*Result*: Plumbagin Ameliorate 5-Fluorouracil-Induced Cognitive Impairment in Adult Zebrafish: In-silico and In-vivo Evidences.
Title:
Plumbagin Ameliorate 5-Fluorouracil-Induced Cognitive Impairment in Adult Zebrafish: In-silico and In-vivo Evidences.
Authors:
Prasad S; Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India.; ICFAI School of Pharmaceutical Sciences, The ICFAI University, Jaipur, Rajasthan, India., Sarkar B; Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India., Chowdhury KR; Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India., Rathee A; ICFAI School of Pharmaceutical Sciences, The ICFAI University, Jaipur, Rajasthan, India., Singh C; Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana, 124001, India., Singh A; Department of Pharmacology, ISF College of Pharmacy, Moga, Punjab, 142001, India. artiniper@gmail.com.; Department of Pharmaceutical Sciences, School of Health Science and Technology, University of Petroleum and Energy Studies - UPES, Dehradun, Uttarakhand, 248007, India. artiniper@gmail.com.
Source:
Molecular neurobiology [Mol Neurobiol] 2026 Jan 26; Vol. 63 (1), pp. 395. Date of Electronic Publication: 2026 Jan 26.
Publication Type:
Journal Article
Language:
English
Journal Info:
Publisher: Humana Press Country of Publication: United States NLM ID: 8900963 Publication Model: Electronic Cited Medium: Internet ISSN: 1559-1182 (Electronic) Linking ISSN: 08937648 NLM ISO Abbreviation: Mol Neurobiol Subsets: MEDLINE
Imprint Name(s):
Original Publication: Clifton, NJ : Humana Press, c1987-
MeSH Terms:
Fluorouracil*/toxicity , Naphthoquinones*/pharmacology , Naphthoquinones*/therapeutic use , Cognitive Dysfunction*/drug therapy , Cognitive Dysfunction*/chemically induced , Cognitive Dysfunction*/metabolism , Computer Simulation*, Animals ; Zebrafish ; Oxidative Stress/drug effects ; Mitochondria/drug effects ; Mitochondria/metabolism ; Molecular Docking Simulation ; Mitochondrial Dynamics/drug effects
References:
Joly F et al (2016) Prospective evaluation of the impact of antiangiogenic treatment on cognitive functions in metastatic renal cancer. Eur Urol Focus 2(6):642–649. (PMID: 2872349910.1016/j.euf.2016.04.009)
Zhang N et al (2008) 5-Fluorouracil: mechanisms of resistance and reversal strategies. Molecules 13(8):1551–1569. (PMID: 18794772624494410.3390/molecules13081551)
Mustafa S et al (2008) 5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Eur J Neurosci 28(2):323–330. (PMID: 1870270310.1111/j.1460-9568.2008.06325.x)
Wigmore PM, Mustafa S, El-Beltagy M, Lyons L, Umka J, Bennett G (2010) Effects of 5-FU. Adv Exp Med Biol. 2010;678:157–164. https://doi.org/10.1007/978-1-4419-6306-2_20.
Gui Y, Famurewa AC, Olatunji OJ (2023) Naringin ameliorates 5-fluorouracil induced cardiotoxicity: an insight into its modulatory impact on oxidative stress, inflammatory and apoptotic parameters. Tissue Cell 81:102035. (PMID: 3675381310.1016/j.tice.2023.102035)
Matsos A, Johnston I (2019) Chemotherapy-induced cognitive impairments: a systematic review of the animal literature. Neurosci Biobehav Rev 102:382–399. (PMID: 3106374010.1016/j.neubiorev.2019.05.001)
Jin P et al (2022) Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management. J Hematol Oncol 15(1):1–42. (PMID: 10.1186/s13045-022-01313-4)
Parment R et al (2022) A Panax quinquefolius-based preparation prevents the impact of 5-FU on activity/exploration behaviors and not on cognitive functions mitigating gut microbiota and inflammation in mice. Cancers 14(18):4403. (PMID: 36139563949671610.3390/cancers14184403)
Padhye S et al (2012) Perspectives on medicinal properties of plumbagin and its analogs. Med Res Rev 32(6):1131–1158. (PMID: 2305976210.1002/med.20235)
Zhang W et al (2015) Plumbagin protects against spinal cord injury-induced oxidative stress and inflammation in Wistar rats through Nrf-2 upregulation. Drug Res 65(09):495–499.
Chen X-J, Zhang J-G, Wu L (2018) Plumbagin inhibits neuronal apoptosis, intimal hyperplasia and also suppresses TNF-α/NF-κB pathway induced inflammation and matrix metalloproteinase-2/9 expression in rat cerebral ischemia. Saudi J Biol Sci 25(6):1033–1039. (PMID: 3017449910.1016/j.sjbs.2017.03.006)
Wilkinson DG et al (2004) Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging 21:453–478. (PMID: 1513271310.2165/00002512-200421070-00004)
Benfante R et al (2021) Acetylcholinesterase inhibitors targeting the cholinergic anti-inflammatory pathway: a new therapeutic perspective in aging-related disorders. Aging Clin Exp Res 33(4):823–834. (PMID: 3158353010.1007/s40520-019-01359-4)
Ongnok B et al (2021) Donepezil protects against doxorubicin-induced chemobrain in rats via attenuation of inflammation and oxidative stress without interfering with doxorubicin efficacy. Neurotherapeutics 18:2107–2125. (PMID: 34312765860896810.1007/s13311-021-01092-9)
John J et al (2021) Animal models of chemotherapy-induced cognitive decline in preclinical drug development. Psychopharmacology 238:3025–3053. (PMID: 34643772860597310.1007/s00213-021-05977-7)
Arora S et al (2023) Piperine loaded metal organic frameworks reverse doxorubicin induced chemobrain in adult zebrafish. J Control Release. https://doi.org/10.1016/j.jconrel.2023.01.077. (PMID: 10.1016/j.jconrel.2023.01.07736739910)
Arora S et al (2023) Piperine loaded metal organic frameworks reverse doxorubicin induced chemobrain in adult zebrafish. J Control Release 355:259–272. (PMID: 3673991010.1016/j.jconrel.2023.01.077)
Verma B, Singh C, Singh A (2021) Effect of hydro-alcoholic extract of Centella asiatica on streptozotocin induced memory dysfunction in adult zebrafish. Curr Res Behav Sciences 2:100059. (PMID: 10.1016/j.crbeha.2021.100059)
Singh S et al (2022) Quercetin ameliorates lipopolysaccharide-induced neuroinflammation and oxidative stress in adult zebrafish. Mol Biol Rep 49(4):3247–3258. (PMID: 3509420910.1007/s11033-022-07161-2)
ELBeltagy M et al (2010) Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil. Behav Brain Res 208(1):112–117. (PMID: 1991429910.1016/j.bbr.2009.11.017)
Jackson S, Ham RJ, Wilkinson D (2004) The safety and tolerability of donepezil in patients with Alzheimer’s disease. Br J Clin Pharmacol 58:1–8. (PMID: 15496217188455610.1111/j.1365-2125.2004.01848.x)
Jangra A et al (2021) Neuroprotective and acetylcholinesterase inhibitory activity of plumbagin in ICV-LPS induced behavioral deficits in rats. Curr Res Behav Sciences 2:100060. (PMID: 10.1016/j.crbeha.2021.100060)
Rowe C et al (2021) The Three-chamber choice behavioral task using Zebrafish as a model system. J Visualized Exp: JoVE (170):e61934.
May Z et al (2016) Object recognition memory in zebrafish. Behav Brain Res 296:199–210. (PMID: 2637624410.1016/j.bbr.2015.09.016)
Singh S, Jamwal S, Kumar P (2017) Neuroprotective potential of Quercetin in combination with piperine against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced neurotoxicity. Neural Regen Res 12(7):1137. (PMID: 28852397555849410.4103/1673-5374.211194)
Kumar V, Singh C, Singh A (2021) Zebrafish an experimental model of Huntington’s disease: molecular aspects, therapeutic targets and current challenges. Mol Biol Rep 48(12):8181–8194. https://doi.org/10.1007/s11033-021-06787-y. (PMID: 10.1007/s11033-021-06787-y34665402)
Wills E (1966) Mechanisms of lipid peroxide formation in animal tissues. Biochem J 99(3):667. (PMID: 5964963126505610.1042/bj0990667)
Ellman GL et al (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7(2):88–95. (PMID: 1372651810.1016/0006-2952(61)90145-9)
de Oliveira Vian C. Efeitos da quercetina em estágios embrio-larvais em zebrafish (DANIO RERIO).
Singh A, Kumar A (2015) Microglial inhibitory mechanism of coenzyme Q10 against Aβ (1-42) induced cognitive dysfunctions: possible behavioral, biochemical, cellular, and histopathological alterations. Front Pharmacol 6:268. (PMID: 26617520463740810.3389/fphar.2015.00268)
Kádár A et al (2009) Improved method for combination of immunocytochemistry and Nissl staining. J Neurosci Methods 184(1):115–118. (PMID: 19615409275383810.1016/j.jneumeth.2009.07.010)
Puri V et al (2022) Inhalation potential of N-Acetylcysteine loaded PLGA nanoparticles for the management of tuberculosis: in vitro lung deposition and efficacy studies. Curr Res Pharmacology and Drug Discovery 3:100084. (PMID: 10.1016/j.crphar.2022.100084)
Groves TR et al (2017) 5-Fluorouracil chemotherapy upregulates cytokines and alters hippocampal dendritic complexity in aged mice. Behav Brain Res 316:215–224. (PMID: 2759961810.1016/j.bbr.2016.08.039)
Abulizi A et al (2021) Ganoderic acid improves 5-fluorouracil-induced cognitive dysfunction in mice. Food Funct 12(24):12325–12337. (PMID: 3482190210.1039/D1FO03055H)
Chaisawang P et al (2017) Asiatic acid protects against cognitive deficits and reductions in cell proliferation and survival in the rat hippocampus caused by 5-fluorouracil chemotherapy. PLoS ONE 12(7):e0180650. (PMID: 28700628550326910.1371/journal.pone.0180650)
Dubois M et al (2014) Chemotherapy-induced long-term alteration of executive functions and hippocampal cell proliferation: role of glucose as adjuvant. Neuropharmacology 79:234–248. (PMID: 2429146510.1016/j.neuropharm.2013.11.012)
Sofis MJ et al (2017) KU32 prevents 5-fluorouracil induced cognitive impairment. Behav Brain Res 329:186–190. (PMID: 28359881584647210.1016/j.bbr.2017.03.042)
Huang X et al (2025) 5-fluorouracil impairs transmission of acetylcholine in the hippocampus and induces cognitive impairments in mice. J Integr Neurosci 24(4):26903. (PMID: 4030226510.31083/JIN26903)
ELBeltagy M et al (2012) The effect of 5-fluorouracil on the long term survival and proliferation of cells in the rat hippocampus. Brain Res Bull 88(5):514–518. (PMID: 2258801410.1016/j.brainresbull.2012.05.005)
Jena A et al (2023) Cellular red-ox system in health and disease: the latest update. Biomed Pharmacother 162:114606. (PMID: 3698971610.1016/j.biopha.2023.114606)
Winocur G, Binns MA, Tannock I (2011) Donepezil reduces cognitive impairment associated with anti-cancer drugs in a mouse model. Neuropharmacology 61(8):1222–1228. (PMID: 2180305510.1016/j.neuropharm.2011.07.013)
Li W, Suwanwela NC, Patumraj S (2016) Curcumin by down-regulating NF-kB and elevating Nrf2, reduces brain edema and neurological dysfunction after cerebral I/R. Microvasc Res 106:117–127. (PMID: 2668624910.1016/j.mvr.2015.12.008)
Iqubal A et al (2019) Molecular mechanism involved in cyclophosphamide-induced cardiotoxicity: old drug with a new vision. Life Sci 218:112–131. (PMID: 3055295210.1016/j.lfs.2018.12.018)
Liu T et al (2017) NF-κb signaling in inflammation. Signal Transduct Target Ther 2(1):1–9.
Kitamura Y et al (2015) Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation. Behav Brain Res 292:184–193. (PMID: 2605736010.1016/j.bbr.2015.06.007)
Sharma S et al (2018) Prophylactic treatment with icariin prevents isoproterenol-induced myocardial oxidative stress via nuclear factor-like 2 activation. Pharmacogn Mag 14. https://doi.org/10.4103/pm.pm.
Fonsêca DV et al (2016) Nerolidol exhibits antinociceptive and anti-inflammatory activity: involvement of the GABA ergic system and proinflammatory cytokines. Fundam Clin Pharmacol 30(1):14–22. (PMID: 2679199710.1111/fcp.12166)
Javed H et al (2016) Neuroprotective effect of nerolidol against neuroinflammation and oxidative stress induced by rotenone. BMC Neurosci 17(1):1–12. (PMID: 10.1186/s12868-016-0293-4)
Cameron NE, Cotter MA (2008) Pro-inflammatory mechanisms in diabetic neuropathy: focus on the nuclear factor kappa B pathway. Curr Drug Targets 9(1):60–67. (PMID: 1822071310.2174/138945008783431718)
Wautier J, Wautier M (2023) Pro- and anti-inflammatory prostaglandins and cytokines in humans: a mini review. Int J Mol Sci. https://doi.org/10.3390/ijms24119647. (PMID: 10.3390/ijms241196473729859710253712)
Almeida S et al (2016) Are polyphenols strong dietary agents against neurotoxicity and neurodegeneration? Neurotox Res 30:345–366. (PMID: 2674596910.1007/s12640-015-9590-4)
Patibandla C et al (2024) Inhibition of glycogen synthase kinase-3 enhances NRF2 protein stability, nuclear localisation and target gene transcription in pancreatic beta cells. Redox Biol. https://doi.org/10.1016/j.redox.2024.103117. (PMID: 10.1016/j.redox.2024.1031173847922310950707)
Sivandzade F et al (2019) NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: molecular mechanisms and possible therapeutic approaches. Redox Biol 21:101059. (PMID: 3057692010.1016/j.redox.2018.11.017)
Torre M, Zanella C, Feany M (2025) The biological intersection between chemotherapy-related cognitive impairment and Alzheimer's disease. Am J Pathol. https://doi.org/10.1016/j.ajpath.2024.12.013.
Suto A et al (1989) MTT assay with reference to the clinical effect of chemotherapy. J Surg Oncol 42(1):28–32. (PMID: 277030710.1002/jso.2930420108)
Rashid M et al (2023) Abstract 2694: blockade of the cyclooxygenase-2 prevents chemotherapy-induced cognitive impairments. Cancer Res. https://doi.org/10.1158/1538-7445.AM2023-2694. (PMID: 10.1158/1538-7445.AM2023-2694)
Li J et al (2010) Inhibition of autophagy augments 5-fluorouracil chemotherapy in human colon cancer in vitro and in vivo model. Eur J Cancer 46(10):1900–1909. (PMID: 2023108610.1016/j.ejca.2010.02.021)
Tambe P et al (2025) Targeted modulation of mitochondrial oxidative stress ameliorates 5-fluorouracil-induced renal injury in BALB/c Mice. Oxidative Medi Cell Longev 2025(1):8892026.
Zhang N et al (2008) 5-Fluorouracil: mechanisms of resistance and reversal strategies. Molecules 13(8):1551–1569. (PMID: 18794772624494410.3390/molecules13081551)
Mustafa S et al (2008) 5-Fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. Eur J Neurosci 28(2):323–330. (PMID: 1870270310.1111/j.1460-9568.2008.06325.x)
Wigmore PM, Mustafa S, El-Beltagy M, Lyons L, Umka J, Bennett G (2010) Effects of 5-FU. Adv Exp Med Biol. 2010;678:157–164. https://doi.org/10.1007/978-1-4419-6306-2_20.
Gui Y, Famurewa AC, Olatunji OJ (2023) Naringin ameliorates 5-fluorouracil induced cardiotoxicity: an insight into its modulatory impact on oxidative stress, inflammatory and apoptotic parameters. Tissue Cell 81:102035. (PMID: 3675381310.1016/j.tice.2023.102035)
Matsos A, Johnston I (2019) Chemotherapy-induced cognitive impairments: a systematic review of the animal literature. Neurosci Biobehav Rev 102:382–399. (PMID: 3106374010.1016/j.neubiorev.2019.05.001)
Jin P et al (2022) Mitochondrial adaptation in cancer drug resistance: prevalence, mechanisms, and management. J Hematol Oncol 15(1):1–42. (PMID: 10.1186/s13045-022-01313-4)
Parment R et al (2022) A Panax quinquefolius-based preparation prevents the impact of 5-FU on activity/exploration behaviors and not on cognitive functions mitigating gut microbiota and inflammation in mice. Cancers 14(18):4403. (PMID: 36139563949671610.3390/cancers14184403)
Padhye S et al (2012) Perspectives on medicinal properties of plumbagin and its analogs. Med Res Rev 32(6):1131–1158. (PMID: 2305976210.1002/med.20235)
Zhang W et al (2015) Plumbagin protects against spinal cord injury-induced oxidative stress and inflammation in Wistar rats through Nrf-2 upregulation. Drug Res 65(09):495–499.
Chen X-J, Zhang J-G, Wu L (2018) Plumbagin inhibits neuronal apoptosis, intimal hyperplasia and also suppresses TNF-α/NF-κB pathway induced inflammation and matrix metalloproteinase-2/9 expression in rat cerebral ischemia. Saudi J Biol Sci 25(6):1033–1039. (PMID: 3017449910.1016/j.sjbs.2017.03.006)
Wilkinson DG et al (2004) Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging 21:453–478. (PMID: 1513271310.2165/00002512-200421070-00004)
Benfante R et al (2021) Acetylcholinesterase inhibitors targeting the cholinergic anti-inflammatory pathway: a new therapeutic perspective in aging-related disorders. Aging Clin Exp Res 33(4):823–834. (PMID: 3158353010.1007/s40520-019-01359-4)
Ongnok B et al (2021) Donepezil protects against doxorubicin-induced chemobrain in rats via attenuation of inflammation and oxidative stress without interfering with doxorubicin efficacy. Neurotherapeutics 18:2107–2125. (PMID: 34312765860896810.1007/s13311-021-01092-9)
John J et al (2021) Animal models of chemotherapy-induced cognitive decline in preclinical drug development. Psychopharmacology 238:3025–3053. (PMID: 34643772860597310.1007/s00213-021-05977-7)
Arora S et al (2023) Piperine loaded metal organic frameworks reverse doxorubicin induced chemobrain in adult zebrafish. J Control Release. https://doi.org/10.1016/j.jconrel.2023.01.077. (PMID: 10.1016/j.jconrel.2023.01.07736739910)
Arora S et al (2023) Piperine loaded metal organic frameworks reverse doxorubicin induced chemobrain in adult zebrafish. J Control Release 355:259–272. (PMID: 3673991010.1016/j.jconrel.2023.01.077)
Verma B, Singh C, Singh A (2021) Effect of hydro-alcoholic extract of Centella asiatica on streptozotocin induced memory dysfunction in adult zebrafish. Curr Res Behav Sciences 2:100059. (PMID: 10.1016/j.crbeha.2021.100059)
Singh S et al (2022) Quercetin ameliorates lipopolysaccharide-induced neuroinflammation and oxidative stress in adult zebrafish. Mol Biol Rep 49(4):3247–3258. (PMID: 3509420910.1007/s11033-022-07161-2)
ELBeltagy M et al (2010) Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil. Behav Brain Res 208(1):112–117. (PMID: 1991429910.1016/j.bbr.2009.11.017)
Jackson S, Ham RJ, Wilkinson D (2004) The safety and tolerability of donepezil in patients with Alzheimer’s disease. Br J Clin Pharmacol 58:1–8. (PMID: 15496217188455610.1111/j.1365-2125.2004.01848.x)
Jangra A et al (2021) Neuroprotective and acetylcholinesterase inhibitory activity of plumbagin in ICV-LPS induced behavioral deficits in rats. Curr Res Behav Sciences 2:100060. (PMID: 10.1016/j.crbeha.2021.100060)
Rowe C et al (2021) The Three-chamber choice behavioral task using Zebrafish as a model system. J Visualized Exp: JoVE (170):e61934.
May Z et al (2016) Object recognition memory in zebrafish. Behav Brain Res 296:199–210. (PMID: 2637624410.1016/j.bbr.2015.09.016)
Singh S, Jamwal S, Kumar P (2017) Neuroprotective potential of Quercetin in combination with piperine against 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced neurotoxicity. Neural Regen Res 12(7):1137. (PMID: 28852397555849410.4103/1673-5374.211194)
Kumar V, Singh C, Singh A (2021) Zebrafish an experimental model of Huntington’s disease: molecular aspects, therapeutic targets and current challenges. Mol Biol Rep 48(12):8181–8194. https://doi.org/10.1007/s11033-021-06787-y. (PMID: 10.1007/s11033-021-06787-y34665402)
Wills E (1966) Mechanisms of lipid peroxide formation in animal tissues. Biochem J 99(3):667. (PMID: 5964963126505610.1042/bj0990667)
Ellman GL et al (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7(2):88–95. (PMID: 1372651810.1016/0006-2952(61)90145-9)
de Oliveira Vian C. Efeitos da quercetina em estágios embrio-larvais em zebrafish (DANIO RERIO).
Singh A, Kumar A (2015) Microglial inhibitory mechanism of coenzyme Q10 against Aβ (1-42) induced cognitive dysfunctions: possible behavioral, biochemical, cellular, and histopathological alterations. Front Pharmacol 6:268. (PMID: 26617520463740810.3389/fphar.2015.00268)
Kádár A et al (2009) Improved method for combination of immunocytochemistry and Nissl staining. J Neurosci Methods 184(1):115–118. (PMID: 19615409275383810.1016/j.jneumeth.2009.07.010)
Puri V et al (2022) Inhalation potential of N-Acetylcysteine loaded PLGA nanoparticles for the management of tuberculosis: in vitro lung deposition and efficacy studies. Curr Res Pharmacology and Drug Discovery 3:100084. (PMID: 10.1016/j.crphar.2022.100084)
Groves TR et al (2017) 5-Fluorouracil chemotherapy upregulates cytokines and alters hippocampal dendritic complexity in aged mice. Behav Brain Res 316:215–224. (PMID: 2759961810.1016/j.bbr.2016.08.039)
Abulizi A et al (2021) Ganoderic acid improves 5-fluorouracil-induced cognitive dysfunction in mice. Food Funct 12(24):12325–12337. (PMID: 3482190210.1039/D1FO03055H)
Chaisawang P et al (2017) Asiatic acid protects against cognitive deficits and reductions in cell proliferation and survival in the rat hippocampus caused by 5-fluorouracil chemotherapy. PLoS ONE 12(7):e0180650. (PMID: 28700628550326910.1371/journal.pone.0180650)
Dubois M et al (2014) Chemotherapy-induced long-term alteration of executive functions and hippocampal cell proliferation: role of glucose as adjuvant. Neuropharmacology 79:234–248. (PMID: 2429146510.1016/j.neuropharm.2013.11.012)
Sofis MJ et al (2017) KU32 prevents 5-fluorouracil induced cognitive impairment. Behav Brain Res 329:186–190. (PMID: 28359881584647210.1016/j.bbr.2017.03.042)
Huang X et al (2025) 5-fluorouracil impairs transmission of acetylcholine in the hippocampus and induces cognitive impairments in mice. J Integr Neurosci 24(4):26903. (PMID: 4030226510.31083/JIN26903)
ELBeltagy M et al (2012) The effect of 5-fluorouracil on the long term survival and proliferation of cells in the rat hippocampus. Brain Res Bull 88(5):514–518. (PMID: 2258801410.1016/j.brainresbull.2012.05.005)
Jena A et al (2023) Cellular red-ox system in health and disease: the latest update. Biomed Pharmacother 162:114606. (PMID: 3698971610.1016/j.biopha.2023.114606)
Winocur G, Binns MA, Tannock I (2011) Donepezil reduces cognitive impairment associated with anti-cancer drugs in a mouse model. Neuropharmacology 61(8):1222–1228. (PMID: 2180305510.1016/j.neuropharm.2011.07.013)
Li W, Suwanwela NC, Patumraj S (2016) Curcumin by down-regulating NF-kB and elevating Nrf2, reduces brain edema and neurological dysfunction after cerebral I/R. Microvasc Res 106:117–127. (PMID: 2668624910.1016/j.mvr.2015.12.008)
Iqubal A et al (2019) Molecular mechanism involved in cyclophosphamide-induced cardiotoxicity: old drug with a new vision. Life Sci 218:112–131. (PMID: 3055295210.1016/j.lfs.2018.12.018)
Liu T et al (2017) NF-κb signaling in inflammation. Signal Transduct Target Ther 2(1):1–9.
Kitamura Y et al (2015) Doxorubicin and cyclophosphamide treatment produces anxiety-like behavior and spatial cognition impairment in rats: possible involvement of hippocampal neurogenesis via brain-derived neurotrophic factor and cyclin D1 regulation. Behav Brain Res 292:184–193. (PMID: 2605736010.1016/j.bbr.2015.06.007)
Sharma S et al (2018) Prophylactic treatment with icariin prevents isoproterenol-induced myocardial oxidative stress via nuclear factor-like 2 activation. Pharmacogn Mag 14. https://doi.org/10.4103/pm.pm.
Fonsêca DV et al (2016) Nerolidol exhibits antinociceptive and anti-inflammatory activity: involvement of the GABA ergic system and proinflammatory cytokines. Fundam Clin Pharmacol 30(1):14–22. (PMID: 2679199710.1111/fcp.12166)
Javed H et al (2016) Neuroprotective effect of nerolidol against neuroinflammation and oxidative stress induced by rotenone. BMC Neurosci 17(1):1–12. (PMID: 10.1186/s12868-016-0293-4)
Cameron NE, Cotter MA (2008) Pro-inflammatory mechanisms in diabetic neuropathy: focus on the nuclear factor kappa B pathway. Curr Drug Targets 9(1):60–67. (PMID: 1822071310.2174/138945008783431718)
Wautier J, Wautier M (2023) Pro- and anti-inflammatory prostaglandins and cytokines in humans: a mini review. Int J Mol Sci. https://doi.org/10.3390/ijms24119647. (PMID: 10.3390/ijms241196473729859710253712)
Almeida S et al (2016) Are polyphenols strong dietary agents against neurotoxicity and neurodegeneration? Neurotox Res 30:345–366. (PMID: 2674596910.1007/s12640-015-9590-4)
Patibandla C et al (2024) Inhibition of glycogen synthase kinase-3 enhances NRF2 protein stability, nuclear localisation and target gene transcription in pancreatic beta cells. Redox Biol. https://doi.org/10.1016/j.redox.2024.103117. (PMID: 10.1016/j.redox.2024.1031173847922310950707)
Sivandzade F et al (2019) NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: molecular mechanisms and possible therapeutic approaches. Redox Biol 21:101059. (PMID: 3057692010.1016/j.redox.2018.11.017)
Torre M, Zanella C, Feany M (2025) The biological intersection between chemotherapy-related cognitive impairment and Alzheimer's disease. Am J Pathol. https://doi.org/10.1016/j.ajpath.2024.12.013.
Suto A et al (1989) MTT assay with reference to the clinical effect of chemotherapy. J Surg Oncol 42(1):28–32. (PMID: 277030710.1002/jso.2930420108)
Rashid M et al (2023) Abstract 2694: blockade of the cyclooxygenase-2 prevents chemotherapy-induced cognitive impairments. Cancer Res. https://doi.org/10.1158/1538-7445.AM2023-2694. (PMID: 10.1158/1538-7445.AM2023-2694)
Li J et al (2010) Inhibition of autophagy augments 5-fluorouracil chemotherapy in human colon cancer in vitro and in vivo model. Eur J Cancer 46(10):1900–1909. (PMID: 2023108610.1016/j.ejca.2010.02.021)
Tambe P et al (2025) Targeted modulation of mitochondrial oxidative stress ameliorates 5-fluorouracil-induced renal injury in BALB/c Mice. Oxidative Medi Cell Longev 2025(1):8892026.
Contributed Indexing:
Keywords: 5-Fluorouracil; Chemotherapy Cognitive impairment; Donepezil; Neuroinflammation; Oxidative stress; Plumbagin; Zebrafish
Substance Nomenclature:
YAS4TBQ4OQ (plumbagin)
U3P01618RT (Fluorouracil)
0 (Naphthoquinones)
U3P01618RT (Fluorouracil)
0 (Naphthoquinones)
Entry Date(s):
Date Created: 20260126 Date Completed: 20260126 Latest Revision: 20260126
Update Code:
20260130
DOI:
10.1007/s12035-026-05668-4
PMID:
41586941
Database:
MEDLINE
*Further Information*
*Background: Chemotherapy is a crucial part of cancer treatment, but it has been linked to a set of cognitive impairments. 5-Fluorouracil, a chemotherapeutic drug causing mitochondrial dysfunction and neurodegeneration. This study primarily aimed to evaluate the effect of Plumbagin on mitochondrial dynamics, neuroinflammation and oxidative stress in adult zebrafish subjected to 5-Fluorouracil-induced cognitive impairment.
Material and Methods: In this study, initially in-silico studies were conducted for lead compound identification. For the in-vivo studies, adult zebrafish (~ 6-8 months old; 470-530 mg; 126 animals are used) were randomly assigned to 7 groups and treated with 5-Fluorouracil (25 mg/kg; i.p.) for 1 day followed by post-treated with Plumbagin (10 and 20 mg/kg; i.p.) and Donepezil (5 mg/kg; i.p.) for 6 days. Behavioral, biochemical, molecular, mitochondrial, and histopathological analyses were performed after completion of the study.
Result: In-silico analyses revealed that Plumbagin exhibits stronger binding affinity as compared to 5-Fluorouracil. In vivo findings further demonstrated that post-treatment with Plumbagin significantly mitigates oxidative stress markers, reduces neuroinflammatory cytokines, and enhances mitochondrial functioning (mitochondrial enzyme complexes, caspases-3, and cellular viability) relative to zebrafish treated with 5-Flurouracil alone. Additionally, Plumbagin treatment led to marked reduction in GSK-3β expression, improvements in mitochondrial structure (as observed through Transmission electron microscopy analysis. Further, post-treatment with Plumbagin significantly improved mitochondrial morphology (as observed through TEM analysis) and neuronal morphology (assessed via Hematoxylin and Eosin staining and Nissl staining) as compared to 5-Fluorouracil -treated zebrafish.
Conclusion: Our findings provide strong evidence that Plumbagin significantly reduced neuroinflammation, provided neuroprotective support, and alleviates cognitive impairment, as demonstrated through in-silico and in-vivo analyses.
(© 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)*
*Declarations. Animal Approval Number: Institutional Biosafety committee (IBSC) with approval number ISFCP/IBSC/M3/2022/33. Clinical Trial Number: Not Applicable. Competing Interest: The authors declare no competing interests.*