Prevention of MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) dopaminergic neurotoxicity in mice by chronic lithium: involvements of Bcl-2 and Bax

Lithium has been reported to exert neuroprotective activity in several neuronal cell cultures and in vivo models against glutamate toxicity. Since this action was reported to be associated with alterations in the antiapoptotic Bcl-2 family proteins, the effect of chronic lithium diet on the ability of the parkinsonism neurotoxin, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to deplete striatal dopamine in mice was determined. Mice were fed for with a diet containing 1.1, 2.2, 3.3, and 4.4 g/kg lithium chloride (LiCl) for 4 weeks, during which time serum levels of lithium were monitored. The 3.3 g/kg lithium diet gave serum level value very similar to what is observed in lithium therapy in man and the 4.4 g/kg well above this. At the end of this period the mice received 24 mg/kg MPTP i.p. once daily for 3 days. A direct relation was established with the increase in serum lithium and its ability to prevent MPTP induced depletion of striatal dopamine (DA) and its metabolites DPOAC and HVA. With the diet containing the highest lithium concentration there was an almost complete prevention of striatal dopamine depletion and the reduction in tyrosine hydroxylase activity and protein and it prevented the increase in dopamine turnover (DOPAC + HVA/DA) normally observed in MPTP treatment. Lithium did not interfere with the metabolism of MPTP, or with its brain uptake, since, the level of its monoamine oxidase (MAO) B derived metabolite, MPP+, in the striata of lithium and non-lithium treated mice were almost identical. Striatal Bcl-2 was significantly decreased, while Bax was increased in MPTP treated mice. Lithium treatment not only increased striatal Bcl-2 in control mice, but also prevented its reduction as induced by MPTP, and an opposing effect was seen with Bax. The neuroprotective action of lithium in this model of Parkinson's disease has been attributed to its antiapoptotic activity which among other factors includes induction of Bcl-2 and reduction of Bax.

[1]  G. Moore,et al.  Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilisers , 2001, British Journal of Psychiatry.

[2]  T. Kato,et al.  A sensitive and inexpensive high-performance liquid chromatographic assay for tyrosine hydroxylase , 2005, Experientia.

[3]  K. Tipton,et al.  Rat striatal monoamine oxidase-B inhibition by l-deprenyl and rasagiline: its relationship to 2-phenylethylamine-induced stereotypy and Parkinson's disease. , 2002, Parkinsonism & related disorders.

[4]  E. Melamed,et al.  Transgenic mice expressing human Bcl-2 in their neurons are resistant to 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine neurotoxicity. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[5]  A. H. Drummond,et al.  Chronic lithium treatment inhibits basal and agonist-stimulated responses in rat cerebral cortex and GH3 pituitary cells. , 1992, Molecular pharmacology.

[6]  T. Dawson,et al.  Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[7]  W Tatton,et al.  The Anti‐Parkinson Drug Rasagiline and Its Cholinesterase Inhibitor Derivatives Exert Neuroprotection Unrelated to MAO Inhibition in Cell Culture and in Vivo , 2001, Annals of the New York Academy of Sciences.

[8]  S. Mandel,et al.  cDNA gene expression profile homology of antioxidants and their antiapoptotic and proapoptotic activities in human neuroblastoma cells , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[9]  D. Chuang,et al.  Neuroprotective effects of lithium in cultured cells and animal models of diseases. , 2002, Bipolar disorders.

[10]  W. Tatton,et al.  (-)-Deprenyl reduces neuronal apoptosis and facilitates neuronal outgrowth by altering protein synthesis without inhibiting monoamine oxidase. , 1996, Journal of neural transmission. Supplementum.

[11]  Moussa B. H. Youdim,et al.  Neuroprotective Strategies in Parkinson’s Disease , 2003, CNS drugs.

[12]  M. Naoi,et al.  The anti-parkinson drug, rasagiline, prevents apoptotic DNA damage induced by peroxynitrite in human dopaminergic neuroblastoma SH-SY5Y cells , 2002, Journal of Neural Transmission.

[13]  H. Manji,et al.  Lithium stimulates gene expression through the AP-1 transcription factor pathway. , 1998, Brain research. Molecular brain research.

[14]  D. Chuang,et al.  Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats , 1998, Neuroreport.

[15]  S. Korsmeyer,et al.  Bax ablation prevents dopaminergic neurodegeneration in the 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[16]  S. Lin-Shiau,et al.  Long‐term lithium treatment prevents neurotoxic effects of β‐bungarotoxin in primary cultured neurons , 2002, Journal of neuroscience research.

[17]  M. Youdim,et al.  Pharmacology of rasagiline (N-propargyl-1R-aminoindan). , 1999, Advances in neurology.

[18]  M. Youdim,et al.  Rasagiline [N‐propargyl‐1R(+)‐aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B , 2001, British journal of pharmacology.

[19]  S. Mandel,et al.  Gene expression analysis in N‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine mice model of Parkinson's disease using cDNA microarray: effect of R‐apomorphine , 2001, Journal of neurochemistry.

[20]  T. Vickers,et al.  Determination of lethium in microliter samples of blood serum using flame atomic emission spectrometry with a tantalum filament vaporizer. , 1975, Analytical chemistry.

[21]  Xiaohua Li,et al.  Regulation of Akt and glycogen synthase kinase-3β phosphorylation by sodium valproate and lithium , 2002, Neuropharmacology.

[22]  K. Shimoke,et al.  Nerve growth factor prevents 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced cell death via the Akt pathway by suppressing caspase‐3‐like activity using PC12 cells: Relevance to therapeutical application for parkinson's disease , 2001, Journal of neuroscience research.

[23]  S. Mandel,et al.  Early and Late Gene Changes in MPTP Mice Model of Parkinson's Disease Employing cDNA Microarray , 2002, Neurochemical Research.

[24]  D. Chuang,et al.  Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[25]  V. Eraković,et al.  Lithium plus pilocarpine induced status epilepticus — biochemical changes , 2000, Neuroscience Research.

[26]  Y. Akao,et al.  Transfection‐enforced Bcl‐2 overexpression and an anti‐Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde‐3‐phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N‐methyl(R)salsolinol , 2001, Journal of neurochemistry.

[27]  D. Chuang,et al.  Lithium‐induced inhibition of Src tyrosine kinase in rat cerebral cortical neurons: a role in neuroprotection against N‐methyl‐D‐aspartate receptor‐mediated excitotoxicity , 2003, FEBS letters.

[28]  D. Chuang,et al.  Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: An essential step for neuroprotection against glutamate excitotoxicity , 2002, Neuropharmacology.

[29]  A. Oke,et al.  Liquid chromatographic analysis of catecholamines routine assay for regional brain mapping. , 1976, Life sciences.

[30]  R. Jope,et al.  Caspase-3 activation induced by inhibition of mitochondrial complex I is facilitated by glycogen synthase kinase-3β and attenuated by lithium , 2001, Brain Research.

[31]  Guang Chen,et al.  Lithium at 50: have the neuroprotective effects of this unique cation been overlooked? , 1999, Biological Psychiatry.

[32]  R. Belmaker,et al.  The mechanism of lithium action: state of the art, ten years later , 2001, Progress in Neuro-Psychopharmacology and Biological Psychiatry.

[33]  M. Carrillo,et al.  Enhancing effect of rasagiline on superoxide dismutase and catalase activities in the dopaminergic system in the rat. , 2000, Life sciences.

[34]  Y. Akao,et al.  An anti-Parkinson's disease drug, N-propargyl-1(R)-aminoindan (rasagiline), enhances expression of anti-apoptotic Bcl-2 in human dopaminergic SH-SY5Y cells , 2002, Neuroscience Letters.

[35]  M. Youdim.  Rasagiline: an anti-Parkinson drug with neuroprotective activity , 2003, Expert review of neurotherapeutics.

[36]  M. Vila,et al.  The parkinsonian toxin MPTP: action and mechanism. , 2000, Restorative neurology and neuroscience.

[37]  R. Belmaker,et al.  How does lithium work on manic depression? Clinical and psychological correlates of the inositol theory. , 1996, Annual review of medicine.

[38]  M. A. El-Masri,et al.  Evaluation of neuroprotection by lithium and valproic acid against ouabain-induced cell damage. , 2002, Bipolar disorders.

[39]  J. Penney,et al.  1-Methyl-4-phenyl-1,2,3,6-tetrahydropyride Neurotoxicity Is Attenuated in Mice Overexpressing Bcl-2 , 1998, The Journal of Neuroscience.

[40]  D. Chuang,et al.  Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[41]  D. Chuang,et al.  Long Term Lithium Treatment Suppresses p53 and Bax Expression but Increases Bcl-2 Expression , 1999, The Journal of Biological Chemistry.

[42]  S. Mandel,et al.  Effects of R- and S-apomorphine on MPTP-induced nigro-striatal dopamine neuronal loss. , 2001 .

[43]  H. Manji,et al.  The Mood‐Stabilizing Agents Lithium and Valproate RobustlIncrease the Levels of the Neuroprotective Protein bcl‐2 in the CNS , 1999, Journal of neurochemistry.

[44]  H. Manji,et al.  PKC, MAP kinases and the bcl-2 family of proteins as long-term targets for mood stabilizers , 2002, Molecular Psychiatry.

[45]  S. Rapoport,et al.  Analysis of gene expression with cDNA microarrays in rat brain after 7 and 42 days of oral lithium administration , 2002, Brain Research Bulletin.

[46]  Y. Akao,et al.  Mitochondrial permeability transition mediates apoptosis induced by N‐methyl(R)salsolinol, an endogenous neurotoxin, and is inhibited by Bcl‐2 and rasagiline, N‐propargyl‐1(R)‐aminoindan , 2002, Journal of neurochemistry.

[47]  D. Ben-shachar,et al.  Intranigral Iron Injection Induces Behavioral and Biochemical “Parkinsonism” in Rats , 1991, Journal of neurochemistry.

[48]  R. Duvoisin,et al.  Prevention of MPTP-induced neurotoxicity by AGN-1133 and AGN-1135, selective inhibitors of monoamine oxidase-B. , 1985, European journal of pharmacology.

[49]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[50]  E. Bechara,et al.  The effect of chlorpromazine and Li2CO3 on the superoxide dismutase and glutathione peroxidase activities of rat brain, liver and erythrocytes. , 1994, Biochemistry and molecular biology international.

[51]  S. Brecht,et al.  Chronic Treatment With a Low Dose of Lithium Protects the Brain Against Ischemic Injury by Reducing Apoptotic Death , 2003, Stroke.

[52]  Y. Akao,et al.  Neuroprotection by propargylamines in Parkinson's disease: suppression of apoptosis and induction of prosurvival genes. , 2002, Neurotoxicology and teratology.

[53]  A. Mayk,et al.  Studies with rasagiline, a MAO-B inhibitor, in experimental focal ischemia in the rat , 1999, Journal of Neural Transmission.