Novel Neuroprotective Effect Of Therapeutic Lithium Carbonate Doses In Rat Brain Tissue During Different Treatment Intervals
Volume 1 - Issue 5, November 2017 Edition
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Author(s)
Nabil M. Abdel-Hamid, Shereen S. El Shaer, Amany M. Gad
Keywords
Lithium; Neuroprotection; Hydroxylation; Amino acids; Proteins.
Abstract
Amino acids are either neurotransmitters or precursors for neurotransmitters. This study aims to investigate the effect of therapeutic dose of lithium carbonate (75 mg/kg) on brain free amino acids thought to contribute in psychotic disorders and declare its effect on phosphate buffer insoluble protein fraction in rat brain at different treatment periods. Phosphate buffer insoluble protein fraction was chosen, being the more stable part of tissue protein. Four groups of rats, 6/each were recruited, randomly assorted into, a control group, given saline, acute study group, given single dose, left for 2 hours, sub-acute study group, given a dose each 3 days for 2 weeks and a chronic study group, given a dose each 3 days for a month. Brain content of l free amino acids; ɣ- aminobutyrate (GABA), aspartate, glutamate, glycine, phenyl alanine, tryptophan, branched chain amino acids and proline was significantly decreased on acute, sub-acute and chronic administration, while hydroxyl and dibasic amino acids were increased. Concomitantly, increased phosphate buffer-insoluble protein fraction after two hours of administration, decreasing to normal level after a month of therapy. These actions indicate an anabolic and neuroprotective impact of lithium on brain tissue with amelioration of nitrogen balance, activated amidation, hydroxylation and peptidases. These pathways, possibly published for the first time, elucidating a novel therapeutic prospect of lithium in psychotic disorders. Increasing a more stable fraction of tissue protein (phosphate-buffer insoluble), is a novel contribution to lithium tissue stabilization in affective disorders.
References
[1] Merikangas KR, Jin R, He J-P, Kessler RC, Lee S, Sampson NA, et al. Prevalence and correlates of bipolar spectrum disorder in the world mental health survey initiative. Archives of general psychiatry 2011;68:241-51.
[2] Isgren A, Jakobsson J, PÃ¥lsson E, Ekman CJ, Johansson AG, Sellgren C, et al. Increased cerebrospinal fluid interleukin-8 in bipolar disorder patients associated with lithium and antipsychotic treatment. Brain, behavior, and immunity 2015;43:198-204.
[3] Rolstad S, Jakobsson J, Sellgren C, Isgren A, Ekman CJ, Bjerke M, et al. CSF neuroinflammatory biomarkers in bipolar disorder are associated with cognitive impairment. European Neuropsychopharmacology 2015;25:1091-8.
[4] Goldstein BI, Young LT. Toward clinically applicable biomarkers in bipolar disorder: focus on BDNF, inflammatory markers, and endothelial function. Current psychiatry reports 2013;15:425.
[5] Pålsson E, Jakobsson J, Södersten K, Fujita Y, Sellgren C, Ekman C-J, et al. Markers of glutamate signaling in cerebrospinal fluid and serum from patients with bipolar disorder and healthy controls. European Neuropsychopharmacology 2015;25:133-40.
[6] Shafti SS. Olanzapine vs. lithium in management of acute mania. Journal of affective disorders 2010;122:273-6.
[7] Lloyd LC, Giaroli G, Taylor D, Tracy DK. Bipolar depression: clinically missed, pharmacologically mismanaged. Therapeutic advances in psychopharmacology 2011;1:153-62.
[8] Marmol F. Lithium: bipolar disorder and neurodegenerative diseases Possible cellular mechanisms of the therapeutic effects of lithium. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2008;32:1761-71.
[9] Dudev T, Lim C. Competition between Li+ and Mg2+ in metalloproteins. Implications for lithium therapy. Journal of the American Chemical Society 2011;133:9506-15.
[10] Chiu C-T, Chuang D-M. Molecular actions and therapeutic potential of lithium in preclinical and clinical studies of CNS disorders. Pharmacology & therapeutics 2010;128:281-304.
[11] Alvarez G, Muñozâ€Montaño JR, Satrústegui J, Avila J, Bogónez E, DÃazâ€Nido J. Regulation of tau phosphorylation and protection against βâ€amyloidâ€induced neurodegeneration by lithium. Possible implications for Alzheimer's disease. Bipolar disorders 2002;4:153-65.
[12] Yasuda S, Liang M, Marinova Z, Yahyavi A, Chuang D. The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Molecular psychiatry 2009;14:51-9.
[13] Guo S, Arai K, Stins MF, Chuang D-M, Lo EH. Lithium upregulates vascular endothelial growth factor in brain endothelial cells and astrocytes. Stroke 2009;40:652-5.
[14] Vo TM, Perry P, Ellerby M, Bohnert K. Is lithium a neuroprotective agent? Annals of Clinical Psychiatry 2015;27:49-54.
[15] Lieb J. Defeating cancer with antidepressants. ecancermedicalscience 2008;2.
[16] Basselin M, Kim H-W, Chen M, Ma K, Rapoport SI, Murphy RC, et al. Lithium modifies brain arachidonic and docosahexaenoic metabolism in rat lipopolysaccharide model of neuroinflammation. Journal of lipid research 2010;51:1049-56.
[17] Rajagopal S, Sangam SR, Singh S, Joginapally VR. Modulatory Effects of Dietary Amino Acids on Neurodegenerative Diseases. The Benefits of Natural Products for Neurodegenerative Diseases: Springer; 2016. p. 401-14.
[18] Elwyn D. The role of the liver in regulation of amino acid and protein metabolism. Mammalian protein metabolism 1970;4:523-57.
[19] Gonchar O, Mankovskaya I, Klyuchko E. Role of complex nucleosides in the reversal of oxidative stress and metabolic disorders induced by acute nitrite poisoning. Indian journal of pharmacology 2006;38:414.
[20] Pae E-K, Yoon AJ, Ahuja B, Lau GW, Nguyen DD, Kim Y, et al. Perinatal intermittent hypoxia alters γ-aminobutyric acid: a receptor levels in rat cerebellum. International Journal of Developmental Neuroscience 2011;29:819-26.
[21] Dhawan D, Singh A, Singh B, Bandhu HK, Chand B, Singh N. Effect of lithium augmentation on the trace elemental profile in diabetic rats. Biometals 1999;12:375-81.
[22] Eipper BA. Rat brain microtubule protein: purification and determination of covalently bound phosphate and carbohydrate. Proc Natl Acad Sci U S A 1972;69:2283-7.
[23] Walton NY, Gunawan S, Treiman DM. Brain amino acid concentration changes during status epilepticus induced by lithium and pilocarpine. Exp Neurol 1990;108:61-70.
[24] Gama FG, Santana AE, Filho Ede C, Nogueira CA. Agarose gel electrophoresis of cerebrospinal fluid proteins of dogs after sample concentration using a membrane microconcentrator technique. Vet Clin Pathol 2007;36:85-8.
[25] Morales I, Guzman-Martinez L, Cerda-Troncoso C, Farias GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches. Frontiers in cellular neuroscience 2014;8:112.
[26] Rawls SM, Gomez T, Stagliano GW, Raffa RB. Measurement of glutamate and aspartate in Planaria. Journal of pharmacological and toxicological methods 2006;53:291-5.
[27] Farber NB, Newcomer JW, Olney JW. The glutamate synapse in neuropsychiatric disorders. Focus on schizophrenia and Alzheimer's disease. Progress in brain research 1998;116:421-37.
[28] Kish PE, Fischer-Bovenkerk C, Ueda T. Active transport of gamma-aminobutyric acid and glycine into synaptic vesicles. Proceedings of the National Academy of Sciences of the United States of America 1989;86:3877-81.
[29] Feng J, Cai X, Zhao J, Yan Z. Serotonin Receptors Modulate GABAA Receptor Channels through Activation of Anchored Protein Kinase C in Prefrontal Cortical Neurons. The Journal of Neuroscience 2001;21:6502.
[30] Tcherkas YV, Kartsova LA, Krasnova IN. Analysis of amino acids in human serum by isocratic reversed-phase high-performance liquid chromatography with electrochemical detection. Journal of Chromatography A 2001;913:303-8.
[31] Sumiyoshi T, Anil AE, Jin D, Jayathilake K, Lee M, Meltzer HY. Plasma glycine and serine levels in schizophrenia compared to normal controls and major depression: relation to negative symptoms. The international journal of neuropsychopharmacology 2004;7:1-8.
[32] Hashimoto K, Sawa A, Iyo M. Increased levels of glutamate in brains from patients with mood disorders. Biological psychiatry 2007;62:1310-6.
[33] Nagasawa M OY, Kurata K, Otsuka T, Yoshida J, Tomonaga S, Furuse M. Furuse,. Hypothesis with abnormal amino acid metabolism in depression and stress vulnerability in Wistar Kyoto rats. Amino acids 2012;2012.
[34] Nag M, Guha S, Turner A. Inhibition of glutaminase activity of rat brain by lithium. Biochemical pharmacology 1983;32:1798-800.
[35] Iwata H, Okamoto H, Kuramoto I. Effect of lithium on serum tryptophan and brain serotonin in rats. The Japanese Journal of Pharmacology 1974;24:235-40.
[36] Cansev M, Wurtman R. 4 Aromatic Amino Acids in the Brain. Handbook of neurochemistry and molecular neurobiology: Springer; 2007. p. 59-97.
[37] McFarlane HG, Steele J, Vinion K, Bongiovanni R, Double M, Jaskiw GE. Acute lithium administration selectively lowers tyrosine levels in serum and brain. Brain research 2011;1420:29-36.
[38] He Y, Yu Z, Giegling I, Xie L, Hartmann A, Prehn C, et al. Schizophrenia shows a unique metabolomics signature in plasma. Translational psychiatry 2012;2:e149.
[39] Sasahara I, Fujimura N, Nozawa Y, Furuhata Y, Sato H. The effect of histidine on mental fatigue and cognitive performance in subjects with high fatigue and sleep disruption scores. Physiology & behavior 2015;147:238-44.
[40] Chen G, Yuan PX, Jiang YM, Huang LD, Manji HK. Lithium increases tyrosine hydroxylase levels both in vivo and in vitro. J Neurochem 1998;70:1768-71.
[41] Sparapani M, Virgili M, Ortali F, Contestabile A. Effects of chronic lithium treatment on ornithine decarboxylase induction and excitotoxic neuropathology in the rat. Brain Res 1997;765:164-8.
[42] Metzler DE. Biochemistry: The Chemical Reactions of Living Cells: Academic Press; 1977.
[43] Moffett JR, Ross B, Arun P, Madhavarao CN, Namboodiri AM. N-Acetylaspartate in the CNS: from neurodiagnostics to neurobiology. Prog Neurobiol 2007;81:89-131.
[44] Yudkoff M, Daikhin Y, Melo TM, Nissim I, Sonnewald U, Nissim I. The ketogenic diet and brain metabolism of amino acids: relationship to the anticonvulsant effect. Annu Rev Nutr 2007;27:415-30.
[45] Mächler P, Wyss MT, Elsayed M, Stobart J, Gutierrez R, von Faber-Castell A, et al. In vivo evidence for a lactate gradient from astrocytes to neurons. Cell metabolism 2016;23:94-102.
[46] Wu G, Bazer FW, Burghardt RC, Johnson GA, Kim SW, Knabe DA, et al. Proline and hydroxyproline metabolism: implications for animal and human nutrition. Amino acids 2011;40:1053-63.
[47] Shoulders MD, Raines RT. Collagen structure and stability. Annual review of biochemistry 2009;78:929-58.
[48] Wu G, Bazer F, Burghardt R, Johnson G, Kim S, Li X, et al. Impacts of amino acid nutrition on pregnancy outcome in pigs: mechanisms and implications for swine production. Journal of animal science 2010;88:E195-E204.
[49] Phang JM, Liu W, Zabirnyk O. Proline metabolism and microenvironmental stress. Annual review of nutrition 2010;30:441-63.
[50] Phang JM, Donald SP, Pandhare J, Liu Y. The metabolism of proline, a stress substrate, modulates carcinogenic pathways. Amino acids 2008;35:681-90.
[51] Abdallah ZMaA-A, F.T. . Some biochemical studies of diazepam (valium) on rabbit brain homogenate. Arab J Med 1982;8:131-9.
[52] Kasuya J, Kaas G, Kitamoto T. Effects of lithium chloride on the gene expression profiles in Drosophila heads. Neurosci Res 2009;64:413-20.
[53] Chiu CT, Wang Z, Hunsberger JG, Chuang DM. Therapeutic potential of mood stabilizers lithium and valproic acid: beyond bipolar disorder. Pharmacol Rev 2013;65:105-42.
[54] da Silva Kagy V, Muniz LTB, Michels AC, Luiz ST, Alanis LRA, Brancher JA, et al. Effect of the Chronic Use of Lithium Carbonate on Induced Tooth Movement in Wistar Rats. PloS one 2016;11:e0160400.
[55] McKnight RF, Adida M, Budge K, Stockton S, Goodwin GM, Geddes JR. Lithium toxicity profile: a systematic review and meta-analysis. The Lancet 2012;379:721-8.