Preventive effects of geraniol in schizophrenia-like symptoms in mice models of psychosis

Christian I. Uruaka; Udeme O. Georgewill; Owunari A.  Georgewill

doi:10.18203/2320-6012.ijrms20230306

Authors

Christian I. Uruaka Department of Pharmacology, Faculty of Basic Medical Sciences, Rivers State University, Port Harcourt, Rivers State, Nigeria
Udeme Owunari Georgewill Department of Pharmacology, Faculty of Basic Medical Sciences, Rivers State University, Port Harcourt, Rivers State, Nigeria
Owunari A. Georgewill Department of Pharmacology, Faculty of Basic Medical Sciences, Rivers State University, Port Harcourt, Rivers State, Nigeria

DOI:

https://doi.org/10.18203/2320-6012.ijrms20230306

Keywords:

Brain derived-neurotrophic factor, Geraniol, Ketamine, Neurotransmitters, Psychosis

Abstract

Background: The pathogenesis of schizophrenia has been linked to N-methyl-D-aspartate receptor (NMDAr) inhibition and DAr hyperfunction. Geraniol is a naturally occurring acyclic monoterpene with diverse pharmacological applications. We aimed to assess the effect of geraniol on schizophrenia-like symptoms, vis a vis its modulatory actions on neurochemicals in mice models of psychosis.

Methods: In acute studies, male Swiss mice (n=5/group) were intraperitoneally treated with geraniol (25, 50 and 100 mg/kg), risperidone (0.5 mg/kg) or vehicle (10 ml/kg) prior to ketamine (KET) (10 mg/kg)-induced stereotypy and hyperlocomotion. In the chronic studies, mice (n=7/group) were exposed to 14 days interventions (geraniol or risperidone) following a preventive treatment with KET (20 mg/kg) from days 7-14 consecutively. The effects of treatments (e.g., geraniol or risperidone) alone and on KET-induced schizophrenia-like symptoms were investigated on the last day, 24 hours after treatments. Following that, neurochemical and neurotrophic alterations in the brain (striatum, prefrontal cortex, and hippocampus) tissues were investigated.

Results: Intoxication with KET was associated with schizophrenia-like symptoms as evidenced by stereotypy behavior and hyperlocomotion. KET further induced hyperlocomotion, behavioral despair, and cognitive impairment in the chronic studies. It altered the levels of dopamine, 5-hydroxytrypamine, glutamic acid decarboxylase (GAD), acetylcholinesterase (AChE), and brain-derived neurotrophic factor (BDNF) in brain tissues. However, GER (50 and 100 mg/kg) administration significantly prevented the brain's insults caused by KET.

Conclusions: Altogether, the findings support geraniol's neuroprotective activity while also adding to the body of knowledge that geraniol inhibits schizophrenia-like symptoms via modulation of neurochemical and neurotrophic pathways.

Metrics

Metrics Loading ...

References

Ben-Azu B, Aderibigbe AO, Ajayi AM, Iwalewa EO. Neuroprotective effects of the ethanol stem bark extracts of Terminalia ivorensis in ketamine-induced schizophrenia-like behaviors and oxidative damage in mice. Pharm Biol. 2016;54(12):2871-9.

Howes OD, McCutcheon R, Owen MJ, Murray RM. The Role of Genes, Stress, and Dopamine in the Development of Schizophrenia. Biol Psychiatry. 2017;81(1):9-20.

Li R, Ma X, Wang G, Yang J, Wang C. Why sex differences in schizophrenia? J Transl Neurosci. 2016;1(1):37.

en-Azu B, Aderibigbe AO, Eneni AO, Ajayi AM, Umukoro S, Iwalewa EO. Morin Attenuates Neurochemical Changes and Increased Oxidative/Nitrergic Stress in Brains of Mice Exposed to Ketamine: Prevention and Reversal of Schizophrenia-Like Symptoms. Neurochem Res. 2018;43(9):1745-55.

Stilo SA, Murray RM. Non-genetic factors in schizophrenia. Curr Psychiatry Rep. 2019;21(10):1-10.

Ben-Azu B, Aderibigbe AO, Omogbiya IA, Ajayi AM, Iwalewa EO. Morin Pretreatment Attenuates Schizophrenia-Like Behaviors in Experimental Animal Models. Drug Res (Stuttg). 2018;68(3):159-67.

Ben-Azu B, Aderibigbe AO, Omogbiya IA, Ajayi AM, Owoeye O, Olonode ET, Iwalewa EO. Probable mechanisms involved in the antipsychotic-like activity of morin in mice. Biomed Pharmacother. 2018;105:1079-90.

Curley AA, Arion D, Volk DW, Asafu-Adjei JK, Sampson AR, Fish KN, Lewis DA. Cortical deficits of glutamic acid decarboxylase 67 expression in schizophrenia: clinical, protein, and cell type-specific features. Am J Psychiatry. 2011;168(9):921-9.

Ben-Azu B, Aderibigbe AO, Ajayi AM, Eneni AO, Umukoro S, Iwalewa EO. 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. 2018;139:292-306.

Babukumar S, Vinothkumar V, Sankaranarayanan C, Srinivasan S. Geraniol, a natural monoterpene, ameliorates hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats. Pharm Biol. 2017;55(1):1442-9.

Lei Y, Fu P, Jun X, Cheng P. Pharmacological properties of geraniol–a review. Planta Medica. 2019;85(01):48-55.

Bubeníková-Valesová V, Horácek J, Vrajová M, Höschl C. Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev. 2008;32(5):1014-23.

Kaypetch R, Rudrakanjana P, Churnjitapirom P, Tua-Ngam P, Tonput P, Tantivitayakul P. Geraniol and thymoquinone inhibit Candida spp. biofilm formation on acrylic denture resin without affecting surface roughness or color. J Oral Sci. 2022;64(2):161-6.

Duncan RE, Lau D, El-Sohemy A, Archer MC. Geraniol and β-ionone inhibit proliferation, cell cycle progression, and cyclin-dependent kinase 2 activity in MCF-7 breast cancer cells independent of effects on HMG-CoA reductase activity. Biochem Pharmacol. 2004;68(9):1739-47.

de Carvalho KI, Bonamin F, Dos Santos RC, Périco LL, Beserra FP, de Sousa DP, Filho JM, da Rocha LR, Hiruma-Lima CA. Geraniol-a flavoring agent with multifunctional effects in protecting the gastric and duodenal mucosa. Naunyn Schmiedebergs Arch Pharmacol. 2014;387(4):355-65.

Prasad SN, Muralidhara M. Analysis of the antioxidant activity of geraniol employing various in-vitro models: Relevance to neurodegeneration in diabetic neuropathy. Asian J Pharm Clin Res. 2017;10(7):101-5.

Murbach Teles Andrade BF, Conti BJ, Santiago KB, Fernandes Júnior A, Sforcin JM. Cymbopogon martinii essential oil and geraniol at noncytotoxic concentrations exerted immunomodulatory/anti-inflammatory effects in human monocytes. J Pharm Pharmacol. 2014;66(10):1491-6.

Farokhcheh M, Hejazian L, Akbarnejad Z, Pourabdolhossein F, Hosseini SM, Mehraei TM, Soltanpour N. Geraniol improved memory impairment and neurotoxicity induced by zinc oxide nanoparticles in male wistar rats through its antioxidant effect. Life Sci. 2021;282:119823.

Rekha KR, Inmozhi Sivakamasundari R. Geraniol protects against the protein and oxidative stress induced by rotenone in an in vitro model of Parkinson’s disease. Neurochem Res. 2018;43(10):1947-62.

Rekha KR, Selvakumar GP, Sethupathy S, Santha K, Sivakamasundari RI. Geraniol ameliorates the motor behavior and neurotrophic factors inadequacy in MPTP-induced mice model of Parkinson's disease. J Mol Neurosci. 2013;51(3):851-62.

Jiang K, Zhang T, Yin N, Ma X, Zhao G, Wu H, Qiu C, Deng G. Geraniol alleviates LPS-induced acute lung injury in mice via inhibiting inflammation and apoptosis. Oncotarget. 2017;8(41):71038-53.

Prasad SN. Protective effects of geraniol (a monoterpene) in a diabetic neuropathy rat model: attenuation of behavioral impairments and biochemical perturbations. J Neurosci Res. 2014;92(9):1205-16.

Lins RF, Cristina L, Santos MA, Melo De S, Sarau´ jo A, Nunes DS, et al. The anticonvulsant effect of geraniol and inclusion complex geraniol: b -cyclodextrin. Boletı ´n Latinoam y Del Caribe Plantas Med y Aromaticas. 2014;13:557-e65.

Medeiros KAAL, Dos Santos JR, Melo TCS, de Souza MF, Santos LG, de Gois AM, Cintra RR, Lins LCRF, Ribeiro AM, Marchioro M. Depressant effect of geraniol on the central nervous system of rats: Behavior and ECoG power spectra. Biomed J. 2018;41(5):298-305.

da Silva Araújo T, Maia Chaves Filho AJ, Monte AS, Isabelle de Góis Queiroz A, Cordeiro RC, de Jesus Souza Machado M, de Freitas Lima R, Freitas de Lucena D, Maes M, Macêdo D. Reversal of schizophrenia-like symptoms and immune alterations in mice by immunomodulatory drugs. J Psychiatr Res. 2017;84:49-58.

Chindo BA, Adzu B, Yahaya TA, Gamaniel KS. Ketamine-enhanced immobility in forced swim test: a possible animal model for the negative symptoms of schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38(2):310-6.

Zhu F, Zheng Y, Ding YQ, Liu Y, Zhang X, Wu R, Guo X, Zhao J. Minocycline and risperidone prevent microglia activation and rescue behavioral deficits induced by neonatal intrahippocampal injection of lipopolysaccharide in rats. PLoS One. 2014;9(4):e93966.

Ellman GL, Courtney KD, Andres V, Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961;7:88-95.

Eduviere AT, Umukoro S, Adeoluwa OA, Omogbiya IA, Aluko OM. Possible Mechanisms Involved in Attenuation of Lipopolysaccharide-Induced Memory Deficits by Methyl Jasmonate in Mice. Neurochem Res. 2016;41(12):3239-49.

Haaf M, Leicht G, Curic S, Mulert C. Glutamatergic Deficits in Schizophrenia - Biomarkers and Pharmacological Interventions within the Ketamine Model. Curr Pharm Biotechnol. 2018;19(4):293-307.

Omeiza NA, Bakre A, Ben-Azu B, Sowunmi AA, Abdulrahim HA, Chimezie J, et al. Mechanisms underpinning Carpolobia lutea G. Don ethanol extract's neurorestorative and antipsychotic-like activities in an NMDA receptor antagonist model of schizophrenia. J Ethnopharmacol. 2023;301:115767.

Ben-Azu B, Adebayo OG, Jarikre TA, Oyovwi MO, Edje KE, Omogbiya IA, et al. 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. 2022;37(8):2807-26.

Kokkinou M, Irvine EE, Bonsall DR, Natesan S, Wells LA, Smith M, et al. Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine. Mol Psychiatry. 2021;26(6):2562-76.

George MY, Menze ET, Esmat A, Tadros MG, El-Demerdash E. Potential therapeutic antipsychotic effects of Naringin against ketamine-induced deficits in rats: Involvement of Akt/GSK-3β and Wnt/β-catenin signaling pathways. Life Sci. 2020;249:117535.

Silver H, Chertkow Y, Weinreb O, Danovich L, Youdim M. Multifunctional pharmacotherapy: what can we learn from study of selective serotonin reuptake inhibitor augmentation of antipsychotics in negative-symptom schizophrenia? Neurotherapeutics. 2009;6(1):86-93.

Siddique YH, Naz F, Jyoti S, Ali F, Fatima A, Rahul, Khanam S. Protective effect of Geraniol on the transgenic Drosophila model of Parkinson's disease. Environ Toxicol Pharmacol. 2016;43:225-31.

Lv Y, Zhang L, Li N, Mai N, Zhang Y, Pan S. Geraniol promotes functional recovery and attenuates neuropathic pain in rats with spinal cord injury. Can J Physiol Pharmacol. 2017;95(12):1389-95.

Suárez-Santiago JE, Orozco-Suárez S, Vega-García A, Bautista-Orozco LÁ, Picazo O. Repeated ketamine administration induces recognition memory impairment together with morphological changes in neurons from ventromedial prefrontal cortex, dorsal striatum, and hippocampus. Behav Pharmacol. 2020;31(7):633-40.

Zuccato C, Cattaneo E. Brain-derived neurotrophic factor in neurodegenerative diseases. Nat Rev Neurol. 2009;5(6):311-22.

Lu B, Nagappan G, Lu Y. BDNF and synaptic plasticity, cognitive function, and dysfunction. Handb Exp Pharmacol. 2014;220:223-50.