Skip to main content

Advertisement

SpringerLink
Log in

Platinum accumulation in the brain and alteration in the central regulation of cardiovascular and respiratory functions in oxaliplatin-treated rats

  • Neuroscience
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

Oxaliplatin is a platinum-based alkylating chemotherapeutic agent used for cancer treatment. Neurotoxicity is one of its major adverse effects that often demands dose limitation. However, the effects of chronic oxaliplatin on the toxicity of the autonomic nervous system regulating cardiorespiratory function and adaptive reflexes are unknown. Male Sprague Dawley rats were treated with intraperitoneal oxaliplatin (3 mg kg−1 per dose) 3 times a week for 14 days. The effects of chronic oxaliplatin treatment on baseline mean arterial pressure (MAP); heart rate (HR); splanchnic sympathetic nerve activity (sSNA); phrenic nerve activity (PNA) and its amplitude (PNamp) and frequency (PNf); and sympathetic reflexes were investigated in anaesthetised, vagotomised and artificially ventilated rats. The same parameters were evaluated after acute oxaliplatin injection, and in the chronic treatment group following a single dose of oxaliplatin. The amount of platinum in the brain was determined with atomic absorption spectrophotometry. Chronic oxaliplatin treatment significantly increased MAP, sSNA and PNf and decreased HR and PNamp, while acute oxaliplatin had no effects. Platinum was accumulated in the brain after chronic oxaliplatin treatment. In the chronic oxaliplatin treatment group, further administration of a single dose of oxaliplatin increased MAP and sSNA. The baroreceptor sensitivity and somatosympathetic reflex were attenuated at rest while the sympathoexcitatory response to hypercapnia was increased in the chronic treatment group. This is the first study to reveal oxaliplatin-induced alterations in the central regulation of cardiovascular and respiratory functions as well as reflexes that may lead to hypertension and breathing disorders which may be mediated via accumulated platinum in the brain.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

AAS:

Atomic absorption spectrophotometry

ANS:

Autonomic nervous system

BP:

Blood pressure

DRG:

Dorsal root ganglia

HR:

Heart rate

i.p.:

Intraperitoneal

i.v.:

Intravenous

MAP:

Mean arterial pressure

NO:

Nitric oxide

PE:

Phenylephrine hydrochloride

PNA:

Phrenic nerve activity

PNamp:

Phrenic nerve amplitude

PNf:

Phrenic nerve frequency

SNP:

Sodium nitroprusside

sSNA:

Splanchnic sympathetic nerve activity

References

  1. Abbott SB, Pilowsky PM (2009) Galanin microinjection into rostral ventrolateral medulla of the rat is hypotensive and attenuates sympathetic chemoreflex. Am J Physiol Regul Integr Comp Physiol 296:R1019–R1026. https://doi.org/10.1152/ajpregu.90885.2008

    Article  CAS  PubMed  Google Scholar 

  2. Adams SC, Schondorf R, Benoit J, Kilgour RD (2015) Impact of cancer and chemotherapy on autonomic nervous system function and cardiovascular reactivity in young adults with cancer: a case-controlled feasibility study. BMC Cancer 15:414. https://doi.org/10.1186/s12885-015-1418-3

    Article  PubMed  PubMed Central  Google Scholar 

  3. Adelsberger H, Quasthoff S, Grosskreutz J, Lepier A, Eckel F, Lersch C (2000) The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons. Eur J Pharmacol 406:25–32

    Article  CAS  Google Scholar 

  4. Cavaletti G, Tredici G, Petruccioli MG, Donde E, Tredici P, Marmiroli P, Minoia C, Ronchi A, Bayssas M, Etienne GG (2001) Effects of different schedules of oxaliplatin treatment on the peripheral nervous system of the rat. Eur J Cancer 37:2457–2463

    Article  CAS  Google Scholar 

  5. Dampney RAL (2017) Resetting of the baroreflex control of sympathetic vasomotor activity during natural behaviors: description and conceptual model of central mechanisms. Front Neurosci 11. https://doi.org/10.3389/fnins.2017.00461

  6. Dermitzakis EV, Kimiskidis VK, Eleftheraki A, Lazaridis G, Konstantis A, Basdanis G, Tsiptsios I, Georgiadis G, Fountzilas G (2014) The impact of oxaliplatin-based chemotherapy for colorectal cancer on the autonomous nervous system. Eur J Neurol 21:1471–1477. https://doi.org/10.1111/ene.12514

    Article  CAS  PubMed  Google Scholar 

  7. Di Cesare ML, Zanardelli M, Failli P, Ghelardini C (2012) Oxaliplatin-induced neuropathy: oxidative stress as pathological mechanism. Protective effect of silibinin. J Pain 13:276–284. https://doi.org/10.1016/j.jpain.2011.11.009

    Article  CAS  Google Scholar 

  8. El-Awady ESE, Moustafa YM, Abo-Elmatty DM, Radwan A (2011) Cisplatin-induced cardiotoxicity: mechanisms and cardioprotective strategies. Eur J Pharmacol 650:335–341. https://doi.org/10.1016/j.ejphar.2010.09.085

    Article  CAS  Google Scholar 

  9. Eloxatin (2014) Product monograph. http://products.sanofi.ca/en/eloxatin.pdf. (accessed 2/2014)

  10. Esteban-Fernandez D, Verdaguer JM, Ramirez-Camacho R, Palacios MA, Gomez-Gomez MM (2008) Accumulation, fractionation, and analysis of platinum in toxicologically affected tissues after cisplatin, oxaliplatin, and carboplatin administration. J Anal Toxicol 32:140–146

    Article  CAS  Google Scholar 

  11. Extra JM, Marty M, Brienza S, Misset JL (1998) Pharmacokinetics and safety profile of oxaliplatin. Semin Oncol 25:13–22

    CAS  PubMed  Google Scholar 

  12. Fathi AR, Yang C, Bakhtian KD, Qi M, Lonser RR, Pluta RM (2011) Carbon dioxide influence on nitric oxide production in endothelial cells and astrocytes: cellular mechanisms. Brain Res 1386:50–57. https://doi.org/10.1016/j.brainres.2011.02.066

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Floyd JD, Nguyen DT, Lobins RL, Bashir Q, Doll DC, Perry MC (2005) Cardiotoxicity of cancer therapy. J Clin Oncol 23:7685–7696. https://doi.org/10.1200/jco.2005.08.789

    Article  CAS  PubMed  Google Scholar 

  14. Gamelin E, Gamelin L, Bossi L, Quasthoff S (2002) Clinical aspects and molecular basis of oxaliplatin neurotoxicity: current management and development of preventive measures. Semin Oncol 29:21–33. https://doi.org/10.1053/sonc.2002.35525

    Article  CAS  PubMed  Google Scholar 

  15. Garry PS, Ezra M, Rowland MJ, Westbrook J, Pattinson KT (2015) The role of the nitric oxide pathway in brain injury and its treatment--from bench to bedside. Exp Neurol 263:235–243. https://doi.org/10.1016/j.expneurol.2014.10.017

    Article  CAS  PubMed  Google Scholar 

  16. Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Mancia G (1998) Baroreflex control of sympathetic nerve activity in essential and secondary hypertension. Hypertension 31:68–72. https://doi.org/10.1161/01.hyp.31.1.68

    Article  CAS  PubMed  Google Scholar 

  17. Gregg RW, Molepo JM, Monpetit VJ, Mikael NZ, Redmond D, Gadia M, Stewart DJ (1992) Cisplatin neurotoxicity: the relationship between dosage, time, and platinum concentration in neurologic tissues, and morphologic evidence of toxicity. J Clin Oncol 10:795–803. https://doi.org/10.1200/jco.1992.10.5.795

    Article  CAS  PubMed  Google Scholar 

  18. Han C, McKeage M (2012) Neuropathies associated with oxaliplatin therapy. Asia Pac J Clin Oncol 8:107–110. https://doi.org/10.1111/j.1743-7563.2012.01547.x

    Article  PubMed  Google Scholar 

  19. Hind D, Tappenden P, Tumur I, Eggington S, Sutcliffe P, Ryan A (2008) The use of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer: systematic review and economic evaluation. Health Technol Assess 12:iii-ix–xi-162

    Article  Google Scholar 

  20. Kent BB, Drane JW, Blumenstein B, Manning JW (1972) A mathematical model to assess changes in the baroreceptor reflex. Cardiology 57:295–310

    Article  CAS  Google Scholar 

  21. Ketch T, Biaggioni I, Robertson R, Robertson D (2002) Four faces of baroreflex failure: hypertensive crisis, volatile hypertension, orthostatic tachycardia, and malignant vagotonia. Circulation 105:2518–2523

    Article  Google Scholar 

  22. Mancia G, Ludbrook J, Ferrari A, Gregorini L, Zanchetti A (1978) Baroreceptor reflexes in human hypertension. Circ Res 43:170–177. https://doi.org/10.1161/01.RES.43.2.170

    Article  CAS  PubMed  Google Scholar 

  23. McDonald ES, Randon KR, Knight A, Windebank AJ (2005) Cisplatin preferentially binds to DNA in dorsal root ganglion neurons in vitro and in vivo: a potential mechanism for neurotoxicity. Neurobiol Dis 18:305–313. https://doi.org/10.1016/j.nbd.2004.09.013

    Article  CAS  PubMed  Google Scholar 

  24. McDowall LM, Dampney RA (2006) Calculation of threshold and saturation points of sigmoidal baroreflex function curves. Am J Phys Heart Circ Phys 291:H2003–H2007. https://doi.org/10.1152/ajpheart.00219.2006

    Article  CAS  Google Scholar 

  25. McQuade RM, Carbone SE, Stojanovska V, Rahman A, Gwynne RM, Robinson AM, Goodman CA, Bornstein JC, Nurgali K (2016) Role of oxidative stress in oxaliplatin-induced enteric neuropathy and colonic dysmotility in mice. Br J Pharmacol 173:3502–3521. https://doi.org/10.1111/bph.13646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Monsuez JJ, Charniot JC, Vignat N, Artigou JY (2010) Cardiac side-effects of cancer chemotherapy. Int J Cardiol 144:3–15. https://doi.org/10.1016/j.ijcard.2010.03.003

    Article  PubMed  Google Scholar 

  27. Narkiewicz K, Pesek CA, Kato M, Phillips BG, Davison DE, Somers VK (1998) Baroreflex control of sympathetic nerve activity and heart rate in obstructive sleep apnea. Hypertension 32:1039–1043. https://doi.org/10.1161/01.hyp.32.6.1039

    Article  CAS  PubMed  Google Scholar 

  28. Narkiewicz K, Pesek CA, van de Borne PJ, Kato M, Somers VK (1999) Enhanced sympathetic and ventilatory responses to central chemoreflex activation in heart failure. Circulation 100:262–267

    Article  CAS  Google Scholar 

  29. Nedoboy PE, Mohammed S, Kapoor K, Bhandare AM, Farnham MM, Pilowsky PM (2016) pSer40 tyrosine hydroxylase immunohistochemistry identifies the anatomical location of C1 neurons in rat RVLM that are activated by hypotension. Neuroscience 317:162–172. https://doi.org/10.1016/j.neuroscience.2016.01.012

    Article  CAS  PubMed  Google Scholar 

  30. Rahman AA, Shahid IZ, Pilowsky PM (2011) Intrathecal neuromedin U induces biphasic effects on sympathetic vasomotor tone, increases respiratory drive and attenuates sympathetic reflexes in rat. Br J Pharmacol 164:617–631

    Article  CAS  Google Scholar 

  31. Rahman AA, Shahid IZ, Pilowsky PM (2012) Differential cardiorespiratory and sympathetic reflex responses to microinjection of neuromedin U in rat rostral ventrolateral medulla. J Pharmacol Exp Ther 341:213–224

    Article  CAS  Google Scholar 

  32. Rahman AA, Shahid IZ, Pilowsky PM (2013) Neuromedin U causes biphasic cardiovascular effects and impairs baroreflex function in rostral ventrolateral medulla of spontaneously hypertensive rat. Peptides 44:15–24. https://doi.org/10.1016/j.peptides.2013.03.017

    Article  CAS  PubMed  Google Scholar 

  33. Raymond E, Faivre S, Woynarowski JM, Chaney SG (1998) Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol 25:4–12

    CAS  PubMed  Google Scholar 

  34. Rea RF, Hamdan M (1990) Baroreflex control of muscle sympathetic nerve activity in borderline hypertension. Circulation 82:856–862. https://doi.org/10.1161/01.CIR.82.3.856

    Article  CAS  PubMed  Google Scholar 

  35. Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661. https://doi.org/10.1096/fj.07-9574LSF

    Article  CAS  Google Scholar 

  36. Renn CL, Carozzi VA, Rhee P, Gallop D, Dorsey SG, Cavaletti G (2011) Multimodal assessment of painful peripheral neuropathy induced by chronic oxaliplatin-based chemotherapy in mice. Mol Pain 7:29. https://doi.org/10.1186/1744-8069-7-29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Rothenberg ML, Oza AM, Bigelow RH, Berlin JD, Marshall JL, Ramanathan RK, Hart LL, Gupta S, Garay CA, Burger BG, Le Bail N, Haller DG (2003) Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 21:2059–2069. https://doi.org/10.1200/jco.2003.11.126

    Article  CAS  PubMed  Google Scholar 

  38. Saif MW, Reardon J (2005) Management of oxaliplatin-induced peripheral neuropathy. Ther Clin Risk Manag 1:249–258

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Screnci D, Er HM, Hambley TW, Galettis P, Brouwer W, McKeage MJ (1997) Stereoselective peripheral sensory neurotoxicity of diaminocyclohexane platinum enantiomers related to ormaplatin and oxaliplatin. Br J Cancer 76:502–510

    Article  CAS  Google Scholar 

  40. Screnci D, McKeage MJ, Galettis P, Hambley TW, Palmer BD, Baguley BC (2000) Relationships between hydrophobicity, reactivity, accumulation and peripheral nerve toxicity of a series of platinum drugs. Br J Cancer 82:966–972. https://doi.org/10.1054/bjoc.1999.1026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Senkus E, Jassem J (2011) Cardiovascular effects of systemic cancer treatment. Cancer Treat Rev 37:300–311. https://doi.org/10.1016/j.ctrv.2010.11.001

    Article  CAS  PubMed  Google Scholar 

  42. Shahid IZ, Rahman AA, Pilowsky PM (2012) Orexin A in rat rostral ventrolateral medulla is pressor, sympatho-excitatory, increases barosensitivity and attenuates the somato-sympathetic reflex. Br J Pharmacol 165:2292–2303

    Article  CAS  Google Scholar 

  43. Slade JH, Alattar ML, Fogelman DR, Overman MJ, Agarwal A, Maru DM, Coulson RL, Charnsangavej C, Vauthey JN, Wolff RA, Kopetz S (2009) Portal hypertension associated with oxaliplatin administration: clinical manifestations of hepatic sinusoidal injury. Clin Colorectal Cancer 8:225–230. https://doi.org/10.3816/CCC.2009.n.038

    Article  CAS  PubMed  Google Scholar 

  44. Sorensen JC, Petersen AC, Timpani CA, Campelj DG, Cook J, Trewin AJ, Stojanovska V, Stewart M, Hayes A, Rybalka E (2017) BGP-15 protects against oxaliplatin-induced skeletal myopathy and mitochondrial reactive oxygen species production in mice. Front Pharmacol 8:137. https://doi.org/10.3389/fphar.2017.00137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ta LE, Espeset L, Podratz J, Windebank AJ (2006) Neurotoxicity of oxaliplatin and cisplatin for dorsal root ganglion neurons correlates with platinum-DNA binding. Neurotoxicology 27:992–1002. https://doi.org/10.1016/j.neuro.2006.04.010

    Article  CAS  PubMed  Google Scholar 

  46. Uchino M, Kuwahara M, Ebukuro S, Tsubone H (2006) Modulation of emetic response by carotid baro- and chemoreceptor activations. Auton Neurosci 128:25–36. https://doi.org/10.1016/j.autneu.2005.12.006

    Article  CAS  PubMed  Google Scholar 

  47. Yeh ET, Tong AT, Lenihan DJ, Yusuf SW, Swafford J, Champion C, Durand JB, Gibbs H, Zafarmand AA, Ewer MS (2004) Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation 109:3122–3131. https://doi.org/10.1161/01.cir.0000133187.74800.b9

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a research support grant from Victoria University. KN and AAR obtained funding.

Author information

Authors and Affiliations

  1. College of Health and Biomedicine, Institute for Health and Sport, Victoria University, Melbourne, Australia

    Ahmed A. Rahman, Vanesa Stojanovska & Kulmira Nurgali

  2. Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia

    Ahmed A. Rahman

  3. Hudson Institute of Medical Research, Monash Health Translation Precinct, Melbourne, Australia

    Vanesa Stojanovska

  4. Heart Research Institute, Central Clinical School, The University of Sydney, Sydney, Australia

    Paul Pilowsky

  5. Department of Medicine Western Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Melbourne, Australia

    Kulmira Nurgali

  6. Regenerative Medicine and Stem Cells Program, Australian Institute of Musculoskeletal Science (AIMSS), Melbourne, Australia

    Kulmira Nurgali

  7. Enteric Neuropathy Lab, Western Centre for Health, Research & Education, Sunshine Hospital, 176 Furlong Road, St Albans, Melbourne, Victoria, 3021, Australia

    Kulmira Nurgali

Authors
  1. Ahmed A. Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vanesa Stojanovska
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paul Pilowsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kulmira Nurgali
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AAR: conception and design, collection, analysis and interpretation of data, manuscript writing; VS: collection, analysis and interpretation of data, manuscript revision; PP: interpretation of data, manuscript revision; KN: conception and design, interpretation of data, manuscript revision. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Kulmira Nurgali.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rahman, A.A., Stojanovska, V., Pilowsky, P. et al. Platinum accumulation in the brain and alteration in the central regulation of cardiovascular and respiratory functions in oxaliplatin-treated rats. Pflugers Arch - Eur J Physiol 473, 107–120 (2021). https://doi.org/10.1007/s00424-020-02480-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-020-02480-4

Keywords

Search

Navigation