, Wahdan SA, Radwan SM (2025) Roflumilast attenuates doxorubicin and cyclophosphamide combination-induced chemobrain in rats through modulation of NLRP3\/ASC\/caspase-1\/GSDMD axis. Life Sci 362:123378","journal-title":"Life Sci"},{"key":"4682_CR52","doi-asserted-by":"publisher","first-page":"1245","DOI":"10.1007\/s10753-017-0567-8","volume":"40","author":"Q Wu","year":"2017","unstructured":"Wu Q, Qi L, Li H, Mao L, Yang M, Xie R et al (2017) Roflumilast reduces cerebral inflammation in a rat model of experimental subarachnoid hemorrhage. Inflammation 40:1245\u201353","journal-title":"Inflammation"},{"key":"4682_CR53","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.fct.2018.08.028","volume":"121","author":"J Cui","year":"2018","unstructured":"Cui J, Wang G, Kandhare AD, Mukherjee-Kandhare AA, Bodhankar SL (2018) Neuroprotective effect of naringin, a flavone glycoside in quinolinic acid-induced neurotoxicity: possible role of PPAR-\u03b3, Bax\/Bcl-2, and caspase-3. Food Chem Toxicol 121:95\u2013108","journal-title":"Food Chem Toxicol"},{"key":"4682_CR54","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.freeradbiomed.2018.04.002","volume":"120","author":"S Agrawal","year":"2018","unstructured":"Agrawal S, Fox J, Thyagarajan B, Fox JH (2018) Brain mitochondrial iron accumulates in Huntington\u2019s disease, mediates mitochondrial dysfunction, and can be removed pharmacologically. Free Radic Biol Med 120:317\u2013329","journal-title":"Free Radic Biol Med"},{"issue":"10","key":"4682_CR55","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0077023","volume":"8","author":"J Chen","year":"2013","unstructured":"Chen J, Marks E, Lai B, Zhang Z, Duce JA, Lam LQ et al (2013) Iron accumulates in Huntington\u2019s disease neurons: protection by deferoxamine. PLoS One 8(10):e77023","journal-title":"PLoS One"},{"issue":"1","key":"4682_CR56","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.neuro.2008.10.007","volume":"30","author":"J Duran-Vilaregut","year":"2009","unstructured":"Duran-Vilaregut J, del Valle J, Camins A, Pall\u00e0s M, Pelegr\u00ed C, Vilaplana J (2009) Blood-brain barrier disruption in the striatum of rats treated with 3-nitropropionic acid. Neurotoxicology 30(1):136\u201343","journal-title":"Neurotoxicology"},{"issue":"12","key":"4682_CR57","doi-asserted-by":"publisher","first-page":"1462","DOI":"10.3390\/antiox13121462","volume":"13","author":"S Kim","year":"2024","unstructured":"Kim S, Jung UJ, Kim SR (2024) Role of oxidative stress in blood\u2013brain barrier disruption and neurodegenerative diseases. Antioxidants 13(12):1462","journal-title":"Antioxidants"},{"issue":"8","key":"4682_CR58","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1111\/j.1742-4658.2012.08485.x","volume":"279","author":"GJ Guillemin","year":"2012","unstructured":"Guillemin GJ (2012) Quinolinic acid, the inescapable neurotoxin. FEBS J 279(8):1356\u20131365","journal-title":"FEBS J"},{"issue":"1","key":"4682_CR59","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-024-00917-5","volume":"30","author":"ME Noureldeen","year":"2024","unstructured":"Noureldeen ME, Shahin NN, Amin HAA, El-Sawalhi MM, Ghaiad HR (2024) Parthenolide ameliorates 3-nitropropionic acid-induced Huntington\u2019s disease-like aberrations via modulating NLRP3 inflammasome, reducing microglial activation and inducing astrocyte shifting. Mol Med 30(1):158","journal-title":"Mol Med"},{"issue":"7","key":"4682_CR60","doi-asserted-by":"publisher","first-page":"8103","DOI":"10.1007\/s12035-025-04762-3","volume":"62","author":"S Jahan","year":"2025","unstructured":"Jahan S, Ikram M, Siraj S, Ullah S, Zakria M, Ahmad N (2025) Emodin, a potent anthraquinone mitigates MPTP-induced parkinsons\u2019 disease pathology by regulating Nrf2 and its downstream targets: in silico and in vivo approach. Mol Neurobiol 62(7):8103\u20138120","journal-title":"Mol Neurobiol"},{"key":"4682_CR61","doi-asserted-by":"crossref","unstructured":"Mahnoor, Jahan S, Elahi L, Zakria M, Rabia, Ikram M, Ullah N (2025) Alpha-linolenic acid for mitigating neuroinflammation and dopaminergic neuronal loss in Parkinson\u2019s disease: insights from in vivo and in silico studies. Clin Exp Pharmacol Physiol 52(6):e70043","DOI":"10.1111\/1440-1681.70043"},{"issue":"3","key":"4682_CR62","doi-asserted-by":"publisher","first-page":"e24786","DOI":"10.1016\/j.heliyon.2024.e24786","volume":"10","author":"S Mohan","year":"2024","unstructured":"Mohan S, Alhazmi HA, Hassani R, Khuwaja G, Maheshkumar VP, Aldahish A, Chidambaram K (2024) Role of ferroptosis pathways in neuroinflammation and neurological disorders: from pathogenesis to treatment. Heliyon 10(3):e24786","journal-title":"Heliyon"},{"issue":"6","key":"4682_CR63","doi-asserted-by":"publisher","first-page":"471","DOI":"10.1016\/j.chom.2010.11.007","volume":"8","author":"P Broz","year":"2010","unstructured":"Broz P, von Moltke J, Jones JW, Vance RE, Monack DM (2010) Differential requirement for caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing. Cell Host Microbe 8(6):471\u2013483","journal-title":"Cell Host Microbe"}],"container-title":["Neurochemical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11064-026-04682-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s11064-026-04682-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s11064-026-04682-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T19:05:06Z","timestamp":1781636706000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s11064-026-04682-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,28]]},"references-count":63,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["4682"],"URL":"https:\/\/doi.org\/10.1007\/s11064-026-04682-1","relation":{},"ISSN":["0364-3190","1573-6903"],"issn-type":[{"value":"0364-3190","type":"print"},{"value":"1573-6903","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,28]]},"assertion":[{"value":"9 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 December 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 January 2026","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 February 2026","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"This study acquired an approval number: BC3524 from the institutional review board, the Ethics Committee for Experimental and Clinical Studies, Faculty of Pharmacy, Cairo University, Cairo, Egypt, which approved all experimental protocols and animal procedures.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval and Consent to Participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent of Publication"}}],"article-number":"92"}}