Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 3/2020

01-09-2020 | Neuropathic Pain | Original Article

Aripiprazole prevents from development of vincristine-induced neuropathic nociception by limiting neural NOS overexpression and NF-kB hyperactivation

Authors: Mina Khalilzadeh, Fereshteh Hassanzadeh, Helia Aghamiri, Ahmad Reza Dehpour, Hamed Shafaroodi

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2020

Login to get access

Abstract

Purpose

Increased nitric oxide (NO) synthesis and NF-kB activation have been shown as critical players in the pathophysiology of vincristine-induced peripheral neuropathy. Consistently, neural nitric oxide synthase (nNOS) inhibitors alleviated the neuropathic pain. Previous studies demonstrated that aripiprazole is capable of modulating NO synthesis and also has been reported its modulatory effect on NF-kB activity.

Methods

Aripiprazole was administered daily to the male Wistar rats at the same time with establishing neuropathic model by I.P. injection of vincristine every 2 days, over 2 weeks. Efficacy of aripiprazole in suppressing the development of neuropathy was evaluated by assessing changes in body weight, mechanical threshold, withdrawal latency, sciatic nerve conduction velocity (SNCV), and compound motor action potential (CMAP) characteristics. Expression of nNOS and NF-kB activation were evaluated by western blotting

Results

Rats receiving aripiprazole during neuropathy establishment period demonstrated a normal weight gain pattern, a significantly higher mechanical withdrawal threshold, and SNCV compared to vincristine-treated group. Furthermore, the amplitude and area of CMAP were significantly higher in aripiprazole group. Western blotting demonstrated a significantly reduced expression of nNOS and NF-kB activation in dorsal root ganglia of aripiprazole co-treated rats.

Conclusion

In conclusion, aripiprazole effectively prevents from vincristine-induced neuropathy by limiting nNOS overexpression and NF-kB hyperactivation.
Appendix
Available only for authorised users
Literature
1.
2.
Mora E, Smith EML, Donohoe C, Hertz DL (2016) Vincristine-induced peripheral neuropathy in pediatric cancer patients. Am J Cancer Res 6(11):2416PubMedPubMedCentral
3.
Nie B, Zhang S, Huang Z, Huang J, Chen X, Zheng Y et al (2017) Synergistic interaction between dexmedetomidine and ulinastatin against vincristine-induced neuropathic pain in rats. J Pain 18(11):1354–1364PubMed
4.
Gewandter JS, Mohile SG, Heckler CE, Ryan JL, Kirshner JJ, Flynn PJ et al (2014) A phase III randomized, placebo-controlled study of topical amitriptyline and ketamine for chemotherapy-induced peripheral neuropathy (CIPN): a University of Rochester CCOP study of 462 cancer survivors. Support Care Cancer 22(7):1807–1814PubMedPubMedCentral
5.
Hammack JE, Michalak JC, Loprinzi CL, Sloan JA, Novotny PJ, Soori GS et al (2002) Phase III evaluation of nortriptyline for alleviation of symptoms of cis-platinum-induced peripheral neuropathy. Pain 98(1–2):195–203PubMed
6.
Park SB, Goldstein D, Krishnan AV, Lin CSY, Friedlander ML, Cassidy J et al (2013) Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin. 63(6):419–437PubMed
7.
Pui C-H, Evans WE (2006) Treatment of acute lymphoblastic leukemia. N Engl J Med 354(2):166–178PubMed
8.
Geisler S, Doan RA, Strickland A, Huang X, Milbrandt J, DiAntonio A (2016) Prevention of vincristine-induced peripheral neuropathy by genetic deletion of SARM1 in mice. Brain 139(12):3092–3108PubMedPubMedCentral
9.
Higuera ES, Luo ZD (2004) A rat pain model of vincristine-induced neuropathy. Pain Research 91–8
10.
Jin X-G, He S-Q, Yan X-T, Zhang G, Wan L, Wang J et al (2009) Variants of neural nitric oxide synthase in the spinal cord of neuropathic rats and their effects on nuclear factor-κB (NF-κB) activity in PC12 cells. J Pain 10(1):80–89PubMed
11.
Čı́žková D, Lukáčová N, Maršala M, Maršala J (2002) Neuropathic pain is associated with alterations of nitric oxide synthase immunoreactivity and catalytic activity in dorsal root ganglia and spinal dorsal horn. Brain Res Bull 58(2):161–171PubMed
12.
Gordh T, Sharma H, Alma P, Westman J (1998) Spinal nerve lesion induces upregulation of neuronal nitric oxide synthase in the spinal cord. Amino Acids 14(1–3):105–112PubMed
13.
O’Rielly DD, Loomis CW (2006) Pain and regional anesthesia-increased expression of cyclooxygenase and nitric oxide isoforms, and exaggerated sensitivity to prostaglandin E2, in the rat lumbar spinal cord 3 days after L5–L6. Anesthesiol-Hagerstown 104(2):328–337
14.
Lui P-W, Lee C-H (2004) Preemptive effects of intrathecal cyclooxygenase inhibitor or nitric oxide synthase inhibitor on thermal hypersensitivity following peripheral nerve injury. Life Sci 75(21):2527–2538PubMed
15.
Mabuchi T, Matsumura S, Okuda-Ashitaka E, Kitano T, Kojima H, Nagano T et al (2003) Attenuation of neuropathic pain by the nociceptin/orphanin FQ antagonist JTC-801 is mediated by inhibition of nitric oxide production. Eur J Neurosci 17(7):1384–1392PubMed
16.
Guan Y, Yaster M, Raja SN, Tao Y-X (2007) Genetic knockout and pharmacologic inhibition of neuronal nitric oxide synthase attenuate nerve injury-induced mechanical hypersensitivity in mice. Mol Pain 3(1):29PubMedPubMedCentral
17.
Ma W, Bisby MA (1998) Increased activation of nuclear factor kappa B in rat lumbar dorsal root ganglion neurons following partial sciatic nerve injuries. Brain Res 797(2):243–254PubMed
18.
Sun T, Song W-G, Fu Z-J, Liu Z-H, Liu Y-M, Yao S-L (2006) Alleviation of neuropathic pain by intrathecal injection of antisense oligonucleotides to p65 subunit of NF-κB. BJA Br J Anaesth 97(4):553–558PubMed
19.
Tegeder I, Niederberger E, Schmidt R, Kunz S, Gühring H, Ritzeler O et al (2004) Specific inhibition of IκB kinase reduces hyperalgesia in inflammatory and neuropathic pain models in rats. J Neurosci 24(7):1637–1645PubMedPubMedCentral
20.
Millan MJ (2002) Descending control of pain. Prog Neurobiol 66(6):355–474PubMed
21.
Ormseth MJ, Scholz BA, Boomershine CS (2011) Duloxetine in the management of diabetic peripheral neuropathic pain. Patient Prefer Adher 5:343
22.
Pergolizzi JV Jr, Raffa RB, Taylor R Jr, Rodriguez G, Nalamachu S, Langley P (2013) A review of duloxetine 60 mg once-daily dosing for the management of diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain due to chronic osteoarthritis pain and low back pain. Pain Pract 13(3):239–252PubMed
23.
Bardin L, Tarayre J-P, Koek W, Colpaert FC (2001) In the formalin model of tonic nociceptive pain, 8-OH-DPAT produces 5-HT1A receptor-mediated, behaviorally specific analgesia. Eur J Pharmacol 421(2):109–114PubMed
24.
Colpaert FC, Wu W-P, Hao J-X, Royer I, Sautel F, Wiesenfeld-Hallin Z et al (2004) High-efficacy 5-HT1A receptor activation causes a curative-like action on allodynia in rats with spinal cord injury. Eur J Pharmacol 497(1):29–33PubMed
25.
Colpaert FC (2006) 5-HT (1A) receptor activation: new molecular and neuroadaptive mechanisms of pain relief. Curr Opin Investig Drugs (Lond Engl 2000) 7(1):40–47
26.
Guo Z-G, Jia X-P, Su X-J, Li P, Hao J-H (2013) Gastrodin attenuates vincristine-induced mechanical hyperalgesia through serotonin 5-HT1A receptors. Bangladesh J Pharmacol 8(4):414–419
27.
Potvin S, Grignon S, Marchand S (2009) Human evidence of a supra-spinal modulating role of dopamine on pain perception. Synapse 63(5):390–402PubMed
28.
Tiemann L, Heitmann H, Schulz E, Baumkötter J, Ploner M (2014) Dopamine precursor depletion influences pain affect rather than pain sensation. PLoS One 9(4):e96167PubMedPubMedCentral
29.
Wood PB (2008) Role of central dopamine in pain and analgesia. Expert Rev Neurother 8(5):781–797PubMed
30.
Dennis SG, Melzack R (1983) Effects of cholinergic and dopaminergic agents on pain and morphine analgesia measured by three pain tests. Exp Neurol 81(1):167–176PubMed
31.
Frussa-Filho R, Rocha J, Conceição IMd, Mello C, Pereira M (1996) Effects of dopaminergic agents on visceral pain measured by the mouse writhing test. Archives Internationales de Pharmacodynamie et de Therapie 331(1):74–93PubMed
32.
Morgan MJ, Franklin KB (1991) Dopamine receptor subtypes and formalin test analgesia. Pharmacol Biochem Behav 40(2):317–322PubMed
33.
Sarkis R, Saadé N, Atweh S, Jabbur S, Al-Amin H (2011) Chronic dizocilpine or apomorphine and development of neuropathy in two rat models I: behavioral effects and role of nucleus accumbens. Exp Neurol 228(1):19–29PubMed
34.
35.
36.
37.
Gil CH, Kim YR, Lee HJ, Jung DH, Shin HK, Choi BT (2018) Aripiprazole exerts a neuroprotective effect in mouse focal cerebral ischemia. Exp Ther Med 15(1):745–750PubMed
38.
Ghirardi O, Vertechy M, Vesci L, Canta A, Nicolini G, Galbiati S et al (2005) Chemotherapy-induced allodinia: neuroprotective effect of acetyl-l-carnitine. In Vivo 19(3):631–637 (Epub 2005/05/07 PubMed PMID: 15875786)PubMed
39.
40.
41.
42.
Tepper SJ, Rapoport AM, Sheftell FD (2002) Mechanisms of action of the 5-HT1B/1D receptor agonists. Arch Neurol 59(7):1084–1088PubMed
43.
Djaldetti R, Hart J, Alexandrova S, Cohen S, Beilin BZ, Djaldetti M et al (1996) Vincristine-induced alterations in Schwann cells of mouse peripheral nerve. Am J Hematol 52(4):254–257PubMed
44.
Konings PN, Philipsen RL, Veeneman GH, Ruigt GF (1994) α-Sialyl cholesterol increases laminin in Schwann cell cultures and attenuates cytostatic drug-induced reduction of laminin. Brain Res 654(1):118–128PubMed
45.
Shamash S, Reichert F, Rotshenker S (2002) The cytokine network of Wallerian degeneration: tumor necrosis factor-α, interleukin-1α, and interleukin-1β. J Neurosci 22(8):3052–3060PubMedPubMedCentral
46.
Thacker MA, Clark AK, Marchand F, McMahon SB (2007) Pathophysiology of peripheral neuropathic pain: immune cells and molecules. Anesth Analg 105(3):838–847PubMed
47.
Khalilzadeh M, Panahi G, Rashidian A, Hadian MR, Abdollahi A, Afshari K et al (2018) The protective effects of sumatriptan on vincristine-induced peripheral neuropathy in a rat model. Neurotoxicology 67:279–286PubMed
48.
Tofaris GK, Patterson PH, Jessen KR, Mirsky R (2002) Denervated Schwann cells attract macrophages by secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process regulated by interleukin-6 and LIF. J Neurosci 22(15):6696–6703PubMedPubMedCentral
49.
White FA, Sun J, Waters SM, Ma C, Ren D, Ripsch M et al (2005) Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. Proc Natl Acad Sci USA 102(39):14092–14097PubMed
50.
Bujalska M, Gumulka SW (2008) Effect of cyclooxygenase and nitric oxide synthase inhibitors on vincristine induced hyperalgesia in rats. Pharmacol Rep 60(5):735PubMed
51.
Marchand F, Perretti M, McMahon SB (2005) Role of the immune system in chronic pain. Nat Rev Neurosci 6(7):521PubMed
52.
Martucci C, Trovato AE, Costa B, Borsani E, Franchi S, Magnaghi V et al (2008) The purinergic antagonist PPADS reduces pain related behaviours and interleukin-1β, interleukin-6, iNOS and nNOS overproduction in central and peripheral nervous system after peripheral neuropathy in mice. Pain® 137(1):81–95
53.
Nicholson R, Small J, Dixon A, Spanswick D, Lee K (2003) Serotonin receptor mRNA expression in rat dorsal root ganglion neurons. Neurosci Lett 337(3):119–122PubMed
54.
Kihara T, Shimohama S, Sawada H, Honda K, Nakamizo T, Kanki R et al (2002) Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade. J Neurosci Res 70(3):274–282PubMed
55.
Kamei J, Tamura N, Saitoh A (2005) Possible involvement of the spinal nitric oxide/cGMP pathway in vincristine-induced painful neuropathy in mice. Pain 117(1–2):112–120PubMed
56.
Kim H, Sasaki T, Maeda K, Koya D, Kashiwagi A, Yasuda H (2003) Protein kinase Cβ selective inhibitor LY333531 attenuates diabetic hyperalgesia through ameliorating cGMP level of dorsal root ganglion neurons. Diabetes 52(8):2102–2109PubMed
57.
Sasaki T, Yasuda H, Maeda K, Kikkawa R (1998) Hyperalgesia and decreased neuronal nitric oxide synthase in diabetic rats. Neuroreport 9(2):177
58.
Sousa AM, Prado WA (2001) The dual effect of a nitric oxide donor in nociception. Brain Res 897(1–2):9–19PubMed
59.
Kato T, Mizoguchi Y, Monji A, Horikawa H, Suzuki SO, Seki Y et al (2008) Inhibitory effects of aripiprazole on interferon-γ-induced microglial activation via intracellular Ca2+ regulation in vitro. J Neurochem 106(2):815–825PubMed
60.
Shafaroodi H, Oveisi S, Hosseini M, Niknahad H, Moezi L (2015) The effect of acute aripiprazole treatment on chemically and electrically induced seizures in mice: the role of nitric oxide. Epilepsy Behav 48:35–40PubMed
61.
Stefano GB, Goumon Y, Bilfinger TV, Welters ID, Cadet P (2000) Basal nitric oxide limits immune, nervous and cardiovascular excitation: human endothelia express a mu opiate receptor. Prog Neurobiol 60(6):513–530PubMed
62.
Welters ID, Menzebach A, Goumon Y, Cadet P, Menges T, Hughes TK et al (2000) Morphine inhibits NF-κB nuclear binding in human neutrophils and monocytes by a nitric oxide–dependent mechanism. Anesthesiol J Am Soc Anesthesiol 92(6):1677–1684
Metadata
Title
Aripiprazole prevents from development of vincristine-induced neuropathic nociception by limiting neural NOS overexpression and NF-kB hyperactivation
Authors
Mina Khalilzadeh
Fereshteh Hassanzadeh
Helia Aghamiri
Ahmad Reza Dehpour
Hamed Shafaroodi
Publication date
01-09-2020
Publisher
Springer Berlin Heidelberg
Published in
Cancer Chemotherapy and Pharmacology / Issue 3/2020
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-020-04127-8

Other articles of this Issue 3/2020

Cancer Chemotherapy and Pharmacology 3/2020 Go to the issue

Original Article

Novel biomimetic dual-mode nanodroplets as ultrasound contrast agents with potential ability of precise detection and photothermal ablation of tumors

Original Article

Asian race and origin have no clinically meaningful effects on polatuzumab vedotin pharmacokinetics in patients with relapsed/refractory B-cell non-Hodgkin lymphoma

Original Article

Identifying optimal magnesium replenishment points based on risk of severe hypomagnesemia in colorectal cancer patients treated with cetuximab or panitumumab

Original Article

Temozolomide desensitization followed by metronomic dosing in patients with hypersensitivity

Original Article

Towards better combination regimens of cytarabine and FLT3 inhibitors in acute myeloid leukemia

Original Article

Effect of high-fat diet on the pharmacokinetics and safety of flumatinib in healthy Chinese subjects
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits