Abstract
The clinical efficacy of haloperidol in the treatment of psychosis has been limited by its tendency to cause parkinsonian-like motor disturbances such as bradykinesia, muscle rigidity and postural instability. Oxidative stress-evoked neuroinflammation has been implicated as the key neuropathological mechanism by which haloperidol induces loss of dopaminergic neurons and motor dysfunctions. This study was therefore designed to evaluate the effect of Jobelyn® (JB), an antioxidant supplement, on haloperidol-induced motor dysfunctions and underlying molecular mechanisms in male Swiss mice. The animals were distributed into 5 groups (n = 8), and treated orally with distilled water (control), haloperidol (1 mg/kg) alone or in combination with each dose of JB (10, 20 and 40 mg/kg), daily for 14 days. Thereafter, changes in motor functions were evaluated on day 14. Brain biomarkers of oxidative stress, proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6), cAMP response-element binding protein (CREB), mitogen-activated protein kinase (MAPK) and histomorphological changes were also investigated. Haloperidol induces postural instability, catalepsy and impaired locomotor activity, which were ameliorated by JB. Jobelyn® attenuated haloperidol-induced elevated brain levels of MDA, nitrite, proinflammatory cytokines and also boosted neuronal antioxidant profiles (GSH and catalase) of mice. It also restored the deregulated brain activities of CREB and MAPK, and reduced the histomorphological distortions as well as loss of viable neuronal cells in the striatum and prefrontal cortex of haloperidol-treated mice. These findings suggest possible benefits of JB as adjunctive remedy in mitigating parkinsonian-like adverse effects of haloperidol through modulation of CREB/MAPK activities and oxidative/inflammatory pathways.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data Availability
The datasets generated during analyses of the experimental results related to the current study are available from the corresponding author on reasonable request.
Abbreviations
- JB:
-
Jobelyn(R)
- PD:
-
Parkinson’s disease
- TBA:
-
Thiobarbituric acid
- DTNB:
-
[5′, 5′-Dithiobis- (2-nitrobenzoate)
- TCA:
-
Tichloroacetic acid
- HAL:
-
Haloperidol
- GSH:
-
Glutathione
- MDA:
-
Malondialdehyde
- CREB:
-
cAMP response-element binding protein
- MAPK:
-
Mitogen-activated protein kinase
References
Alabi AO, Ajayi AM, Ben-Azu B, Bakre G, Umukoro S (2019) Methyl jasmonate abrogates rotenone-induced parkinsonian-like symptoms through inhibition of oxidative stress, release of pro-inflammatory cytokines, and down-regulation of immnopositive cells of NF-κB and α-synuclein expressions in mice. Neurotoxicol 74:172–183. https://doi.org/10.1016/j.neuro.2019.07.003
Alam A, Schmidt WJ (2002) Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats. Behav Brain Res 136:317–324. https://doi.org/10.1016/s0166-4328(02)00180-8
Andreassen OA, Jorgensen HA (2000) Neurotoxicity associated with neuroleptic-induced oral dyskinesia in rats: implication for tardive dyskinesia. Prog Neurobiol 61:525–541. https://doi.org/10.1016/s0301-0082(99)00064-7
Behl C, Rupprecht R, Skutella T, Holsboer F (1995) Haloperidol-induced cell death-mechanism and protection with vitamin E in vitro. NeuroReport 7:360–364
Ben-Azu B, Aderibigbe AO, Omogbiya IA, Ajayi AM, Owoeye O, Olonode ET, Iwalewa EO (2018a) Probable mechanisms involved in the antipsychotic-like activity of morin in mice. Biomed Pharmacother 105:1079–1090. https://doi.org/10.1016/j.biopha.2018.06.057
Ben-Azu B, Aderibigbe AO, Eneni AO, Ajayi AM, Umukoro S, Iwalewa EO (2018b) Morin attenuates neurochemical changes and increased Oxidative/nitrergic stress in brains of mice exposed to ketamine: Prevention and reversal of Schizophrenia-like symptoms. Neurochemical Res 43:1745–1755. https://doi.org/10.1007/s11064-018-2590-z
Ben-Azu B, Aderibigbe AO, Ajayi AM, Eneni A-EO, Umukoro S, Iwalewa EO (2018c) Involvement of GABAergic, BDNF and Nox-2 mechanisms in the prevention and reversal of ketamine- induced schizophrenia-like behavior by morin in mice. Brain Res Bull 139:292–306
Ben-Azu B, Aderibigbe AO, Omogbiya IA, Ajayi AM, Iwalewa EO (2018d) Morin pretreatment attenuates Schizophrenia-Like Behaviors in Experimental Animal Models. Drug Res (stuttg) 68:159–167
Ben-Azu B, Aderibigbe AO, Ajayi AM, Eneni AO, Omogbiya IA, Owoeye O et al (2019) Morin decreases cortical pyramidal neuron degeneration via inhibition of neuroinflammation in mouse model of schizophrenia. Int Immunopharmacol 70:338–345. https://doi.org/10.1016/j.intimp.2019.02.052
Ben-Azu B, Adebayo OG, Jarikre TA, Oyovwi MO, Edje KE, Omogbiya IA, Eduviere AT, Moke EG, Chijioke BS, Odili OS, Omondiabge OP, Oyovbaire A, Esuku DT, Ozah EO, Japhet K (2022) Taurine, an essential β-amino acid insulates against ketamine-induced experimental psychosis by enhancement of cholinergic neurotransmission, inhibition of oxidative/nitrergic imbalances, and suppression of COX-2/iNOS immunoreactions in mice. Metab Brain Dis 37(8):2807–2826. https://doi.org/10.1007/s11011-022-01075-5
Benson KF, Beaman JL, Ou B, Okubena A, Okubena O, Jensen GS (2013) West african Sorghum bicolor leaf sheaths have anti-inflammatory and immune-modulating properties in vitro. J Med Food 16:230–238. https://doi.org/10.1089/jmf.2012.0214
Bezard E, Przedborski S (2011) A tale on animal models of Parkinson’s disease. Mov Disord 26:993–1002. https://doi.org/10.1002/mds.23696
Cadet JL, Kahler LA (1994) Free radical mechanisms in schizophrenia and tardive dyskinesia. Neurosci Biobehav Rev 18:457–467. https://doi.org/10.1016/0149-7634(94)90001-9
Casey DE (2000) Tardive dyskinesia: pathophysiology and animal models. J Clin Psychiatry 61:5–9
Chen WW, Zhang X, Huang WJ (2016) Role of neuroinflammation in neurodegenerative diseases (review). Mol Med Rep 13:3391–3396. https://doi.org/10.3892/mmr.2016.4948
Costall B, Naylor RJ (1974) On catalepsy and catatonia and the predictability of the cataleptic test for neuroleptics activity. Psychopharmacologia 34:233–241. https://doi.org/10.1007/BF00421964
Dauer W, Przedborski S (2003) Parkinson’s disease: mechanisms and models. Neuron 39:889–909. https://doi.org/10.1016/j.taap.2018.09.012
Emokpae O, Ben-Azu B, Ajayi AM, Umukoro S (2020) D-Ribose-L-cysteine attenuates lipopolysaccharide-induced memory deficits through inhibition of oxidative stress, release of proinflammatory cytokines and nuclear factor-kappa B expression in mice. Naunyn Schmiedebergs Arch Pharmacol 393:909–925. https://doi.org/10.1007/s00210-019-01805-0
Eyles DW, Avent KM, Stedman TJ, Pond M (1997) Two pyridinium metabolites of haloperidol are present in the brain of patients at post-mortem. Life Sci 60:529–534. https://doi.org/10.1016/s0024-3205(96)00656-x
Geera B, Ojwang LO, Awika JM (2012) New highly stable dimeric 3-deoxyanthocyanidin pigments from sorghum bicolor leaf sheath. J Food Sci 77:C566–C572
Goth L (1991) A simple method for determination of serum catalase activity and revision of reference range. Clin Chim Acta 196:143–151. https://doi.org/10.1016/0009-8981(91)90067-m
Green LC, Tannenbaum SR, Goldman P (1981) Nitrate synthesis in the germfree and conventional rat. Science 212:56–58. https://doi.org/10.1126/science.6451927
Halliday GM, Pond SM, Cartwright H, McRitchie DA, Castagnoli N, Van der Shyf CJ (1999) Clinical and neuropathological abnormalities in baboons treated with HPTP, tetrahydropyridine analog of haloperidol. Exp Neurol 158:155–163. https://doi.org/10.1006/exnr.1999.7090
John R, Abolaji AO, Adedara A, Ajayi AM, Aderibigbe AO, Umukoro S (2022) Jobelyn® extends the life span and improves motor function in Drosophila melanogaster exposed to lipopolysaccharide via augmentation of antioxidant status. Metabolic Brain Dis DOI. https://doi.org/10.1007/s11011-022-00919-4
Kelley JJ, Gao XM, Tamminga CA, Roberts RC (1997) The effect of chronic haloperidol treatment on dendritic spines in the rat striatum. Exp Neurol 146:471–478. https://doi.org/10.1006/exnr.1997.6552
Li R, Wang X, Qin T, Qu R, Ma S (2016) Apigenin ameliorates chronic mild stress-induced depressive behavior by inhibiting interleukin-1β production and NLRP3 inflammasome activation in the rat brain. Behav Brain Res 296:318–325. https://doi.org/10.1016/j.bbr.2015.09.031
Lou H, Jing X, Wei X, Shi H, Ren D, Zhang X (2014) Naringenin protects against 6-OHDA-induced neurotoxicity via activation of the Nrf2/ARE signaling pathway. Neuropharmacology 79:380–388. https://doi.org/10.1016/j.neuropharm.2013.11.026
Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ (1951) Protein measurement with Folin phenol reagent. J Biol Chem 193:265–275
Makanjuola SBL, Dosunmu D, Ajonuma L, Ogundaini A, Okubena O (2016) Newly isolated compounds from west african Sorghum bicolor leaf sheaths Jobelyn® show potential in cancer immunosurveillance, 2016. J Cancer Res Therapy 4(4):31–37
Mansour RM, Ahmed MAE, El-Sahar AE, El Sayed NS (2018) Montelukast attenuates rotenone-induced microglial activation/p38 MAPK expression in rats: possible role of its antioxidant, anti-inflammatory and antiapoptotic effects. Toxicol Appl Pharmacol. https://doi.org/10.1016/j.taap.2018.09.012
McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, Cory-Slechta DA, Di Monte DA (2002) Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 10:119–127. https://doi.org/10.1006/nbdi.2002.0507
Misra P, Fridovich I (1972) The role of superoxide anion in the autooxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247:3170–3175
Moron MS, Depierre JW, Mannervik B (1979) Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta 582:67–78. https://doi.org/10.1016/0304-4165(79)90289-7
Noh JS, Kang HJ, Kim EY, Sohn S, Chung YK, Kim SU, Gwag BJ (2000) Haloperidol-induced neuronal apoptosis: role of p38 and c-Jun-NH2-terminal protein kinase. J Neurochem 75:2327–2334. https://doi.org/10.1046/j.1471-4159.2000.0752327.x
Ohkawa HN, Ohishi dK, Yagi (1979) Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358. https://doi.org/10.1016/0003-2697(79)90738-3
Olugbemide AS, Ben-Azu B, Bakre AG, Ajayi AM (2021) Naringenin improves depressive- and anxiety-like behaviors in mice exposed to repeated hypoxic stress through modulation of oxido-inflammatory mediators and NF-kB/BDNF expressions. Brain Res Bull 169:214–227. https://doi.org/10.1016/j.brainresbull.2020.12.003
Omogbiya AI, Umukoro S, Aderibigbe AO, Bakre GA (2013) Jobelyn® pretreatment attenuates symptoms of psychosis in experimental models. Basic & Clinical Physiol & Pharmacol 24:331–336. https://doi.org/10.1515/jbcpp-2012-0073
Omorogbe O, Ajayi AM, Ben-Azu B, Oghwere EE, Adebesin A, Aderibigbe AO, Umukoro S (2018) Jobelyn® attenuates inflammatory responses and neurobehavioural deficits associated with complete Freund-adjuvant-induced arthritis in mice. Biomed Pharmacother 98:585–593. https://doi.org/10.1016/j.biopha.2017.12.098
Osacka J, Kiss A, Bacova Z, Tillinger A (2022) Effect of Haloperidol and Olanzapine on hippocampal cells’ proliferation in animal model of Schizophrenia. Int J Mol Sci 23:7711. https://doi.org/10.3390/ijms23147711
Oyinbo CA, Dare WN, Avwioro OG, Igbigbi PS (2015) Neuroprotective effect of Jobelyn® in the hippocampus of alcoholic rat is mediated in part by alterations in GFAP and NF protein expressions. Adv Biol Res 9(5):305–317
Post A, Holsboer F, Behl C (1998) Induction of NF-κB activity during haloperidol-induced oxidative toxicity in clonal hippocampal cells: suppression of NF-κB and neuroprotection by antioxidants. J Neurosci 15:8236–8246. https://doi.org/10.1523/JNEUROSCI.18-20-08236.1998
Post A, Rucker M, Ohl F, Holsboer F, Almeida OFX, Michaelidis TM (2002) Mechanisms underlying the protective potential of α-tocopherol (vitamin E) against haloperidol-associated neurotoxicity. Neuropsychparmacology 26:397–407. https://doi.org/10.1016/S0893-133X(01)00364-5
Qian L, Flood PM, Hong JS (2010) Neuroinflammation is a key player in Parkinson’s disease and a prime target for therapy. J Neural Transm 117:971–979. https://doi.org/10.1007/s00702-010-0428-1
Saadullah M, Arif S, Hussain L, Asif M, Khurshid U (2022) Dose Dependent Effects of Breynia cernua Against the Paraquat Induced Parkinsonism like Symptoms in Animals’ Model: In Vitro, In Vivo and Mechanistic Studies. Dose-response: a publication of International Hormesis Society, 20(3), 15593258221125478. https://doi.org/10.1177/15593258221125478
Saeed A, Shakir L, Khan MA, Ali A, Yousaf M, Zaidi AA (2017) Haloperidol induced Parkinson’s disease mice model and motor-function modulation with pyridine-3-carboxylic acid. Biomed Res Ther 4:1305–1317. https://doi.org/10.15419/bmrat.v4i05.169
Sagara Y (1998) Induction of reactive oxygen species in neurons by haloperidol. J Neurochem 71:1002–1012. https://doi.org/10.1046/j.1471-4159.1998.71031002.x
Saleem U, Hussain L, Shahid F, Anwar F, Chauhdary Z, Zafar A (2022) Pharmacological Potential of the Standardized Methanolic Extract of Prunus armeniaca L. in the Haloperidol-Induced Parkinsonism Rat Model. Evidence-based complementary and alternative medicine: eCAM, 2022, 3697522. https://doi.org/10.1155/2022/3697522
Saura CA, Cardinaux J-R (2017) Emerging roles of CREB-regulated transcription coactivators in brain physiology and pathology. Trends Neurosci 40:720–733. https://doi.org/10.1016/j.tins.2017.10.002
Schapira AH, Jenner P (2011) Etiology and pathogenesis of Parkinson’s disease. Mov Disord 26:1049–1055. https://doi.org/10.1002/mds.23732
Schapira AH, Olanow CW (2004) Neuroprotection in Parkinson disease: mysteries, myths, and misconceptions. JAMA 291:358–364. https://doi.org/10.1001/jama.291.3.358
Sharma AK, Gupta S, Patel RK, Wardhan N (2017) Haloperidol-induced parkinsonism is attenuated by varenicline in mice. J Basic Clin Physiol Pharmacol. https://doi.org/10.1515/jbcpp-2017-0107
Shivakumar BR, Ravindranath V (1993) Oxidative stress and thiol modification induced by chronic administration of haloperidol. J Pharmacol Exp Ther 3:1137–1141
Sun C, Yun Wang M, Mo C, Song X, Wang S, Chen Y, Liu (2019) Minocycline protects against rotenone-induced neurotoxicity correlating with upregulation of Nurr1 in a Parkinson’s disease rat model. BioMed Res Inter Article ID 6843265, 7 pages, 2019. https://doi.org/10.1155/2019/6843265
Sutachan JJ, Casas Z, Albarracin SL, Stab BR, Samudio J, Gonzalez J, Morales L, Barreto GE (2012) Cellular and molecular mechanisms of antioxidants in Parkinson’s disease. Nutr Neurosci 15:120–126. https://doi.org/10.1179/1476830511Y.0000000033
Sykes DA, Moore H, Stott L, Holliday N, Javitch JA, Lane JR, Chariton SJ (2017) Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors. Nat Commun 8:763. https://doi.org/10.1038/s41467-017-00716-z
Taylor JM, Main BS, Crack PJ (2013) Neuroinflammation and oxidative stress: co-conspirators in the pathology of Parkinson’s disease. Neurochem Int 62:803–819. https://doi.org/10.1016/j.neuint.2012.12.016
Thomas T, Timmer M, Cesnulevicius K, Hitti E, Kotlyarov A, Gaestel M (2018) MAPKAP kinase 2-deficiency prevents neurons from cell death by reducing neuroinflammation–relevance in a mouse model of Parkinson’s disease. J Neurochem 105:2039–2052. https://doi.org/10.1111/j.1471-4159.2008.05310.x
Tong H, Zhang X, Meng X, Lu L, Mai D, Qu S (2018) Simvastatin inhibits activation of NADPH Oxidase/p38 MAPK pathway and enhances expression of antioxidant protein in Parkinson disease models. Front Mol Neurosci. https://doi.org/10.3389/fnmol.2018.00165
Umukoro S, Ugbomah A, Aderibigbe AO, Omogbiya AI (2013) Antioxidant property of Jobelyn as the possible mechanism underlying its anti-amnesic effect in rodents. Basic and Clinical Neurosci 4:42–49
Umukoro S, Ejiroghene EO, Ben-Azu B, Olatunde O, Ajayi MA, Omoregbe O, Okubena O (2018a) Jobelyn ameliorates neurological deficits in rats with ischemic stroke through inhibition of release of pro-inflammatory cytokines and NF-kB pathway. Pathophysiol 26:77–88. 10.1016/j.pathophys.2018a.10.002
Umukoro S, Kalejaye HA, Ben-Azu B, Ajayi AM (2018b) Naringenin attenuates behavioral derangements induced by social defeat stress in mice via inhibition of acetylcholinesterase activity, oxidative stress and release of pro-inflammatory cytokines. Biomed Pharmacother 105:714–723. 10.1016/j.biopha.2018b.06.016
Waku I, Magalhaes MS, Alves CO, de Oliveira RA (2021) Haloperidol-induced catalepsy as an animal model for parkinsonism: a systematic review of experimental studies. Eur J Neurosci 53(11):3743–3767. https://doi.org/10.1111/ejn.15222
Wang H, Zhang Y, Qiao M (2013) Mechanisms of extracellular signal-regulated kinase/cAMP response element-binding protein/brain-derived neurotrophic factor signal transduction pathway in depressive disorder. Neural Regen Res 8:843–852. https://doi.org/10.3969/j.issn.1673-5374.2013.09.009
Yokoyama H, Kasai N, Ueda Y, Niwa R, Konaka R, Mori N, Tsuchihashi N, Matsue T, Ohya-Nishiguchi H, Kamada H (1998) In vivo analysis of hydrogen peroxide and lipid radicals in the striatum of rats under long-term administration of a neuroleptic. Free Radic Biol Med 24:1056–1060. https://doi.org/10.1016/s0891-5849(97)00435-8
Zhang Y, Liu B, Chen X, Zhang N, Li G, Zhang LH, Tan LY (2017) Naringenin ameliorates behavioral dysfunction and neurological deficits in a d-galactose-induced aging mouse model through activation of PI3K/AKT/NRF2 pathway. Rejuvenation Res 20:462–472. https://doi.org/10.1089/rej.2017.1960
Zhuravliova E, Barbakadze T, Natsvlishvili N, Mikeladze DG (2007) Haloperidol induces neurotoxicity by the NMDA receptor downstream signaling pathway, alternative from glutamate excitotoxicity. Neurochemist Int 50:976–982. https://doi.org/10.1016/j.neuint.2006.09.015
Acknowledgements
Authors thank the technical staff of the Department of Pharmacology & Therapeutics, University of Ibadan, Nigeria for their assistance.
Funding
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Author information
Authors and Affiliations
Contributions
SU and JA designed the study; JA and AMA did the experiments; SU and BB did the analysis and wrote the draft of the manuscript. All authors read and approved the final version of the manuscript.
Corresponding author
Ethics declarations
Competing Interests
The authors have no relevant financial or non-financial interests to disclose.
Ethics approval
The ethical principles established by the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8523, revised 2011) were followed.
Consent to participate
Not applicable.
Consent to publish
Not applicable.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Umukoro, S., Ajayi, A.M., Ben-Azu, B. et al. Jobelyn® improves motor dysfunctions induced by haloperidol in mice via neuroprotective mechanisms relating to modulation of cAMP response-element binding protein and mitogen-activated protein kinase. Metab Brain Dis 38, 2269–2280 (2023). https://doi.org/10.1007/s11011-023-01253-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-023-01253-z