||Preventive Hypothermia as a Neuroprotective Strategy for Paclitaxel-induced Peripheral Neuropathy
||Institute of Basic Medical Sciences
Chemotherapy-induced peripheral neuropathy
化學治療引起的周邊神經病變(chemotherapy-induced peripheral neuropathy, CIPN)為癌症治療中常見的嚴重副作用，目前並沒有有效的預防或治療策略。低溫治療(therapeutic hypothermia)已被證實有效對抗中樞與周邊神經系統的損傷。然而，目前並沒有文獻探討低溫治療對於由化學治療引起的周邊神經病變的療效。我們在已建立的由紫杉醇(paclitaxel)所引起的周邊神經病變的大鼠模式中使用低背低溫治療(lower back hypothermia, LBH)，發現當低溫之溫度在坐骨神經(sciatic nerve)達到24度及在給予紫杉醇90分鐘前給予低溫治療，低溫治療會抑制由紫杉醇引起之行為、電生理、與組織上的損傷。低溫治療也抑制了脊髓中的星形膠質細胞(astrocyte)和微小膠質細胞(microglia)的活化、背跟神經節(dorsal root ganglia) 和坐骨神經的巨噬細胞(macrophage)浸潤與神經元損傷以及促炎性细胞因子(pro-inflammatory cytokine)在背跟神經節、坐骨神經和脊髓背角(spinal dorsal horn)的表現與釋放。此外，低溫治療降低了局部血流量及紫杉醇局部組織濃度。最後，我們在由紫杉醇所引起的周邊神經病變的大鼠模式使用單側後肢低溫治療(unilateral hind limb hypothermia)，發現低溫治療對接受治療的該側有效但對身體對側沒有效果。更重要的是，當癌細胞接種到接近低溫治療的區域於免疫缺陷小鼠腫瘤模式中，紫杉醇的抗腫瘤生長效果不受低溫治療的影響。綜合以上結果，局部低溫治療的早期介入可減輕由紫杉醇引起的周圍神經病變。低溫治療可作為對抗局部實體腫瘤癌症病患所引起的周邊神經病變之簡單和非藥物預防策略。
Chemotherapy-induced peripheral neuropathy (CIPN) is a severe adverse effect that occurs secondary to chemotherapeutic treatments and has no known preventive or therapeutic strategy. Therapeutic hypothermia has been shown to be effective in protecting against central and peripheral nervous system injuries. However, the effects of therapeutic hypothermia on CIPN have rarely been explored. We induced lower back hypothermia (LBH) in an established paclitaxel-induced CIPN rat model and found that the paclitaxel-induced impairments observed in behavioral, electrophysiological, and histological impairments were inhibited by LBH when applied at an optimal setting of 24°C to the sciatic nerve and initiated 90 minutes before paclitaxel infusion. Lower back hypothermia also inhibited the paclitaxel-induced activation of astroglia and microglia in the spinal cord, macrophage infiltration into and neuronal injury in the dorsal root ganglia and sciatic nerves, as well as the release of pro-inflammatory cytokines in the dorsal root ganglia, sciatic nerves, and spinal dorsal horn. Furthermore, LBH decreased the local blood flow and local tissue concentrations of paclitaxel. Finally, we induced unilateral hind limb hypothermia in paclitaxel-induced CIPN rat model and found that regional cooling is achieved with no effect on the contralateral side. Importantly, in NOD/SCID mice inoculated with cancer cells, the antiproliferative effect of paclitaxel was not affected by the distal application of hypothermia. In conclusion, our findings indicate that early exposure to regional hypothermia alleviates paclitaxel-induced peripheral neuropathy. Therapeutic hypothermia may therefore represent an economical and nonpharmaceutical preventive strategy for CIPN in patients with localized solid tumors.
Chinese abstract I
English abstract III
Table of Contents V
List of Tables VIII
List of Figures IX
1.1 Chemotherapy-induced peripheral neuropathy 1
1.2 Paclitaxel 2
1.3 Pathophysiological mechanisms of paclitaxel-induced peripheral neuropathy 2
1.3.1 Structural changes in peripheral nerves 3
1.3.2 Increased ion channels activity 3
1.3.3 Mitochondrial damage 4
1.3.4 Neuroinflammation and neuronal injury 4
1.4 Therapeutic strategies 5
1.5 Therapeutic hypothermia 6
1.6 Objectives and specific aims 7
Materials and methods 8
2.1 Animals 8
2.2 Paclitaxel infusion protocol 8
2.3 Behavioral assessment 9
2.3.1 Cold-water immersion test 10
2.3.2 Tail-flick test 10
2.3.3 Von Frey test 11
2.3.4 Rotarod performance test 11
2.4 Temperature measurements 12
2.5 Therapeutic hypothermia procedure 13
2.5.1 Lower back hypothermia 13
2.5.2 Unilateral hind limb hypothermia 13
2.6 Preparation of stock solutions, calibration standards, and quality control samples 14
2.7 Sample preparation for UPLC-MS/MS analysis 15
2.8 Ultra-performance liquid choromatography-tandem mass spectrometer analysis 16
2.9 Measurement of electrophysiology parameters 16
2.10 Imaging of vasculature hemodynamics in the rat sciatic nerve 18
2.11 Morphometric measurements of the sciatic and spinal nerves 19
2.12 Tissue processing and immunofluorescence staining 20
2.13 Immunofluorescence image analysis and quantification 21
2.14 Enzyme-linked immunosorbent assay 22
2.15 Cell cultures 22
2.16 Tumor xenograft model 23
2.17 Statistical analysis 23
3.1 Paclitaxel disturbs sensory and motor function in rats 25
3.2 Lower back hypothermia alleviates paclitaxel-induced neuropathy in rats 25
3.3 Lower back hypothermia prevents paclitaxel-induced peripheral nerve dysfunction 26
3.4 Lower back hypothermia reduces paclitaxel-induced pathological changes in the sciatic nerve 27
3.5 Paclitaxel treatment causes abnormalities in the axons of dorsal and ventral roots 28
3.6 Lower back hypothermia attenuates paclitaxel-induced glial activation and neuronal injury 28
3.7 Lower back hypothermia ameliorates paclitaxel-induced changes in cytokines expression 30
3.8 Hypothermia decreases local hemodynamics and drug distributions 30
3.9 Unilateral hind limb hypothermia alleviates paclitaxel-induced neuropathy in rats 31
3.10 Unilateral hind limb hypothermia prevents paclitaxel-induced peripheral nerve dysfunction 32
3.11 Unilateral hind limb hypothermia reduces paclitaxel-induced pathological changes in the sciatic nerve 32
3.12 Unilateral hind limb hypothermia ameliorates paclitaxel-induced changes in cytokines expression 32
3.13 Unilateral hind limb hypothermia decreases the toxic accumulation of paclitaxel in the sciatic nerve 33
3.14 Hypothermia does not interfere with the antitumor effect of paclitaxel 34
1. Meuser T, Pietruck C, Radbruch L, Stute P, Lehmann KA and Grond S. Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain. 2001;93:247-257.
2. Brown MRD, Ramirez JD and Farquhar-Smith P. Pain in cancer survivors. British Journal of Pain. 2014;8:139-153.
3. Quasthoff S and Hartung HP. Chemotherapy-induced peripheral neuropathy. Journal of Neurology. 2002;249:9-17.
4. Mielke S, Sparreboom A and Mross K. Peripheral neuropathy: a persisting challenge in paclitaxel-based regimes. European Journal of Cancer. 2006;42:24-30.
5. Kautio AL, Haanpaa M, Kautiainen H, Kalso E and Saarto T. Burden of chemotherapy-induced neuropathy--a cross-sectional study. Supportive Care in Cancer. 2011;19:1991-1996.
6. Smith EM, Cohen JA, Pett MA and Beck SL. The reliability and validity of a modified total neuropathy score-reduced and neuropathic pain severity items when used to measure chemotherapy-induced peripheral neuropathy in patients receiving taxanes and platinums. Cancer Nursing. 2010;33:173-183.
7. Han Y and Smith MT. Pathobiology of cancer chemotherapy-induced peripheral neuropathy (CIPN). Frontiers in Pharmacology. 2013;4:156.
8. Boyette-Davis JA, Cata JP, Driver LC, Novy DM, Bruel BM, Mooring DL, Wendelschafer-Crabb G, Kennedy WR and Dougherty PM. Persistent chemoneuropathy in patients receiving the plant alkaloids paclitaxel and vincristine. Cancer Chemotherapy and Pharmacology. 2013;71:619-626.
9. Krishnan AV, Goldstein D, Friedlander M and Kiernan MC. Oxaliplatin-induced neurotoxicity and the development of neuropathy. Muscle & Nerve. 2005;32:51-60.
10. Mols F, van de Poll-Franse LV, Vreugdenhil G, Beijers AJ, Kieffer JM, Aaronson NK and Husson O. Reference data of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-CIPN20 Questionnaire in the general Dutch population. European Journal of Cancer. 2016;69:28-38.
11. Hile ES, Fitzgerald GK and Studenski SA. Persistent mobility disability after neurotoxic chemotherapy. Physical Therapy. 2010;90:1649-1657.
12. Marshall TF, Zipp GP, Battaglia F, Moss R and Bryan S. Chemotherapy-induced-peripheral neuropathy, gait and fall risk in older adults following cancer treatment. Journal of Cancer Research and Practice. 2017;4:134-138.
13. Pignata S, De Placido S, Biamonte R, Scambia G, Di Vagno G, Colucci G, Febbraro A, Marinaccio M, Lombardi AV, Manzione L, Carteni G, Nardi M, Danese S, Valerio MR, de Matteis A, Massidda B, Gasparini G, Di Maio M, Pisano C and Perrone F. Residual neurotoxicity in ovarian cancer patients in clinical remission after first-line chemotherapy with carboplatin and paclitaxel: the Multicenter Italian Trial in Ovarian cancer (MITO-4) retrospective study. BMC Cancer. 2006;6:5.
14. Lexell J. Muscle structure and function in chronic neurological disorders: the potential of exercise to improve activities of daily living. Exercise and Sport Sciences Reviews. 2000;28:80-84.
15. Hershman DL, Lacchetti C, Dworkin RH, Lavoie Smith EM, Bleeker J, Cavaletti G, Chauhan C, Gavin P, Lavino A, Lustberg MB, Paice J, Schneider B, Smith ML, Smith T, Terstriep S, Wagner-Johnston N, Bak K and Loprinzi CL. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology. 2014;32:1941-1967.
16. Singla AK, Garg A and Aggarwal D. Paclitaxel and its formulations. International Journal of Pharmaceutics. 2002;235:179-192.
17. Rowinsky EK. The development and clinical utility of the taxane class of antimicrotubule chemotherapy agents. Annual Review of Medicine. 1997;48:353-374.
18. Jordan MA and Wilson L. Microtubules as a target for anticancer drugs. Nature Reviews Cancer. 2004;4:253-265.
19. Horwitz SB. Taxol (paclitaxel): mechanisms of action. Annals of Oncology. 1994;5 Suppl 6:S3-S6.
20. Peters CM, Jimenez-Andrade JM, Jonas BM, Sevcik MA, Koewler NJ, Ghilardi JR, Wong GY and Mantyh PW. Intravenous paclitaxel administration in the rat induces a peripheral sensory neuropathy characterized by macrophage infiltration and injury to sensory neurons and their supporting cells. Experimental Neurology. 2007;203:42-54.
21. Postma TJ, Vermorken JB, Liefting AJ, Pinedo HM and Heimans JJ. Paclitaxel-induced neuropathy. Annals of Oncology. 1995;6:489-494.
22. Lipton RB, Apfel SC, Dutcher JP, Rosenberg R, Kaplan J, Berger A, Einzig AI, Wiernik P and Schaumburg HH. Taxol produces a predominantly sensory neuropathy. Neurology. 1989;39:368-373.
23. van Gerven JM, Moll JW, van den Bent MJ, Bontenbal M, van der Burg ME, Verweij J and Vecht CJ. Paclitaxel (Taxol) induces cumulative mild neurotoxicity. European Journal of Cancer. 1994;30a:1074-1077.
24. Dougherty PM, Cata JP, Cordella JV, Burton A and Weng HR. Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients. Pain. 2004;109:132-142.
25. Park SB, Krishnan AV, Lin CS, Goldstein D, Friedlander M and Kiernan MC. Mechanisms underlying chemotherapy-induced neurotoxicity and the potential for neuroprotective strategies. Current Medicinal Chemistry. 2008;15:3081-3094.
26. Authier N, Balayssac D, Marchand F, Ling B, Zangarelli A, Descoeur J, Coudore F, Bourinet E and Eschalier A. Animal models of chemotherapy-evoked painful peripheral neuropathies. Neurotherapeutics. 2009;6:620-629.
27. Carozzi VA, Canta A and Chiorazzi A. Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms? Neuroscience letters. 2015;596:90-107.
28. Jacobs JM. Vascular permeability and neurotoxicity. Environmental Health Perspectives. 1978;26:107-116.
29. Pettersson CA, Sharma HS and Olsson Y. Vascular permeability of spinal nerve roots. A study in the rat with Evans blue and lanthanum as tracers. Acta Neuropathologica. 1990;81:148-154.
30. Melli G, Jack C, Lambrinos GL, Ringkamp M and Hoke A. Erythropoietin protects sensory axons against paclitaxel-induced distal degeneration. Neurobiology of Disease. 2006;24:525-530.
31. Yang IH, Siddique R, Hosmane S, Thakor N and Höke A. Compartmentalized microfluidic culture platform to study mechanism of paclitaxel-induced axonal degeneration. Experimental Neurology. 2009;218:124-128.
32. Boehmerle W, Huehnchen P, Peruzzaro S, Balkaya M and Endres M. Electrophysiological, behavioral and histological characterization of paclitaxel, cisplatin, vincristine and bortezomib-induced neuropathy in C57Bl/6 mice. Scientific Reports. 2014;4:6370.
33. Boyette-Davis J, Xin W, Zhang H and Dougherty PM. Intraepidermal nerve fiber loss corresponds to the development of taxol-induced hyperalgesia and can be prevented by treatment with minocycline. Pain. 2011;152:308-313.
34. Bennett GJ, Liu GK, Xiao WH, Jin HW and Siau C. Terminal arbor degeneration--a novel lesion produced by the antineoplastic agent paclitaxel. European Journal of Neuroscience. 2011;33:1667-1676.
35. Sahenk Z, Barohn R, New P and Mendell JR. Taxol neuropathy. Electrodiagnostic and sural nerve biopsy findings. Archives of Neurology. 1994;51:726-729.
36. Materazzi S, Fusi C, Benemei S, Pedretti P, Patacchini R, Nilius B, Prenen J, Creminon C, Geppetti P and Nassini R. TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism. Pflugers Archiv. 2012;463:561-569.
37. Nieto FR, Entrena JM, Cendan CM, Pozo ED, Vela JM and Baeyens JM. Tetrodotoxin inhibits the development and expression of neuropathic pain induced by paclitaxel in mice. Pain. 2008;137:520-531.
38. Xiao W, Boroujerdi A, Bennett GJ and Luo ZD. Chemotherapy-evoked painful peripheral neuropathy: analgesic effects of gabapentin and effects on expression of the alpha-2-delta type-1 calcium channel subunit. Neuroscience. 2007;144:714-720.
39. Musatov A and Robinson NC. Susceptibility of mitochondrial electron-transport complexes to oxidative damage. Focus on cytochrome c oxidase. Free Radical Research. 2012;46:1313-1326.
40. Flatters SJ and Bennett GJ. Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain. 2004;109:150-161.
41. Hara T, Chiba T, Abe K, Makabe A, Ikeno S, Kawakami K, Utsunomiya I, Hama T and Taguchi K. Effect of paclitaxel on transient receptor potential vanilloid 1 in rat dorsal root ganglion. Pain. 2013;154:882-889.
42. Alessandri-Haber N, Dina OA, Yeh JJ, Parada CA, Reichling DB and Levine JD. Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. Journal of Neuroscience. 2004;24:4444-4452.
43. Flatters SJ and Bennett GJ. Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain. 2006;122:245-257.
44. Flatters SJL and Bennett GJ. Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction. Pain. 2006;122:245-257.
45. Xiao WH, Zheng H, Zheng FY, Nuydens R, Meert TF and Bennett GJ. Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat. Neuroscience. 2011;199:461-469.
46. Jin HW, Flatters SJ, Xiao WH, Mulhern HL and Bennett GJ. Prevention of paclitaxel-evoked painful peripheral neuropathy by acetyl-L-carnitine: effects on axonal mitochondria, sensory nerve fiber terminal arbors, and cutaneous Langerhans cells. Experimental Neurology. 2008;210:229-237.
47. Andre N, Braguer D, Brasseur G, Goncalves A, Lemesle-Meunier D, Guise S, Jordan MA and Briand C. Paclitaxel induces release of cytochrome c from mitochondria isolated from human neuroblastoma cells. Cancer Research. 2000;60:5349-5353.
48. Zheng H, Xiao WH and Bennett GJ. Functional deficits in peripheral nerve mitochondria in rats with paclitaxel- and oxaliplatin-evoked painful peripheral neuropathy. Experimental Neurology. 2011;232:154-161.
49. Milligan ED and Watkins LR. Pathological and protective roles of glia in chronic pain. Nature Reviews Neuroscience. 2009;10:23-36.
50. Watkins LR and Maier SF. Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiological Reviews. 2002;82:981-1011.
51. Gosselin RD, Suter MR, Ji RR and Decosterd I. Glial cells and chronic pain. The Neuroscientist. 2010;16:519-531.
52. Hald A, Nedergaard S, Hansen RR, Ding M and Heegaard AM. Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain. European Journal of Pain. 2009;13:138-45.
53. Robinson CR, Zhang H and Dougherty PM. Astrocytes, but not microglia, are activated in oxaliplatin and bortezomib-induced peripheral neuropathy in the rat. Neuroscience. 2014;274:308-317.
54. Yoon SY, Robinson CR, Zhang H and Dougherty PM. Spinal astrocyte gap junctions contribute to oxaliplatin-induced mechanical hypersensitivity. The Journal of Pain. 2013;14:205-214.
55. Ledeboer A, Jekich BM, Sloane EM, Mahoney JH, Langer SJ, Milligan ED, Martin D, Maier SF, Johnson KW, Leinwand LA, Chavez RA and Watkins LR. Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats. Brain, Behavior, and Immunity. 2007;21:686-698.
56. Doyle T, Chen Z, Muscoli C, Bryant L, Esposito E, Cuzzocrea S, Dagostino C, Ryerse J, Rausaria S, Kamadulski A, Neumann WL and Salvemini D. Targeting the overproduction of peroxynitrite for the prevention and reversal of paclitaxel-induced neuropathic pain. Journal of Neuroscience. 2012;32:6149-6160.
57. Gornstein E and Schwarz TL. The paradox of paclitaxel neurotoxicity: Mechanisms and unanswered questions. Neuropharmacology. 2014;76 Pt A:175-183.
58. Cavaletti G, Cavalletti E, Oggioni N, Sottani C, Minoia C, D'Incalci M, Zucchetti M, Marmiroli P and Tredici G. Distribution of paclitaxel within the nervous system of the rat after repeated intravenous administration. Neurotoxicology. 2000;21:389-393.
59. Peters CM, Jimenez-Andrade JM, Kuskowski MA, Ghilardi JR and Mantyh PW. An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat. Brain Research. 2007;1168:46-59.
60. Jimenez-Andrade JM, Peters CM, Mejia NA, Ghilardi JR, Kuskowski MA and Mantyh PW. Sensory neurons and their supporting cells located in the trigeminal, thoracic and lumbar ganglia differentially express markers of injury following intravenous administration of paclitaxel in the rat. Neuroscience Letters. 2006;405:62-67.
61. Siau C, Xiao W and Bennett GJ. Paclitaxel- and vincristine-evoked painful peripheral neuropathies: loss of epidermal innervation and activation of Langerhans cells. Experimental Neurology. 2006;201:507-514.
62. Liu CC, Lu N, Cui Y, Yang T, Zhao ZQ, Xin WJ and Liu XG. Prevention of paclitaxel-induced allodynia by minocycline: Effect on loss of peripheral nerve fibers and infiltration of macrophages in rats. Molecular Pain. 2010;6:76.
63. Sisignano M, Baron R, Scholich K and Geisslinger G. Mechanism-based treatment for chemotherapy-induced peripheral neuropathic pain. Nature Reviews Neurology. 2014;10:694-707.
64. Tsai YJ, Huang CT, Lin SC and Yeh JH. Effects of regional and whole-body hypothermic treatment before and after median nerve injury on neuropathic pain and glial activation in rat cuneate nucleus. Anesthesiology. 2012;116:415-431.
65. Ha KY and Kim YH. Neuroprotective effect of moderate epidural hypothermia after spinal cord injury in rats. Spine. 2008;33:2059-2065.
66. Saito T, Saito S, Yamamoto H and Tsuchida M. Neuroprotection following mild hypothermia after spinal cord ischemia in rats. Journal of Vascular Surgery. 2013;57:173-181.
67. Wang CF, Zhao CC, Jiang G, Gu X, Feng JF and Jiang JY. The Role of Posttraumatic Hypothermia in Preventing Dendrite Degeneration and Spine Loss after Severe Traumatic Brain Injury. Scientific Reports. 2016;6:37063.
68. Liu P, Yang R and Zuo Z. Application of a novel rectal cooling device in hypothermia therapy after cerebral hypoxia-ischemia in rats. BMC Anesthesiology. 2015;16:77.
69. Grulova I, Slovinska L, Nagyova M, Cizek M and Cizkova D. The effect of hypothermia on sensory-motor function and tissue sparing after spinal cord injury. Spine. 2013;13:1881-1891.
70. Ok JH, Kim YH and Ha KY. Neuroprotective effects of hypothermia after spinal cord injury in rats: comparative study between epidural hypothermia and systemic hypothermia. Spine. 2012;37:e1551-1559.
71. Liu T, Zhao DX, Cui H, Chen L, Bao YH, Wang Y and Jiang JY. Therapeutic hypothermia attenuates tissue damage and cytokine expression after traumatic brain injury by inhibiting necroptosis in the rat. Scientific Reports. 2016;6:24547.
72. Jin Y, Lin Y, Feng JF, Jia F, Gao GY and Jiang JY. Moderate Hypothermia Significantly Decreases Hippocampal Cell Death Involving Autophagy Pathway after Moderate Traumatic Brain Injury. Journal of Neurotrauma. 2015;32:1090-1100.
73. Barbosa MO, Cristante AF, Santos GB, Ferreira R, Marcon RM and Barros Filho TE. Neuroprotective effect of epidural hypothermia after spinal cord lesion in rats. Clinics. 2014;69:559-564.
74. Yenari MA and Han HS. Neuroprotective mechanisms of hypothermia in brain ischaemia. Nature Reviews Neuroscience. 2012;13:267-278.
75. Klahr AC, Nadeau CA and Colbourne F. Temperature Control in Rodent Neuroprotection Studies: Methods and Challenges. Therapeutic Hypothermia and Temperature Management. 2017;7:42-49.
76. Ohta H, Terao Y, Shintani Y and Kiyota Y. Therapeutic time window of post-ischemic mild hypothermia and the gene expression associated with the neuroprotection in rat focal cerebral ischemia. Neuroscience Research. 2007;57:424-433.
77. Wood T, Osredkar D, Puchades M, Maes E, Falck M, Flatebo T, Walloe L, Sabir H and Thoresen M. Treatment temperature and insult severity influence the neuroprotective effects of therapeutic hypothermia. Scientific Reports. 2016;6:23430.
78. Sundar R, Bandla A, Tan SS, Liao LD, Kumarakulasinghe NB, Jeyasekharan AD, Ow SG, Ho J, Tan DS, Lim JS, Vijayan J, Therimadasamy AK, Hairom Z, Ang E, Ang S, Thakor NV, Lee SC and Wilder-Smith EP. Limb Hypothermia for Preventing Paclitaxel-Induced Peripheral Neuropathy in Breast Cancer Patients: A Pilot Study. Frontiers in Oncology. 2016;6:274.
79. Nair AB and Jacob S. A simple practice guide for dose conversion between animals and human. Journal of Basic and Clinical Pharmacy. 2016;7:27-31.
80. Bannon AW and Malmberg AB. Models of nociception: hot-plate, tail-flick, and formalin tests in rodents. Current Protocols in Neuroscience. 2007;Chapter 8:Unit 8.9.
81. Cunha TM, Verri WA, Jr., Vivancos GG, Moreira IF, Reis S, Parada CA, Cunha FQ and Ferreira SH. An electronic pressure-meter nociception paw test for mice. Brazilian Journal of Medical and Biological Research. 2004;37:401-407.
82. Chaplan SR, Bach FW, Pogrel JW, Chung JM and Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. Journal of Neuroscience Methods. 1994;53:55-63.
83. Huehnchen P, Boehmerle W and Endres M. Assessment of Paclitaxel Induced Sensory Polyneuropathy with “Catwalk” Automated Gait Analysis in Mice. PLoS One. 2013;8:e76772.
84. Schulz A, Walther C, Morrison H and Bauer R. In Vivo Electrophysiological Measurements on Mouse Sciatic Nerves. Journal of Visualized Experiments. 2014;86:e51181.
85. Xia RH, Yosef N and Ubogu EE. Dorsal caudal tail and sciatic motor nerve conduction studies in adult mice: technical aspects and normative data. Muscle & Nerve. 2010;41:850-856.
86. Liao LD, Lin CT, Shih YYI, Lai HY, Zhao WT, Duong TQ, Chang JY, Chen YY and Li ML. Investigation of the cerebral hemodynamic response function in single blood vessels by functional photoacoustic microscopy. Journal of Biomedical Optics. 2012;17:061210-1-061210-10.
87. Liao LD, Li ML, Lai HY, Shih YY, Lo YC, Tsang S, Chao PC, Lin CT, Jaw FS and Chen YY. Imaging brain hemodynamic changes during rat forepaw electrical stimulation using functional photoacoustic microscopy. NeuroImage. 2010;52:562-570.
88. Zhang HF, Maslov K and Wang LV. In vivo imaging of subcutaneous structures using functional photoacoustic microscopy. Nature Protocols. 2007;2:797-804.
89. Rupp A, Dornseifer U, Fischer A, Schmahl W, Rodenacker K, Jutting U, Gais P, Biemer E, Papadopulos N and Matiasek K. Electrophysiologic assessment of sciatic nerve regeneration in the rat: surrounding limb muscles feature strongly in recordings from the gastrocnemius muscle. Journal of Neuroscience Methods. 2007;166:266-277.
90. Ghnenis AB, Czaikowski RE, Zhang ZJ and Bushman JS. Toluidine Blue Staining of Resin-Embedded Sections for Evaluation of Peripheral Nerve Morphology. Journal of visualized experiments. 2018;137:e58031.
91. Zaimi A, Duval T, Gasecka A, Cote D, Stikov N and Cohen-Adad J. AxonSeg: Open Source Software for Axon and Myelin Segmentation and Morphometric Analysis. Frontiers in Neuroinformatics. 2016;10:37.
92. Makker PGS, Duffy SS, Lees JG, Perera CJ, Tonkin RS, Butovsky O, Park SB, Goldstein D and Moalem-Taylor G. Characterisation of Immune and Neuroinflammatory Changes Associated with Chemotherapy-Induced Peripheral Neuropathy. PLoS One. 2017;12:e0170814.
93. Peters CM, Jimenez-Andrade JM, Kuskowski MA, Ghilardi JR and Mantyh PW. An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat. Brain Research. 2007;1168:46-59.
94. Tasnim A, Rammelkamp Z, Slusher AB, Wozniak K, Slusher BS and Farah MH. Paclitaxel causes degeneration of both central and peripheral axon branches of dorsal root ganglia in mice. BMC Neuroscience. 2016;17:47.
95. Scholz J and Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nature Neuroscience. 2007;10:1361-1368.
96. Uceyler N, Kafke W, Riediger N, He L, Necula G, Toyka KV and Sommer C. Elevated proinflammatory cytokine expression in affected skin in small fiber neuropathy. Neurology. 2010;74:1806-1813.
97. Argyriou AA, Bruna J, Marmiroli P and Cavaletti G. Chemotherapy-induced peripheral neurotoxicity (CIPN): an update. Critical Reviews in Oncology/Hematology. 2012;82:51-77.
98. Robinson R. For Some Sensory Neurons, Motor Response Shapes Their Output. PLoS Biology. 2006;4:e429.
99. Wang MS, Davis AA, Culver DG, Wang Q, Powers JC and Glass JD. Calpain inhibition protects against Taxol-induced sensory neuropathy. Brain. 2004;127:671-679.
100. Rowinsky EK, Eisenhauer EA, Chaudhry V, Arbuck SG and Donehower RC. Clinical toxicities encountered with paclitaxel (Taxol). Seminars in Oncology. 1993;20:1-15.
101. Forsyth PA, Balmaceda C, Peterson K, Seidman AD, Brasher P and DeAngelis LM. Prospective study of paclitaxel-induced peripheral neuropathy with quantitative sensory testing. Journal of Neuro-Oncology. 1997;35:47-53.
102. Kerckhove N, Collin A, Condé S, Chaleteix C, Pezet D and Balayssac D. Long-Term Effects, Pathophysiological Mechanisms, and Risk Factors of Chemotherapy-Induced Peripheral Neuropathies: A Comprehensive Literature Review. Frontiers in Pharmacology. 2017;8:86.
103. Bandla A, Sundar R, Liao LD, Sze Hui Tan S, Lee SC, Thakor NV and Wilder-Smith EP. Hypothermia for preventing chemotherapy-induced neuropathy - a pilot study on safety and tolerability in healthy controls. Acta Oncologica. 2016;55:430-436.
104. Li J, Wei GH, Huang H, Lan YP, Liu B, Liu H, Zhang W and Zuo YX. Nerve injury-related autoimmunity activation leads to chronic inflammation and chronic neuropathic pain. Anesthesiology. 2013;118:416-429.
105. Sparreboom A, van Tellingen O, Nooijen WJ and Beijnen JH. Tissue distribution, metabolism and excretion of paclitaxel in mice. Anti-Cancer Drugs. 1996;7:78-86.
106. Motl S, Zhuang Y, Waters CM and Stewart CF. Pharmacokinetic considerations in the treatment of CNS tumours. Clinical Pharmacokinetics. 2006;45:871-903.
107. Eiseman JL, Eddington ND, Leslie J, MacAuley C, Sentz DL, Zuhowski M, Kujawa JM, Young D and Egorin MJ. Plasma pharmacokinetics and tissue distribution of paclitaxel in CD2F1 mice. Cancer Chemotherapy and Pharmacology. 1994;34:465-471.
108. Jimenez-Andrade JM, Herrera MB, Ghilardi JR, Vardanyan M, Melemedjian OK and Mantyh PW. Vascularization of the dorsal root ganglia and peripheral nerve of the mouse: Implications for chemical-induced peripheral sensory neuropathies. Molecular Pain. 2008;4:10-10.
109. Alva N, Palomeque J and Carbonell T. Oxidative stress and antioxidant activity in hypothermia and rewarming: can RONS modulate the beneficial effects of therapeutic hypothermia? Oxidative Medicine and Cellular Longevity. 2013;2013:e957054.
110. Du G, Liu Y, Li J, Liu W, Wang Y and Li H. Hypothermic microenvironment plays a key role in tumor immune subversion. International Immunopharmacology. 2013;17:245-253.