open access

Vol 82, No 1 (2023)
Original article
Submitted: 2021-12-24
Accepted: 2022-01-09
Published online: 2022-01-21
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Cisplatin-induced alterations in the blood-nerve barrier: effects of combination of vitamin B1, B6 and B12

A. Tothonglor1, P. Kobutree1, A. Roumwong1, D. Jindatip1, S. Agthong1
·
Pubmed: 35099041
·
Folia Morphol 2023;82(1):53-62.
Affiliations
  1. Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Pathumwan, Bangkok, Thailand

open access

Vol 82, No 1 (2023)
ORIGINAL ARTICLES
Submitted: 2021-12-24
Accepted: 2022-01-09
Published online: 2022-01-21

Abstract

Background: Cisplatin is a chemotherapeutic agent against solid cancers. However, neuropathy is a major side effect and has no effective treatment so far. Emerging evidence suggests that cisplatin might damage nerve capillaries leading to impaired blood-nerve barrier (BNB). This study aimed to investigate the ultrastructural changes of the BNB in the sciatic nerves and dorsal root ganglia of rats with cisplatin neuropathy and the effects of B1-6-12.
Materials and methods and Results: The results showed that cisplatin 2 mg/kg injected intraperitoneally twice a week for 5 consecutive weeks caused thermal hypoalgesia and structural abnormalities of nerves and ganglia. Co-treatment with oral B1-6-12 (100:100:1) 100, 300 and 600 mg/kg/day for 5 weeks reduced the sensory deficit and structural alterations. Electron microscopic analysis demonstrated the higher frequencies and wider distances of pericyte detachment in the capillaries of cisplatin than control groups. Vitamin B1, B6 and B12 especially the medium dose, reversed these abnormalities. Culture of endothelial cells and pericytes with cisplatin demonstrated reduced cell viability, increased caspase-3 activity, lower transendothelial electrical resistance and decreased expression of tight junction proteins, occludin and zonula occluden-2.
Conclusions: Vitamin B1, B6 and B12 could correct these toxic effects of cisplatin. These data confirm that cisplatin causes pathological alterations in the components of BNB which correlate with the severity of neuropathy. Furthermore, B1-6-12 is effective against these abnormalities and deserves further investigations as potential treatment for cisplatin-induced neuropathy.

Abstract

Background: Cisplatin is a chemotherapeutic agent against solid cancers. However, neuropathy is a major side effect and has no effective treatment so far. Emerging evidence suggests that cisplatin might damage nerve capillaries leading to impaired blood-nerve barrier (BNB). This study aimed to investigate the ultrastructural changes of the BNB in the sciatic nerves and dorsal root ganglia of rats with cisplatin neuropathy and the effects of B1-6-12.
Materials and methods and Results: The results showed that cisplatin 2 mg/kg injected intraperitoneally twice a week for 5 consecutive weeks caused thermal hypoalgesia and structural abnormalities of nerves and ganglia. Co-treatment with oral B1-6-12 (100:100:1) 100, 300 and 600 mg/kg/day for 5 weeks reduced the sensory deficit and structural alterations. Electron microscopic analysis demonstrated the higher frequencies and wider distances of pericyte detachment in the capillaries of cisplatin than control groups. Vitamin B1, B6 and B12 especially the medium dose, reversed these abnormalities. Culture of endothelial cells and pericytes with cisplatin demonstrated reduced cell viability, increased caspase-3 activity, lower transendothelial electrical resistance and decreased expression of tight junction proteins, occludin and zonula occluden-2.
Conclusions: Vitamin B1, B6 and B12 could correct these toxic effects of cisplatin. These data confirm that cisplatin causes pathological alterations in the components of BNB which correlate with the severity of neuropathy. Furthermore, B1-6-12 is effective against these abnormalities and deserves further investigations as potential treatment for cisplatin-induced neuropathy.

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Keywords

pericyte, endothelial cell, cisplatin, nerve, neuropathy

About this article
Title

Cisplatin-induced alterations in the blood-nerve barrier: effects of combination of vitamin B1, B6 and B12

Journal

Folia Morphologica

Issue

Vol 82, No 1 (2023)

Article type

Original article

Pages

53-62

Published online

2022-01-21

Page views

3460

Article views/downloads

1145

DOI

10.5603/FM.a2022.0008

Pubmed

35099041

Bibliographic record

Folia Morphol 2023;82(1):53-62.

Keywords

pericyte
endothelial cell
cisplatin
nerve
neuropathy

Authors

A. Tothonglor
P. Kobutree
A. Roumwong
D. Jindatip
S. Agthong

References (30)
  1. Al Moundhri MS, Al-Salam S, Al Mahrouqee A, et al. The effect of curcumin on oxaliplatin and cisplatin neurotoxicity in rats: some behavioral, biochemical, and histopathological studies. J Med Toxicol. 2013; 9(1): 25–33.
  2. Authier N, Gillet JP, Fialip J, et al. An animal model of nociceptive peripheral neuropathy following repeated cisplatin injections. Exp Neurol. 2003; 182(1): 12–20.
  3. Bartoszyk GD, Wild A. B-vitamins potentiate the antinociceptive effect of diclofenac in carrageenin-induced hyperalgesia in the rat tail pressure test. Neurosci Lett. 1989; 101(1): 95–100.
  4. Chentanez V, Cha-oumphol P, Kaewsema A, et al. Accuracy of the three-window sampling method in morphometric analysis of human sural nerve. J Neurosci Methods. 2006; 157(1): 154–157.
  5. Dieckmann KP, Struss WJ, Budde U. Evidence for acute vascular toxicity of cisplatin-based chemotherapy in patients with germ cell tumour. Anticancer Res. 2011; 31(12): 4501–4505.
  6. Dilruba S, Kalayda GV. Platinum-based drugs: past, present and future. Cancer Chemother Pharmacol. 2016; 77(6): 1103–1124.
  7. Dore-Duffy P, Owen C, Balabanov R, et al. Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res. 2000; 60(1): 55–69.
  8. Dursun B, He Z, Somerset H, et al. Caspases and calpain are independent mediators of cisplatin-induced endothelial cell necrosis. Am J Physiol Renal Physiol. 2006; 291(3): F578–F587.
  9. Eguchi R, Fujimori Y, Ohta T, et al. Calpain is involved in cisplatin-induced endothelial injury in an in vitro three-dimensional blood vessel model. Int J Oncol. 2010; 37(5): 1289–1296.
  10. Hadtstein F, Vrolijk M. Vitamin B-6-induced neuropathy: exploring the mechanisms of pyridoxine toxicity. Adv Nutr. 2021; 12(5): 1911–1929.
  11. Jindatip D, Fujiwara K, Sarachana T, et al. Characteristics of pericytes in diethylstilbestrol (DES)-induced pituitary prolactinoma in rats. Med Mol Morphol. 2018; 51(3): 147–155.
  12. Jindatip D, Nopparat W, Kobutree P, et al. Pericyte loss and detachment in experimental cisplatin-induced neuropathy. Int J Morphol. 2019; 37(2): 509–514.
  13. Jolivalt CG, Mizisin LM, Nelson A, et al. B vitamins alleviate indices of neuropathic pain in diabetic rats. Eur J Pharmacol. 2009; 612(1-3): 41–47.
  14. Kanda T, Numata Y, Mizusawa H. Chronic inflammatory demyelinating polyneuropathy: decreased claudin-5 and relocated ZO-1. J Neurol Neurosurg Psychiatry. 2004; 75(5): 765–769.
  15. Kirchmair R, Walter DH, Ii M, et al. Antiangiogenesis mediates cisplatin-induced peripheral neuropathy: attenuation or reversal by local vascular endothelial growth factor gene therapy without augmenting tumor growth. Circulation. 2005; 111(20): 2662–2670.
  16. Krarup-Hansen A, Helweg-Larsen S, Schmalbruch H, et al. Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies. Brain. 2007; 130(Pt 4): 1076–1088.
  17. Li SH, Chen WH, Tang Y, et al. Incidence of ischemic stroke post-chemotherapy: a retrospective review of 10,963 patients. Clin Neurol Neurosurg. 2006; 108(2): 150–156.
  18. Liu YW, Liu CT, Su YL, et al. A narrative review of complementary nutritional supplements for chemotherapy-induced peripheral neuropathy. Altern Ther Health Med. 2020; 26(4): 43–49.
  19. Nuver J, De Haas EC, Van Zweeden M, et al. Vascular damage in testicular cancer patients: A study on endothelial activation by bleomycin and cisplatin in vitro. Oncol Rep. 2009; 23(1).
  20. Peltonen S, Alanne M, Peltonen J. Barriers of the peripheral nerve. Tissue Barriers. 2013; 1(3): e24956.
  21. Pfister F, Feng Y, vom Hagen F, et al. Pericyte migration: a novel mechanism of pericyte loss in experimental diabetic retinopathy. Diabetes. 2008; 57(9): 2495–2502.
  22. Quasthoff S, Hartung H. Chemotherapy-induced peripheral neuropathy. J Neurol. 2002; 249(1): 9–17.
  23. Roelofs RI, Hrushesky W, Rogin J, et al. Peripheral sensory neuropathy and cisplatin chemotherapy. Neurology. 1984; 34(7): 934–938.
  24. Santos NA, Ferreira RS, Santos AC. Overview of cisplatin-induced neurotoxicity and ototoxicity, and the protective agents. Food Chem Toxicol. 2020; 136: 111079.
  25. Shimizu F, Sano Y, Abe MA, et al. Peripheral nerve pericytes modify the blood-nerve barrier function and tight junctional molecules through the secretion of various soluble factors. J Cell Physiol. 2011; 226(1): 255–266.
  26. Shimizu F, Sano Y, Haruki H, et al. Advanced glycation end-products induce basement membrane hypertrophy in endoneurial microvessels and disrupt the blood-nerve barrier by stimulating the release of TGF-β and vascular endothelial growth factor (VEGF) by pericytes. Diabetologia. 2011; 54(6): 1517–1526.
  27. Thompson SW, Davis LE, Kornfeld M, et al. Cisplatin neuropathy. Clinical, electrophysiologic, morphologic, and toxicologic studies. Cancer. 1984; 54(7): 1269–1275, doi: 10.1002/1097-0142(19841001)54:7<1269::aid-cncr2820540707>3.0.co;2-9.
  28. Wongtawatchai T, Agthong S, Kaewsema A, et al. Sex-related differences in cisplatin-induced neuropathy in rats. J Med Assoc Thai. 2009; 92(11): 1485–1491.
  29. Wongtawatchai T, Agthong S, Kaewsema A, et al. Altered phosphorylation of mitogen-activated protein kinases in dorsal root ganglia and sciatic nerve of rats with cisplatin-induced neuropathy. Asian Biomed (Res Rev News). 2012; 6: 397–411.
  30. Zhang N, Cai J, Xu L, et al. Cisplatin-Induced stria vascularis damage is associated with inflammation and fibrosis. Neural Plast. 2020; 2020: 8851525.

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