open access

Vol 80, No 1 (2021)
Original article
Submitted: 2019-12-12
Accepted: 2020-01-27
Published online: 2020-03-11
Get Citation

Stereological analysis of hippocampus in rat treated with chemotherapeutic agent oxaliplatin

J. Sadeghinezhad1, I. Amrein2
·
Pubmed: 32159839
·
Folia Morphol 2021;80(1):26-32.
Affiliations
  1. Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
  2. Institute of Anatomy, Division of Functional Neuroanatomy, University of Zurich, Zurich, Switzerland; Department of Health Sciences and Technology, ETH, Zurich, Switzerland

open access

Vol 80, No 1 (2021)
ORIGINAL ARTICLES
Submitted: 2019-12-12
Accepted: 2020-01-27
Published online: 2020-03-11

Abstract

Background: Oxaliplatin (OX) has been widely used for treatment of colorectal and other cancers. Adverse effect of OX and other anticancer agents on cognition have been reported, but studies on the effects of chemotherapy on brain structure are scarce. This study describes the morphometrical features of the hippocampus structures in rat following OX treatment using design-based stereological methods.

Materials and methods: Ten male Wistar rats were randomised into two groups. The rats from OX group received 2.4 mg/kg OX in vehicle for 5 consecutive days every week for 2 weeks intraperitoneally. Controls received vehicle only. Cavalieri’s method and the optical fractionator method were used for volume and neuron estimation, respectively.

Results: Cavalieri’s method was used to estimate volume and showed that the volume of the hippocampus was significantly decreased in OX group (31.84 ± ± 1.24 mm3) compared with the vehicle control group (36.95 ± 3.48 mm3). The optical fractionator method was used to estimate neuron number and showed that the number of neurons in dentate gyrus, cornu ammonis 1 and 3 in OX group (8.147 ± 2.84 × 105, 4.257 ± 0.59 × 105 and 2.133 ± 0.22 × 105, respectively) did not differ from those of vehicle control group (7.36 ± 1.42 × 105, 3.521 ± ± 0.54 × 105 and 1.989 ± 0.46 × 105, respectively).

Conclusions: These findings suggested that OX treatment induces loss of hippocampal volume without neuronal loss which might help to clarify the mechanism by which OX affects cognition and to improve preventive treatment strategies.

Abstract

Background: Oxaliplatin (OX) has been widely used for treatment of colorectal and other cancers. Adverse effect of OX and other anticancer agents on cognition have been reported, but studies on the effects of chemotherapy on brain structure are scarce. This study describes the morphometrical features of the hippocampus structures in rat following OX treatment using design-based stereological methods.

Materials and methods: Ten male Wistar rats were randomised into two groups. The rats from OX group received 2.4 mg/kg OX in vehicle for 5 consecutive days every week for 2 weeks intraperitoneally. Controls received vehicle only. Cavalieri’s method and the optical fractionator method were used for volume and neuron estimation, respectively.

Results: Cavalieri’s method was used to estimate volume and showed that the volume of the hippocampus was significantly decreased in OX group (31.84 ± ± 1.24 mm3) compared with the vehicle control group (36.95 ± 3.48 mm3). The optical fractionator method was used to estimate neuron number and showed that the number of neurons in dentate gyrus, cornu ammonis 1 and 3 in OX group (8.147 ± 2.84 × 105, 4.257 ± 0.59 × 105 and 2.133 ± 0.22 × 105, respectively) did not differ from those of vehicle control group (7.36 ± 1.42 × 105, 3.521 ± ± 0.54 × 105 and 1.989 ± 0.46 × 105, respectively).

Conclusions: These findings suggested that OX treatment induces loss of hippocampal volume without neuronal loss which might help to clarify the mechanism by which OX affects cognition and to improve preventive treatment strategies.

Get Citation

Keywords

stereology, hippocampus, oxaliplatin, chemotherapy, rat

About this article
Title

Stereological analysis of hippocampus in rat treated with chemotherapeutic agent oxaliplatin

Journal

Folia Morphologica

Issue

Vol 80, No 1 (2021)

Article type

Original article

Pages

26-32

Published online

2020-03-11

Page views

1393

Article views/downloads

1693

DOI

10.5603/FM.a2020.0031

Pubmed

32159839

Bibliographic record

Folia Morphol 2021;80(1):26-32.

Keywords

stereology
hippocampus
oxaliplatin
chemotherapy
rat

Authors

J. Sadeghinezhad
I. Amrein

References (48)
  1. Apple AC, Ryals AJ, Alpert KI, et al. Subtle hippocampal deformities in breast cancer survivors with reduced episodic memory and self-reported cognitive concerns. Neuroimage Clin. 2017; 14: 685–691.
  2. Barnes CA, Rao G, Houston FP. LTP induction threshold change in old rats at the perforant path--granule cell synapse. Neurobiol Aging. 2000; 21(5): 613–620.
  3. Bergouignan L, Lefranc JP, Chupin M, et al. Breast cancer affects both the hippocampus volume and the episodic autobiographical memory retrieval. PLoS One. 2011; 6(10): e25349.
  4. Bianchi E, Di Cesare Mannelli L, Micheli L, et al. Apoptotic process induced by oxaliplatin in rat hippocampus causes memory impairment. Basic Clin Pharmacol Toxicol. 2017; 120(1): 14–21.
  5. Di Patre PL, Abbamondi A, Bartolini L, et al. GM1 ganglioside counteracts cholinergic and behavioral deficits induced in the rat by intracerebral injection of vincristine. Eur J Pharmacol. 1989; 162(1): 43–50.
  6. Dorph-Petersen KA, Nyengaard JR, Gundersen HJ. Tissue shrinkage and unbiased stereological estimation of particle number and size. J Microsc. 2001; 204(Pt 3): 232–246.
  7. Dubois M, Lapinte N, Villier V, et al. Chemotherapy-induced long-term alteration of executive functions and hippocampal cell proliferation: role of glucose as adjuvant. Neuropharmacology. 2014; 79: 234–248.
  8. ElBeltagy M, Mustafa S, Umka J, et al. Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil. Behav Brain Res. 2010; 208(1): 112–117.
  9. Fardell JE, Vardy J, Shah JD, et al. Cognitive impairments caused by oxaliplatin and 5-fluorouracil chemotherapy are ameliorated by physical activity. Psychopharmacology (Berl). 2012; 220(1): 183–193.
  10. Fardell JE, Vardy J, Monds LA, et al. The long-term impact of oxaliplatin chemotherapy on rodent cognition and peripheral neuropathy. Behav Brain Res. 2015; 291: 80–88.
  11. Foley JJ, Raffa RB, Walker EA. Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory. Psychopharmacology (Berl). 2008; 199(4): 527–538.
  12. Goncalves MB, Williams EJ, Yip P, et al. The COX-2 inhibitors, meloxicam and nimesulide, suppress neurogenesis in the adult mouse brain. Br J Pharmacol. 2010; 159(5): 1118–1125.
  13. Gundersen HJ, Jensen EB, Kiêu K, et al. The efficiency of systematic sampling in stereology--reconsidered. J Microsc. 1999; 193(Pt 3): 199–211.
  14. Hosseini-Sharifabad M, Nyengaard JR. Design-based estimation of neuronal number and individual neuronal volume in the rat hippocampus. J Neurosci Methods. 2007; 162(1-2): 206–214.
  15. Howard V, Reed MG. Unbiased stereology: three-dimensional measurement in microscopy. BIOS Scientific Publishers, Taylor & Francis Group, New York 2005.
  16. Iñiguez C, Gayoso MJ, Carreres J. A versatile and simple method for staining nervous tissue using Giemsa dye. J Neurosci Methods. 1985; 13(1): 77–86.
  17. Jacobs SS, Fox E, Dennie C, et al. Plasma and cerebrospinal fluid pharmacokinetics of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates. Clin Cancer Res. 2005; 11(4): 1669–1674.
  18. Jacobs S, McCully CL, Murphy RF, et al. Extracellular fluid concentrations of cisplatin, carboplatin, and oxaliplatin in brain, muscle, and blood measured using microdialysis in nonhuman primates. Cancer Chemother Pharmacol. 2010; 65(5): 817–824.
  19. Janelsins MC, Roscoe JA, Berg MJ, et al. IGF-1 partially restores chemotherapy-induced reductions in neural cell proliferation in adult C57BL/6 mice. Cancer Invest. 2010; 28(5): 544–553.
  20. Joelving FC, Billeskov R, Christensen JR, et al. Hippocampal neuron and glial cell numbers in Parkinson's disease: a stereological study. Hippocampus. 2006; 16(10): 826–833.
  21. Kaae SS, Chen F, Wegener G, et al. Quantitative hippocampal structural changes following electroconvulsive seizure treatment in a rat model of depression. Synapse. 2012; 66(8): 667–676.
  22. Kesler S, Janelsins M, Koovakkattu D, et al. Reduced hippocampal volume and verbal memory performance associated with interleukin-6 and tumor necrosis factor-alpha levels in chemotherapy-treated breast cancer survivors. Brain Behav Immun. 2013; 30 Suppl: S109–S116.
  23. Konat GW, Kraszpulski M, James I, et al. Cognitive dysfunction induced by chronic administration of common cancer chemotherapeutics in rats. Metab Brain Dis. 2008; 23(3): 325–333.
  24. Korbo L, Amrein I, Lipp HP, et al. No evidence for loss of hippocampal neurons in non-Alzheimer dementia patients. Acta Neurol Scand. 2004; 109(2): 132–139.
  25. Li J, Li Y, Su H, et al. The influence of environment stimulation on learning and memory function in rats with medication chemotherapy. Annu Int Conf IEEE Eng Med Biol Soc. 2018; 2018: 3537–3540.
  26. Li CQ, Liu D, Huang L, et al. Cytosine arabinoside treatment impairs the remote spatial memory function and induces dendritic retraction in the anterior cingulate cortex of rats. Brain Res Bull. 2008; 77(5): 237–240.
  27. Liedke PE, Reolon GK, Kilpp B, et al. Systemic administration of doxorubicin impairs aversively motivated memory in rats. Pharmacol Biochem Behav. 2009; 94(2): 239–243.
  28. Lomeli N, Di K, Czerniawski J, et al. Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats. Free Radic Biol Med. 2017; 102: 274–286.
  29. Madhyastha S, Somayaji SN, Rao MS, et al. Hippocampal brain amines in methotrexate-induced learning and memory deficit. Can J Physiol Pharmacol. 2002; 80(11): 1076–1084.
  30. Marksteiner J, Lechner T, Kaufmann WA, et al. Distribution of chromogranin B-like immunoreactivity in the human hippocampus and its changes in Alzheimer's disease. Acta Neuropathol. 2000; 100(2): 205–212.
  31. Nowakowski C, Kaufmann WA, Adlassnig C, et al. Reduction of chromogranin B-like immunoreactivity in distinct subregions of the hippocampus from individuals with schizophrenia. Schizophr Res. 2002; 58(1): 43–53.
  32. Olesen MV, Needham EK, Pakkenberg B. The optical fractionator technique to estimate cell numbers in a rat model of electroconvulsive therapy. J Vis Exp. 2017(125).
  33. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. Elsevier, Amsterdam 2007.
  34. Park JH, Chae J, Roh K, et al. Oxaliplatin-Induced Peripheral Neuropathy via TRPA1 Stimulation in Mice Dorsal Root Ganglion Is Correlated with Aluminum Accumulation. PLoS One. 2015; 10(4): e0124875.
  35. Rebert CS, Pryor GT, Frick MS. Effects of vincristine, maytansine, and cis-platinum on behavioral and electrophysiological indices of neurotoxicity in the rat. J Appl Toxicol. 1984; 4(6): 330–338.
  36. Reiriz AB, Reolon GK, Preissler T, et al. Cancer chemotherapy and cognitive function in rodent models: memory impairment induced by cyclophosphamide in mice. Clin Cancer Res. 2006; 12(16): 5000–5001.
  37. Seigers R, Schagen SB, Beerling W, et al. Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat. Behav Brain Res. 2008; 186(2): 168–175.
  38. Sprowl JA, Ciarimboli G, Lancaster CS, et al. Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2. Proc Natl Acad Sci U S A. 2013; 110(27): 11199–11204.
  39. Sharpe MJ, Fardell JE, Vardy J, et al. The chemotherapy agent oxaliplatin impairs the renewal of fear to an extinguished conditioned stimulus in rats. Behav Brain Res. 2012; 227(1): 295–299.
  40. Ueno T, Endo K, Hori K, et al. Assessment of antitumor activity and acute peripheral neuropathy of 1,2-diaminocyclohexane platinum (II)-incorporating micelles (NC-4016). Int J Nanomedicine. 2014; 9: 3005–3012.
  41. Vardy J, Tannock I. Cognitive function after chemotherapy in adults with solid tumours. Crit Rev Oncol Hematol. 2007; 63(3): 183–202.
  42. Winocur G, Vardy J, Binns MA, et al. The effects of the anti-cancer drugs, methotrexate and 5-fluorouracil, on cognitive function in mice. Pharmacol Biochem Behav. 2006; 85(1): 66–75.
  43. Wafai L, Taher M, Jovanovska V, et al. Effects of oxaliplatin on mouse myenteric neurons and colonic motility. Front Neurosci. 2013; 7: 30.
  44. Yang M, Kim JS, Kim J, et al. Acute treatment with methotrexate induces hippocampal dysfunction in a mouse model of breast cancer. Brain Res Bull. 2012; 89(1-2): 50–56.
  45. Yang M, Kim JS, Song MS, et al. Cyclophosphamide impairs hippocampus-dependent learning and memory in adult mice: Possible involvement of hippocampal neurogenesis in chemotherapy-induced memory deficits. Neurobiol Learn Mem. 2010; 93(4): 487–494.
  46. Yanovski JA, Packer RJ, Levine JD, et al. An animal model to detect the neuropsychological toxicity of anticancer agents. Med Pediatr Oncol. 1989; 17(3): 216–221.
  47. Yoshikawa E, Matsuoka Y, Inagaki M, et al. No adverse effects of adjuvant chemotherapy on hippocampal volume in Japanese breast cancer survivors. Breast Cancer Res Treat. 2005; 92(1): 81–84.
  48. Zhou W, Kavelaars A, Heijnen CJ. Metformin prevents cisplatin-induced cognitive impairment and brain damage in mice. PLoS One. 2016; 11(3): e0151890.

Regulations

Important: This website uses cookies. More >>

The cookies allow us to identify your computer and find out details about your last visit. They remembering whether you've visited the site before, so that you remain logged in - or to help us work out how many new website visitors we get each month. Most internet browsers accept cookies automatically, but you can change the settings of your browser to erase cookies or prevent automatic acceptance if you prefer.

By VM Media Group sp. z o.o., Grupa Via Medica, Świętokrzyska 73, 80–180 Gdańsk, Poland

tel.: +48 58 320 94 94, faks: +48 58 320 94 60, e-mail: viamedica@viamedica.pl