PROTECTIVE EFFECT OF CILOSTAZOL AGAINST KETAMINE-INDUCED BIOCHEMICAL AND BEHAVIORAL PHENOTYPE OF SCHIZOPHRENIA IN MICE

RUCHIKA SRIVASTAVA; PRABHAT SINGH; AJEET

doi:10.22159/ajpcr.2025v18i4.53622

Authors

RUCHIKA SRIVASTAVA Department of Pharmacology, Faculty of Pharmacy, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India https://orcid.org/0000-0002-1767-1308
PRABHAT SINGH Department of Pharmacology, Faculty of Pharmacy, Swami Vivekanand Subharti University, Meerut, Uttar Pradesh, India
AJEET Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sankar College of Pharmacy and Research, Ghaziabad, Uttar Pradesh, India.

DOI:

https://doi.org/10.22159/ajpcr.2025v18i4.53622

Keywords:

Social withdrawal, Phosphodiesterase, Oxidative stress, Cognition, Immobility time, Catalepsy, Lipid peroxidation

Abstract

Objective: Schizophrenia (SCZ), a mental illness affecting 1% of the world population, is characterized by extensive structural and functional brain changes. It is brought on by a confluence of psychological, environmental, and hereditary variables. It is frequently coexisted with other diseases, lowering the quality of life and increasing the risk of early death. The objective of this research is to explored the potential of cilostazol (Phosphodiesterase-3 inhibitor) in ketamine (KET)-induced SCZ -like behavioral and biochemical alterations in mice.

Methods: In mice, SCZ was induced by injecting KET (30 mg/kg; i.p.) for 10 days in a row. Different behavioral parameters such as immobility time (Forced swim test), locomotor and anxiety (open field test), cognitive dysfunction (Morris water maze), social interactions, and catalepsy were examined. Histopathological and biochemical changes (lipid peroxides, glutathione [GSH], acetylcholinesterase [AChE] activity) were also examined. Cilostazol (25 and 50 mg/kg; p.o.) as a test and clozapine (7.5 mg/kg p.o.), as a standard drug were used in this investigation. Tukey’s multiple comparison test and one-way analysis of variance were used for statistical analysis of all the findings. p<0.050 was regarded as statistically significant.

Results: Significant (p<0.05) behavioral changes have been observed following 28 days of KET treatment (increased immobility time, impaired locomotor and anxiety-like behaviors, cognitive dysfunction, social interactions, and catalepsy). Increased oxidative stress (higher lipid peroxides and decreased GSH), AChE activity, and histopathological changes were also noted significantly in KET -treated mice. Cilostazol and clozapine treatment significantly (p<0.05) corrected the histological changes, biochemical alterations, and behavioral problems.

Conclusion: As per the behavioral, histopathological, and biochemical outcomes, we can draw a conclusion that cilostazol may provide neurodefensive effects against KET -induced SCZ in mice.

Downloads

Download data is not yet available.

References

Arzoo MP. Anti-psychotic activity of Pyrus communis juice. Int J Pharm Pharm Sci. 2017;9(4):113-20.

Hsiao CY, Tsai YF. Factors of caregiver burden and family functioning among Taiwanese family caregivers living with schizophrenia. J Clin Nurs. 2015;24:1546-56.

Correll CU, Solmi M, Croatto G, Schneider LK, Rohani-Montez SC, Fairley L, et al. Mortality in people with schizophrenia: A systematic review and meta-analysis of relative risk and aggravating or attenuating factors. World Psychiatry. 2022 Jun;21(2):248-71.

Lu C, Jin D, Palmer N, Fox K, Kohane IS, Smoller JW, et al. Large-scale real-world data analysis identifies comorbidity patterns in schizophrenia. Transl Psychiatry. 2022 Apr 11;12(1):154.

Yao JK, Dougherty GG Jr., Reddy RD, Keshavan MS, Montrose DM, Matson WR, et al. Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia. Mol psychiatry. 2010 Sep;15(9):938-53.

Crismon L, Argo TR, Buckley PF. Pharmacotherapy: A Pathophysiologic Approach. New York: McGraw-Hill; 2014.

Shrivastava A, Aggarwal R, Singh RP, Khabiya R. A mini review on properties, mechanism of action, pharmacokinetic and pharmacodynamics and analytical methods of cariprazine. Int J App Pharm. 2023;15(1):31-5.

Andreasen NC, Nopoulos P, Schultz S, Miller D, Gupta S, Swayze V, et al. Positive and negative symptoms of schizophrenia: Past, present, and future. Acta Psychiatr Scand Suppl. 1994 Nov;384:51-9.

Bagney A, Rodriguez-Jimenez R, Martinez-Gras I, Sanchez- Morla EM, Santos JL, Jimenez-Arriero MA, et al. Negative symptoms and executive function in schizophrenia: Does their relationship change with illness duration? Psychopathology. 2013 Nov 9;46(4):241-8.

Thaker GK. Defining the schizophrenia phenotype. Curr Psychiatry Rep. 2000;2:398-403.

Stevenson C. Ketamine: A review. Update Anaesth. 2005;20(20):25-9.

Krystal JH, Karper LP, Seibyl JP, Freeman GK, Delaney R, Bremner JD, et al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994 Mar 1;51(3):199-214.

Hebb AL, Robertson HA. Role of phosphodiesterases in neurological and psychiatric disease. Curr Opin Pharmacol. 2007 Feb 1;7(1):86-92.

Kumar A, Kumar A, Jaggi AS, Singh N. Efficacy of cilostazol a selective phosphodiesterase-3 inhibitor in rat model of streptozotocin diabetes induced vascular dementia. Pharmacol Biochem Behav. 2015 Aug 1;135:20-30.

Abuelezz SA, Hendawy N. Insights into the potential antidepressant mechanisms of cilostazol in chronically restraint rats: Impact on the Nrf2 pathway. Behav Pharmacol. 2018;29(1):28-40.

Zhang X, Wang LP, Ziober A, Zhang PJ, Bagg A. Ionized calcium binding adaptor molecule 1 (IBA1) a novel, highly sensitive, and specific marker for histiocytic, dendritic, and monocytic neoplasms. Am J Clin Pathol. 2021 Jul 1;156(1):86-99.

Itoh T, Tokumura M, Abe K. Effects of rolipram, a phosphodiesterase 4 inhibitor, in combination with imipramine on depressive behavior, CRE-binding activity and BDNF level in learned helplessness rats. Eur J Pharmacol. 2004;498:135-42.

Campbell E, Edwards T. Zaprinast consolidates long-term memory when administered to neonate chicks trained using a weakly reinforced single trial passive avoidance task. Behav Brain Res. 2006 Apr 25;169(1):181-5.

Patel DS, Anand IS, Bhatt PA. Evaluation of antidepressant and anxiolytic activity of phosphodiesterase 3 inhibitor-cilostazol. Indian J Psychol Med. 2012 Apr;34(2):124-8.

Shougrakpam P, Bhattacharjee A, Medhabati M, Gunindro N. Comparative study of antidepressant-like effect of the leaves of Sapindus Emarginatus and Acorus Calamus in experimental animal models. Int J Curr Pharm Res. 2021 Jan 15;13:28-31.

Seibenhener ML, Wooten MC. Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp. 2015 Feb 6;96:e52434.

Singh P, Sharma B. Agonism of histaminergic-H1 receptors in ischemic postconditioning during cerebral ischemia-reperfusion injury is protective. Curr Neurovasc Res. 2020 Dec 1;17(5):686-99.

Dubey N, Agrawal OP, Gidwani B. Optimization, characterization and in vivo study of rivastigmine tartrate nanoparticles by using 22 full factorial design for oral delivery. Int J App Pharm. 2023;15(3):80-9.

Kaidanovich-Beilin O, Lipina T, Vukobradovic I, Roder J, Woodgett JR. Assessment of social interaction behaviors. J Vis Exp. 2011 Feb 25;48:2473.

Luciani KR, Frie JA, Khokhar JY. An open source automated bar test for measuring catalepsy in rats. eNeuro. 2020 May 1;7(3):0488.

Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351-8. doi: 10.1016/0003-2697(79)90738-3, PMID: 36810

Beutler RG. Reduced glutathion estimation. J Lab Clin Med. 1963;61:82.

Ellman GL, Courtney KD, Andres V Jr., Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961;7(2):88-95.

Gupta VK, Kumar A, Siddiqi NJ, Sharma B. Rat brain acetyl cholinesterase as a biomarker of cadmium induced neurotoxicity. J Toxicol. 2016 Jan 8;1(1):1-7.

Ben-Azu B, Adebayo OG, Fokoua AR, Oritsemuelebi B, Chidebe EO, Nwogueze CB, et al. Antipsychotic effect of diosgenin in ketamine-induced murine model of schizophrenia: Involvement of oxidative stress and cholinergic transmission. IBRO Neurosci Rep. 2024 Jun 1;16:86-97.

Monte AS, De Souza GC, McIntyre RS, Soczynska JK, Dos Santos JV, Cordeiro RC, et al. Prevention and reversal of ketamine-induced schizophrenia related behavior by minocycline in mice: Possible involvement of antioxidant and nitrergic pathways. J Psychopharmacol. 2013 Nov;27(11):1032-43.

You W, Zuo G, Shen H, Tian X, Li H, Zhu H, et al. Potential dual role of nuclear factor-kappa B in experimental subarachnoid hemorrhage-induced early brain injury in rabbits. Inflamm Res. 2016;65(12):975-84.

Khalid I, Saleem U, Ahmad B, Hawwal MF, Mothana RA. NMDA receptor modulation by Esculetin: Investigating behavioral, biochemical and neurochemical effects in schizophrenic mice model. Saudi Pharm J. 2024 Apr 1;32(4):101994.

Adell A. Brain NMDA receptors in schizophrenia and depression. Biomolecules. 2020 Jun 23;10(6):947.

Hope S, Hoseth E, Dieset I, Mørch RH, Aas M, Aukrust P, et al. Inflammatory markers are associated with general cognitive abilities in schizophrenia and bipolar disorder patients and healthy controls. Schizophr Res. 2015 Jul 1;165(2-3):188-94.

Moghaddam AH, Estalkhi FM, Jelodar SK, Hasan TA, Farhadi- Pahnedari S, Karimian M. Neuroprotective effects of alpha-pinene against behavioral deficits in ketamine-induced mice model of schizophrenia: Focusing on oxidative stress status. IBRO Neurosci Rep. 2024 Jun 1;16:182-9.

Abdel-Salam OM, El-Shamarka M, Omara EA. Brain oxidative stress and neurodegeneration in the ketamine model of schizophrenia during antipsychotic treatment: Effects of N-acetylcysteine treatment. React Oxygen Species. 2018 Jul 1;6(16):253-66.

Vasconcelos GS, Ximenes NC, De Sousa CN, De Queiroz Oliveira T, Lima LL, De Lucena DF, et al. Alpha-lipoic acid alone and combined with clozapine reverses schizophrenia-like symptoms induced by ketamine in mice: Participation of antioxidant, nitrergic and neurotrophic mechanisms. Schizophr Res. 2015 Jul 1;165(2-3):163-70.

McCutcheon RA, Abi-Dargham A, Howes OD. Schizophrenia, dopamine and the striatum: From biology to symptoms. Trends Neurosci. 2019 Mar 1;42(3):205-20.

Sobota R, Mihara T, Forrest A, Featherstone RE, Siegel SJ. Oxytocin reduces amygdala activity, increases social interactions, and reduces anxiety-like behavior irrespective of NMDAR antagonism. Behav Neurosci. 2015 Aug;129(4):389-98.

De Araújo FY, Chaves Filho AJ, Nunes AM, De Oliveira GV, Gomes PX, Vasconcelos GS, et al. Involvement of anti-inflammatory, antioxidant, and BDNF up-regulating properties in the antipsychotic-like effect of the essential oil of Alpinia Zerumbet in mice: A comparative study with olanzapine. Metab Brain Dis. 2021 Dec;36:2283-97.

Schiavone S, Tucci P, Trabace L, Morgese MG. Early celastrol administration prevents ketamine-induced psychotic-like behavioral dysfunctions, oxidative stress and IL-10 reduction in the cerebellum of adult mice. Molecules. 2019 Nov 5;24(21):3993.

Watkins CC, Andrews SR. Clinical studies of neuroinflammatory mechanisms in schizophrenia. Schizophr Res. 2016 Sep 1;176(1): 14-22.

Monji A, Kato T, Kanba S. Cytokines and schizophrenia: Microglia hypothesis of schizophrenia. Psychiatry Clin Neurosci. 2009 Jun;63(3):257-65.

Debatin KM, Poncet D, Kroemer G. Chemotherapy: Targeting the mitochondrial cell death pathway. Oncogene. 2002 Dec;21(57):8786-803.

Kherallah RY, Khawaja M, Olson M, Angiolillo D, Birnbaum Y. Cilostazol: A review of basic mechanisms and clinical uses. Cardiovasc Drugs Ther. 2022 Aug;36:777-92.

Kimura Y, Tani T, Kanbe T, Watanabe K. Effect of cilostazol on platelet aggregation and experimental thrombosis. Arzneimittelforschung. 1985 Jan 1;35(7A):1144-9.

El-Abhar H, Abd El Fattah MA, Wadie W, El-Tanbouly DM. Cilostazol disrupts TLR-4, Akt/GSK-3β/CREB, and IL-6/JAK-2/STAT-3/ SOCS-3 crosstalk in a rat model of Huntington’s disease. PLoS One. 2018 Sep 27;13(9):e0203837.

Hong KW, Lee JH, Kim KY, Park SY, Lee WS. Cilostazol: Therapeutic potential against focal cerebral ischemic damage. Curr Pharm Des. 2006 Feb 1;12(5):565-73.

Gupta S, Sharma B. Neuroprotective potential of cilostazol in 3-NP provoked Huntington’s disease-associated symptoms. Res J Pharm Technol. 2021;14(5):2472-8.

Khalifa M, Abdelsalam RM, Safar MM, Zaki HF. Phosphodiesterase (PDE) III inhibitor, cilostazol, improved memory impairment in aluminum chloride-treated rats: Modulation of cAMP/CREB pathway. Inflammopharmacology. 2022 Dec;30(6):2477-88.

Yanai S, Tago T, Toyohara J, Arasaki T, Endo S. Reversal of spatial memory impairment by phosphodiesterase 3 inhibitor cilostazol is associated with reduced neuroinflammation and increased cerebral glucose uptake in aged male mice. Front Pharmacol. 2022 Dec 21;13:1031637.

Money SR, Herd JA, Isaacsohn JL, Davidson M, Cutler B, Heckman J, et al. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg. 1998 Feb 1;27(2):267-75.

Zaki OS, Nassar NN, Abdallah DM, Safar MM, Mohammed RA. Cilostazol alleviates NLRP3 inflammasome-induced allodynia/ hyperalgesia in murine cerebral cortex following transient ischemia: Focus on TRPA1/glutamate and akt/dopamine/BDNF/Nrf2 trajectories. Mol Neurobiol. 2022 Dec;59(12):7194-211.

Kurtoglu T, Basoglu H, Ozkisacik EA, Cetin NK, Tataroglu C, Yenisey C, et al. Effects of cilostazol on oxidative stress, systemic cytokine release, and spinal cord injury in a rat model of transient aortic occlusion. Ann Vasc Surg. 2014 Feb 1;28(2):479-88.

Chattipakorn SC, Thummasorn S, Sanit J, Chattipakorn N. Phosphodiesterase-3 inhibitor (cilostazol) attenuates oxidative stress-induced mitochondrial dysfunction in the heart. J Geriatr Cardiol. 2014 Jun;11(2):151-7.