Temporal dynamics of hippocampal morphological changes in cisplatin-induced neurotoxicity and prophylactic and therapeutic effects of pioglitazone

H. B. Kulynych; S. B. Herashchenko; M. I. Polyvkan; R. P. Oliinyk; V. M. Fedorak; I. O. Mykhailiuk

doi:10.15421/0226028

H. B. Kulynych Ivano-Frankivsk National Medical University
S. B. Herashchenko Ivano-Frankivsk National Medical University
M. I. Polyvkan Ivano-Frankivsk National Medical University
R. P. Oliinyk Ivano-Frankivsk National Medical University
V. M. Fedorak Ivano-Frankivsk National Medical University
I. O. Mykhailiuk Ivano-Frankivsk National Medical University

Keywords: cisplatin, pioglitazone, hippocampus, neurotoxicity, morphology, PPARγ, prophylactic neuroprotection, morphometry.

Abstract

Cisplatin-induced neurotoxicity is widely investigated using experimental animal models to elucidate structural alterations of the central nervous system; however, temporal morphological changes in specific brain regions and the effectiveness of pharm a cological correction strategies remain incompletely understood. The hippocampus represents one of the most vulnerable targets of chemotherapy-induced injury due to its high metabolic activity, pronounced synaptic plasticity, and critical dependence on the integrity of neurogliovascular complexes. The present study aimed to evaluate the temporal dynamics of hippocampal morph o logical and morphometric alterations under cisplatin-induced neurotoxicity and to compare the neuroprotective efficacy of pioglitazone administered in prophylactic and therapeutic regimens. The experiment was conducted on 120 sexually mature male white inbred rats. Cisplatin was administered intraperitoneally at a dose of 2 mg/kg once weekly for six weeks to induce chronic cumulative neurotoxicity. Pioglitazone was administered intragastrically either prophylactically (from day – 5 to day +14 relative to the start of cisplatin treatment) or therapeutically (starting from day 3 after completion of the cisplatin course for 14 days). Morphological and morphometric analyses of the hippocampus (CA1 and CA3 regions) were performed on days 14, 28, 60, 90, and 120 using light microscopy and digital morphometry, including assessment of neuronal perikaryon area, nuclear diameter, nuclear-to-cytoplasmic ratio, and neuronal density. Results demonstrated that cisplatin induced a progressive cascade of hipp o campal damage with maximal structural disorganization of the pyramidal layer on day 28, whereas prophylactic pioglitazone administration significantly preserved hippocampal cytoarchitecture and normalized key morphometric parameters more effe c tively than therapeutic treatment. At later observation periods, prophylactic pioglitazone ensured near-complete restoration of hippocampal structural organization, while therapeutic administration promoted partial stabilization without full morphological recovery. These findings indicate a clear temporal and mechanistic advantage of early PPARγ-targeted intervention in limiting cisplatin-induced hippocampal injury.

References

Alhowail, A. H. (2025). Cisplatin induces hippocampal neurotoxicity and cognitive impairment in rats through neuroinflammation, oxidative stress, and overexpression of glutamatergic receptors mRNA. Frontiers in Pharmacology, 16, 1592511.

Alotayk, L. I., Aldubayan, M. A., Alenezi, S. K., Anwar, M. J., & Alhowail, A. H. (2023). Comparative evaluation of chemotherapeutics on cognitive dysfunction. Biomedicine and Pharmacotherapy, 165, 115245.

Alsaud, M. M., Alhowail, A. H., Aldubayan, M. A., & Almami, I. S. (2023). The ameliorative effect of pioglitazone against neuroinflammation caused by doxorubicin in rats. Molecules, 28(12), 4775.

Altunkaya, M., Ateş, M. B., Bulut, A., Abuşoğlu, G., & Öztürk, B. (2025). Cisplatin-induced toxicity in the hippocampus: Dose-dependent damage. BMC Pharmacology and Toxicology, 26(1), 215.

Barbosa-Azevedo, M., Dias-Carvalho, A., Carvalho, F., & Costa, V. M. (2024). Chemotherapy-induced cognitive impairment and glia. Toxicology and Applied Pharmacology, 492, 117085.

Carozzi, V. A., Chiorazzi, A., Canta, A., Oggioni, N., Gilardini, A., Rodriguez-Menendez, V., & Cavaletti, G. (2009). Effect of chronic combined administration of cisplatin and paclitaxel in a rat model of neurotoxicity. European Journal of Cancer, 45(4), 656–665.

Christie, L. A., Acharya, M. M., Parihar, V. K., Nguyen, A., Martirosian, V., & Limoli, C. L. (2012). Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy. Clinical Cancer Research, 18(7), 1954–1965.

Csik, B., Vali Kordestan, K., Gulej, R., Patai, R., Nyul-Toth, A., Shanmugarama, S., & Csiszar, A. (2025). Cisplatin and methotrexate induce brain microvascular endothelial and microglial senescence in mouse models of chemotherapy-associated cognitive impairment. GeroScience, 47, 3447–3459.

Dietrich, J., Prust, M., & Kaiser, J. (2015). Chemotherapy, cognitive impairment and hippocampal toxicity. Neuroscience, 309, 224–232.

Domouky, A. M., Deraz, R. H., & Abdel-Kareem, R. H. (2022). Neurotoxicity of cisplatin in the rat hippocampus: histological and biochemical study. Egyptian Society of Clinical Toxicology Journal, 10(1), 29–48.

Groves, T. R., Farris, R., Anderson, J. E., Alexander, T. C., Kiffer, F., Carter, G., & Allen, A. R. (2017). Chemotherapy with 5-fluorouracil upregulates cytokine expression and alters hippocampal dendritic complexity in aged mice. Behavioural Brain Research, 316, 215–224.

Heneka, M. T., Sastre, M., Dumitrescu-Ozimek, L., Hanke, A., Dewachter, I., Kuiperi, C., & Landreth, G. E. (2005). Acute treatment with the PPARγ agonist pioglitazone reduces glial inflammation. Brain, 128(6), 1442–1453.

Hussien, M., & Yousef, M. I. (2022). Neuroprotective effects against cisplatin-induced neurotoxicity. Environmental Science and Pollution Research International, 29(41), 62042–62654.

Kang, S., Lee, S., Kim, J., Kim, J. C., Kim, S. H., Son, Y., Shin, T., Youn, B. H., Kim, J. S., Wang, H., & Yang, M. (2018). Chronic chemotherapy affects hippocampal micromorphometry. Experimental Neurobiology, 27(5), 419–436.

Kirchev, V. V., Jctapenko, I. O., Tertyshnyi, S. V., Buryachkivskyi, S. E., & Vastyanov, R. S. (2025). Neuroprotective effects of deproteinized calf blood haemodialysate in case of intranasally administration under chronic cerebral ischemia. Odessa Medical Journal, 192, 14–19.

Kumar, A., Kaundal, R. K., Iyer, S., & Sharma, S. S. (2009). Effects of pioglitazone on cognitive dysfunction and oxidative stress. Behavioural Brain Research, 197(2), 472–479.

Lomelí-Cardona, N., Chávez-Munguía, B., García-Rodríguez, A., & Bota, D. A. (2017). Cisplatin-induced mitochondrial dysfunction and oxidative stress in the brain. Free Radical Biology and Medicine, 108, 41–50.

Magdy, O., Eshra, M., Rashed, L., Maher, M., Hosny, S. A., & Shams Eldeen, A. M. (2024). Amelioration of cisplatin-induced neurodegenerative changes in rats and restoration of mitochondrial biogenesis by 6-bromoindirubin-3′-oxime: The implication of the GSK-3β/PGC1-α axis. Tissue and Cell, 88, 102393.

Manohar, S., Jamesdaniel, S., & Salvi, R. (2014). Cisplatin inhibits hippocampal cell proliferation and alters hippocampal neurogenesis. Neurotoxicology Research, 25(4), 369–380.

Morales-Garcia, J. A., Luna-Medina, R., Alfaro-Cervello, C., Cortes-Canteli, M., Santos, A., Garcia‐Verdugo, J. M., & Perez-Castillo, A. (2011). PPARγ activation promotes neural stem cell proliferation. Glia, 59(2), 293–307.

Nair, A. B., & Jacob, S. (2016). A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy, 7(2), 27–31.

Oliveros, A., Yoo, K. H., Rashid, M. A., Corujo-Ramirez, A., Hur, B., Sung, J., & Jang, M. H. (2022). Adenosine A2A receptor blockade prevents cisplatin-induced impairments in neurogenesis and cognitive function. Proceedings of the National Academy of Sciences of the United States of America, 119(28), e2206415119.

Ongnok, B., Chattipakorn, N., & Chattipakorn, S. C. (2020). Doxorubicin and cisplatin induced cognitive impairment: possible mechanisms and interventions. Experimental Neurology, 324, 113118.

Qutifan, S., Saleh, T., Shahin, N. A., ELBeltagy, M., Obeidat, F., Qattan, D., & Alsalem, M. (2024). Melatonin mitigates cisplatin-induced cognitive impairment in rats and improves hippocampal dendritic spine density. Neuroreport, 35(10), 657–663.

Reagan-Shaw, S., Nihal, M., & Ahmad, N. (2008). Dose translation from animal to human studies revisited. FASEB Journal, 22(3), 659–661.

Ren, X., St Clair, D. K., & Butterfield, D. A. (2017). Dysregulation of cytokine-mediated chemotherapy-induced cognitive impairment. Pharmacological Research, 117, 267–273.

Squillace, S., Niehoff, M. L., Doyle, T. M., Green, M., Esposito, E., Cuzzocrea, S., Christopher, K. Arnatt, Spiegel, S., Farr, S. A., & Salvemini, D. (2022). S1PR1 activation drives cisplatin-induced cognitive impairment. Journal of Clinical Investigation, 132(17), e157738.

Umfress, A., Speed, H. E., Tan, C., Ramezani, S., Birnbaum, S., Brekken, R. A., Sun, Х, & Plattner, F (2021). Neuropathological effects of chemotherapeutic drugs. ACS Chemical Neuroscience, 12, 3038–3048.

Was, H., Borkowska, A., Bagues, A., Tu, L., Liu, J. Y., Lu, Z., & Abalo, R. (2022). Mechanisms of chemotherapy-induced neurotoxicity. Frontiers in Pharmacology, 13, 750507.

Wellenberg, A., Brinkmann, V., Bornhorst, J., Ventura, N., Honnen, S., & Fritz, G. (2021). Cisplatin-induced neurotoxicity and serotonergic disruption. Pharmacological Research, 174, 105921.

Xing, B., Xin, T., Hunter, R. L., & Bing, G. (2007). Pioglitazone inhibition of microglial activation reduces neuronal loss. Journal of Neuroimmunology, 189(1–2), 38–46.