Cyanocobalamin improves memory impairment via inhibition of necrosis and apoptosis of hippocampal cell death after transient global ischemia/reperfusion

Document Type : Original Article

Authors

1 School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran

2 Neurosciences Research Center, Shahroud University of Medical Sciences, Shahroud, Iran

3 Neurobiomedical Research Center, Shahid Sadoughi University of Medical Sciences, Yazd, Iran

4 Department of Sport Sciences, Ilam University, Ilam, Iran

5 Student Research Committee, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran

Abstract

Objective(s): Brain ischemia/reperfusion (I/R) causes irreversible damage, particularly in the hippocampus. Cyanocobalamin (CNCbl) is known to be crucial for the proper operation of the nervous system. Vitamin B12 has been demonstrated to exert antioxidant effects via direct and indirect mechanisms. It can also protect cortical neurons against glutamate cytotoxicity. This research was conducted to examine CNCbl protection against neuronal cell death in the rat hippocampal region following transient cerebral ischemia.
Materials and Methods: In this experiment, 48 male Wistar rats were selected, which were randomly divided into four groups (n=12 in each group): sham, ischemia/reperfusion, ischemia/reperfusion + CNCbl 200 and 400 (µg/kg). By occlusion of both common carotids, ischemia induction was performed within 20 min. CNCbl at the doses of 200 and 400 µg/kg was injected (IP) at the start of the reperfusion, 24 and 48 hr following reperfusion. The spatial memory was assessed 7 days following ischemia through the Morris water maze test. Antioxidant enzymes, apoptosis, and necrosis were measured after behavioral tests.
Results: CNCbl significantly improved spatial memory impairments (p <0.05), also CNCbl therapy significantly increased both glutathione (p <0.01) and superoxide dismutase (p <0.05) and reduced malondialdehyde (p <0.01) and TNF-α (p <0.05) in comparison with the ischemia group. In addition, CNCbl significantly decreased both apoptosis and necrosis in the hippocampus CA1 (p <0.01).
Conclusion: CNCbl improves memory impairment following ischemia injury by decreasing neuronal cell death via its antioxidant properties.

Keywords


1. Flynn R, MacWalter R, Doney A. The cost of cerebral ischaemia. Neuropharmacology 2008; 55:250-256.
2. Kirino T, Tamura A, Sano K. Selective vulnerability of the hippocampus to ischemia—reversible and irreversible types of ischemic cell damage. Prog Brain Res 1985; 63:39-58.
3. Mitani A, Andou Y, Kataoka K. Selective vulnerability of hippocampal CA1 neurons cannot be explained in terms of an increase in glutamate concentration during ischemia in the gerbil: brain microdialysis study. Neuroscience 1992; 48:307-313.
4. Smith M-L, Auer R, Siesjö B. The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia. Acta Neuropathol 1984; 64:319-332.
5. Florian C, Roullet P. Hippocampal CA3-region is crucial for acquisition and memory consolidation in Morris water maze task in mice. Behav Brain Res 2004; 154:365-374.
6. Tuttolomondo A, Pecoraro R, Arnao V, Maugeri R, Iacopino DG, Pinto A. Developing drug strategies for the neuroprotective treatment of acute ischemic stroke. Expert Rev Neurother 2015;15:1271-1284.
7. Okada K, Tanaka H, Temporin K, Okamoto M, Kuroda Y, Moritomo H, et al. Methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle and promotes nerve regeneration in a rat sciatic nerve injury model. Exp Neurol 2010; 222:191-203.
8. Banerjee R, Ragsdale SW. The many faces of vitamin B12: catalysis by cobalamin-dependent Enzymes. Annu Rev Biochem 2003; 72:209-247.
9. Toohey JI. Vitamin B_ {12} and methionine synthesis: A critical review. Is nature’s most beautiful cofactor misunderstood? Biofactors 2006; 26:45-57.
10.    Hemendinger RA, Armstrong III EJ, Brooks BR. Methyl Vitamin B12 but not methylfolate rescues a motor neuron-like cell line from homocysteine-mediated cell death. Toxicol Appl Pharmacol 2011; 251:217-225.
11.    Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol  2006; 5:949-960.
12.    Andrès E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE, et al. Vitamin B12 (cobalamin) deficiency in elderly patients. Can Med Assoc J 2004;b171:251-259.
13.    Yagihashi S, Tokui A, Kashiwamura H, Takagi S, Imamura K. In vivo effect of methylcobalamin on the peripheral nerve structure in streptozotocin diabetic rats. Horm Metab Res 1982; 14:10-13.
14.    Suarez-Moreira E, Yun J, Birch CS, Williams JH, McCaddon A, Brasch NE. Vitamin B12 and redox homeostasis: cob (II) alamin reacts with superoxide at rates approaching superoxide dismutase (SOD). J Am Chem Soc 2009;b131:15078-15079.
15.    Peracchi M, Bamonti Catena F, Pomati M, De Franceschi M, Scalabrino G. Human cobalamin deficiency: alterations in serum tumour necrosis factor‐α and epidermal growth factor.  Eur J Haematol 2001; 67:123-127.
16.    Scalabrino G, Carpo M, Bamonti F, Pizzinelli S, D’Avino C, Bresolin N, et al. High tumor necrosis factor‐α in levels in cerebrospinal fluid of cobalamin‐deficient patients. Ann Neuro 2004; 56:886-890.
17.    Chawla-Sarkar M, Bauer JA, Lupica JA, Morrison BH, Tang Z, Oates RK, et al. Suppression of NF-κB survival signaling by nitrosylcobalamin sensitizes neoplasms to the anti-tumor effects of Apo2L/TRAIL. J BIOL CHEM 2003; 278:39461-39469.
18.    Erfani S, Moghimi A, Aboutaleb N, Khaksari M. Nesfatin-1 improve spatial memory impairment following transient global cerebral ischemia/reperfusion via inhibiting microglial and caspase-3 activation. J Mol Neurosci 2018; 65:377-384.
19.    Aski ML, Rezvani ME, Khaksari M, Hafizi Z, Pirmoradi Z, Niknazar S, et al. Neuroprotective effect of berberine chloride on cognitive impairment and hippocampal damage in experimental model of vascular dementia. Iran J Basic Med Sci 2018; 21:53-58.
20.    Ghanbari F, Khaksari M, Vaezi G, Hojati V, Shiravi A. Hydrogen sulfide protects hippocampal neurons against methamphetamine neurotoxicity via inhibition of apoptosis and neuroinflammation. J Mol Neurosci 2019; 67:133-141.
21.    Tiwari V, Chopra K. Resveratrol abrogates alcohol-induced cognitive deficits by attenuating oxidative–nitrosative stress and inflammatory cascade in the adult rat brain. Neurochem Int 2013; 62:861-869.
22.    Khaksari M, Mehrjerdi FZ, Rezvani ME, Safari F, Mirgalili A, Niknazar S. The role of erythropoietin in remote renal preconditioning on hippocampus ischemia/reperfusion injury. J Physiol Sci 2017; 67:163-171.
23.    Zare Mehrjerdie F, Shoshtari A, Mohseni F, Khastar H, Norouzi P, Asadi Y, et al. Sulfur dioxide reduces hippocampal cells death and improves learning and memory deficits in rat model of transient global ischemia/reperfusion. Iran J Basic Med Sci 2018; 21:998-1003.
24.    Erfani S, Khaksari M, Oryan S, Shamsaei N, Aboutaleb N, Nikbakht F. Nampt/PBEF/visfatin exerts neuroprotective effects against ischemia/reperfusion injury via modulation of Bax/Bcl-2 ratio and prevention of caspase-3 activation. J Mol Neurosci 2015; 56:237-243.
25.    Wang C, Liu M, Pan Y, Bai B, Chen J. Global gene expression profile of cerebral ischemia-reperfusion injury in rat MCAO model. Oncotarget 2017; 8:74607.
26.    Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol Therapeut 2008; 120:1-34.
27.    Rolo AP, Palmeira CM. Diabetes and mitochondrial function: role of hyperglycemia and oxidative stress. Toxicol Appl Pharmacol 2006; 212:167-178.
28.    de Zwart LL, Meerman JH, Commandeur JN, Vermeulen NP. Biomarkers of free radical damage: applications in experimental animals and in humans. Free Radic Biol Med 1999; 26:202-226.
29.    Warner DS, Sheng H, Batinić-Haberle I. Oxidants, anti-oxidants and the ischemic brain. J Exp Biol. 2004; 207:3221-3231.
30.    Tucker MS, Khan I, Fuchs-Young R, Price S, Steininger TL, Greene G, et al. Localization of immunoreactive epidermal growth factor receptor in neonatal and adult rat hippocampus. Brain Res 1993; 631:65-71.
31.    Xiang Y-Y, Dong H, Wan Y, Li J, Yee A, Yang BB, et al. Versican G3 domain regulates neurite growth and synaptic transmission of hippocampal neurons by activation of epidermal growth factor receptor. J Biol Chem 2006; 281:19358-19368.
32.    Wong RWC, Guillaud L. The role of epidermal growth factor and its receptors in mammalian CNS. Cytokine Growth Factor Rev 2004; 15:147-156.
33.    Peng H, Wen T-C, Tanaka J, Maeda N, Matsuda S, Desaki J, et al. Epidermal growth factor protects neuronal cells in vivo and in vitro against transient forebrain ischemia-and free radical-induced injuries. J Cereb Blood Flow Metab  1998; 18:349-360.
34.    Scalabrino G, Tredici G, Buccellato F, Manfridi A. Further evidence for the involvement of epidermal growth factor in the signaling pathway of vitamin B12 (cobalamin) in the rat central nervous system. J Neuropathol Exp Neurol 2000; 59:808-814.
35.    Scalabrino G, Nicolini G, Buccellato FR, Peracchi M, Tredici G, Manfridi A, et al. Epidermal growth factor as a local mediator of the neurotrophic action of vitamin B12 (cobalamin) in the rat central nervous system. FASEB J 1999; 13:2083-2090.
36.    Tomimoto H, Ihara M, Wakita H, Ohtani R, Lin J-X, Akiguchi I, et al. Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat. Acta Neuropathol 2003; 106:527-534.
37.    Barone F, Arvin B, White R, Miller A, Webb C, Willette R, et al. Tumor necrosis factor-α: a mediator of focal ischemic brain injury. Stroke 1997; 28:1233-1244.
38.    Terai K, Matsuo A, McGeer PL. Enhancement of immunoreactivity for NF-κB in the hippocampal formation and cerebral cortex of Alzheimer’s disease. Brain Res 1996; 735:159-168.
39.    Rong Y, Baudry M. Seizure activity results in a rapid induction of nuclear factor‐κB in adult but not juvenile rat limbic structures. J Neurochem 1996; 67:662-668.
40.    Ridder D, Schwaninger M. NF-κB signaling in cerebral ischemia. Neuroscience 2009; 158:995-1006.
41.    Zhang W, Potrovita I, Tarabin V, Herrmann O, Beer V, Weih F, et al. Neuronal activation of NF-κB contributes to cell death in cerebral ischemia. J Cereb Blood Flow Metab 2005; 25:30-40.
42.    Veber D, Mutti E, Tacchini L, Gammella E, Tredici G, Scalabrino G. Indirect down‐regulation of nuclear NF‐κB levels by cobalamin in the spinal cord and liver of the rat. J Neurosci Res 2008; 86:1380-1387.