Effects of Lithium on Peripheral Neuropathy Induced by Vincristine in Rats

  • Houman Alimoradi Toxicology Research Center, Jundishapur University of Medical Sciences, Ahvaz, Iran.
  • Nasir Pourmohammadi Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Shahram Ejtemaei Mehr Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Gholamreza Hassanzadeh Department of Anatomy, Tehran University of Medical Sciences, Tehran, Iran.
  • Mohammad Reza Hadian Brain and Spinal Injury Repair Research center, Tehran University of Medical Sciences, Tehran, Iran.
  • Mohammad Sharifzadeh Department of Toxicology and Pharmacology, Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran, Iran.
  • Azam Bakhtiarian Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
  • Ahmad Reza Dehpour Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Keywords:
Vincristine, Lithium chloride, Rat, Peripheral neuropathy

Abstract

Vincristine (VCR) as a frequently used antimitotic agent which is commonly prescribed for wide spectrum of neoplasm, causes mixed sensorimotor neuropathy. Several evidences show lithium could be a neuroprotective agent, therefore to assess whether a pretreatment and at subtherapeutic dose it could prevent the peripheral neuropathy produced by VCR, rats were treated with VCR 0.1mg/kg i.p. for 3 alternative doses and / or lithium chloride (20mg/kg or 40 mg/kg i.p. daily from the first day to the day of sacrifice). Erythrocyte lithium concentration (ELC) and plasma lithium concentration (PLC) were measured at the seventh day of study and the day of scarification. After seventh day of lithium administration, PLC and ELC reached to a steady state at subtheraputic dose and they did not significantly change at normal housing situation. Hot plate, open field test and nerve conduction velocity were used to evaluate the sensory and motor neuropathy. Only VCR treated rats showed behavioral, electrophysiological and histological evidences of a mixed sensorimotor neuropathy by significant increase in hot plate latencies and a marked decrease in total distance moved and conduction velocities in both sensory and motor nerves. Lithium at the dose of 20mg/kg and specially 40mg/kg robustly reduced the rate of mortality, general toxicity and was able to ameliorate mixed sensorimotor neuropathy induced by VCR. These results suggest that lithium at dose of 20mg/kg and 40 mg/kg, potentially by its effects on cell survival pathways such as inhibition of glycogen synthase kinase-3 (GSK3β), can prevent both motor and sensory components of VCR neuropathy.

References

Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non- Hodgkin's lymphoma. N Engl J Med 1993;328(14):1002-6.

Kantarjian HM, Walters RS, Keating MJ, Smith TL, O'Brien S, Estey EH, Huh YO, Spinolo J, Dicke K, Barlogie B. Results of the vincristine, doxorubicin, and dexamethasone regimen in adults with standard- and highrisk acute lymphocytic leukemia. J Clin Oncol 1990;8(6):994-1004.

Owellen RJ, Owens AH Jr, Donigian DW. The binding of vincristine, vinblastine and colchicine to tubulin. Biochem Biophys Res Commun 1972;47(4):685-91.

Rosenthal S, Kaufman S. Vincristine neurotoxicity. Ann Intern Med 1974;80(6):733-7.

Chuang DM, Chen RW, Chalecka-Franaszek E, Ren M, Hashimoto R, Senatorov V, Kanai H, Hough C, Hiroi T, Leeds P. Neuroprotective effects of lithium in cultured cells and animal models of diseases. Bipolar Disord 2002;4(2):129-36.

Zhu ZF, Wang QG, Han BJ, William CP. Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice. Brain Res Bull 2010;83(5):272-7.

Pourmohammadi N, Alimoradi H, Mehr SE, Hassanzadeh G, Hadian MR, Sharifzadeh M, Bakhtiarian A, Dehpour AR. Lithium attenuates peripheral neuropathy induced by paclitaxel in rats. Basic Clin Pharmacol Toxicol 2012;110(3):231-7.

Petrini M, Vaglini F, Cervetti G, Cavalletti M, Sartucci F, Murri L, Corsini GU. Is lithium able to reverse neurological damage induced by vinca alkaloids? (Short communication. J Neural Transm 1999;106(5-6):569-75.

Dashti-Khavidaki S, Ahmadi-Abhari SA, Ghaeli P, Farsam H, Dehpour AR, Mahdavi-Mazdeh M, Hatmi ZN, Fahimi F. Relationship between erythrocyte lithium concentration and renal concentrating capacity. J Clin Pharm Ther 2003;28(6):451-6.

Aloe L, Manni L, Properzi F, De Santis S, Fiore M. Evidence that nerve growth factor promotes the recovery of peripheral neuropathy induced in mice by cisplatin: behavioral, structural and biochemical analysis. Auton Neurosci 2000;86(1-2):84-93.

Jadavji NM, Kolb B, Metz GA. Enriched environment improves motor function in intact and unilateral dopaminedepleted rats. Neuroscience 2006;140(4):1127-38.

Wallace VC, Blackbeard J, Pheby T, Segerdahl AR, Davies M, Hasnie F, Hall S, McMahon SB, Rice AS.Pharmacological, behavioural and mechanistic analysis of HIV-1 gp120 induced painful neuropathy. Pain 2007;133(1-3):47-63.

Ja'afer FM, Hamdan FB, Mohammed FH. Vincristineinduced neuropathy in rat: electrophysiological and histological study. Exp Brain Res 2006;173(2):334-45.

Rahimi Balaei M, Momeny M, Babaeikelishomi R, Ejtemaei Mehr S, Tavangar SM, Dehpour AR. The modulatory effect of lithium on doxorubicin-induced cardiotoxicity in rat. Eur J Pharmacol 2010;641(2-3):193-8.

Bhattacharyya B, Wolff J. Stabilization of microtubules by lithium ion. Biochem Biophys Res Commun 1976;73(2):383-90.

Burstein DE, Seeley PJ, Greene LA. Lithium ion inhibits nerve growth factor-induced neurite outgrowth and phosphorylation of nerve growth factor-modulated microtubule-associated proteins. J Cell Biol 1985;101(3):862-70.

Goold RG, Owen R, Gordon-Weeks PR. Glycogen synthase kinase 3beta phosphorylation of microtubuleassociated protein 1B regulates the stability of microtubules in growth cones. J Cell Sci 1999;112 ( Pt 19):3373-84.

Hong M, Chen DC, Klein PS, Lee VM. Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. J Biol Chem 1997;272(40):25326-32.

Chen RW, Chuang DM. Long term lithium treatment suppresses p53 and Bax expression but increases Bcl-2 expression. A prominent role in neuroprotection against excitotoxicity. J Biol Chem 1999;274(10):6039-42.

Xu J, Culman J, Blume A, Brecht S, Gohlke P. Chronic treatment with a low dose of lithium protects the brain against ischemic injury by reducing apoptotic death. Stroke 2003;34(5):1287-92.

How to Cite
1.
Alimoradi H, Pourmohammadi N, Ejtemaei Mehr S, Hassanzadeh G, Hadian MR, Sharifzadeh M, Bakhtiarian A, Dehpour AR. Effects of Lithium on Peripheral Neuropathy Induced by Vincristine in Rats. Acta Med Iran. 50(6):373-379.
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