Implications of the Neuroprotective Effects of Lithium for the Treatment of Bipolar and Neurodegenerative Disorders

Bipolar disorder is increasingly recognized as an illness that may progress to impairment in neurocognitive functioning and cell loss in cortical and limbic brain regions. Glutamatergic damage and/or damage due to high glucocorticoid levels that inhibit adult neurogenesis are likely contributing mechanisms. Drug treatments with possible neuroprotective effects are becoming increasingly important both clinically and as research tools. Mood stabilizing drugs and lithium in particular may act to prevent neuronal damage and tissue loss that may occur in the brain of patients with bipolar disorders. Lithium has been shown to exert neuroprotective effects in vitro and to stimulate neurogenesis in the hippocampus. Animal studies have demonstrated pharmacological effects of lithium suggestive of its role in neuroprotection, which range from reducing excitotoxicity through increased glutamate uptake, to regulation of a number of signal transduction intermediates such as myo-inositol, protein kinase C, phosphotidylinositol-3 kinase (PI-3K)/protein kinase B (Akt), ras-mitogen-activated protein kinase (MAPK), glycogen synthase kinase (GSK)-3α and -3β and calcium. It remains to be established whether lithium treatment protects against possible cell damage in the same manner as it protects against recurrences of the illness. We propose to examine the effect of long-term lithium treatment on neurocognitive functioning of bipolar patients and the use of lithium in the treatment of chronic neuropsychiatric disorders.

Key words

Lithium - bipolar disorder - neuroprotection - neurodegeneration - signal transduction - Alzheimer's disease - Huntington's disease

References

• 1 Altshuler L L, Bartzokis G, Grieder T, Curran J, Jimenez T, Leight K, Wilkins J, Gerner R, Mintz J. An MRI study of temporal lobe structures in men with bipolar disorder or schizophrenia.  Biol Psychiatry. 2000;  48 147-162
• 2 Bezchlibnyk Y, Young L T. The neurobiology of bipolar disorder: focus on signal transduction pathways and the regulation of gene expression.  Can J Psychiatry. 2002;  47 135-148
• 3 Bown C D, Wang JF and Young L T. Attenuation of NMDA-mediated cytoplasmic vacuolization in primary rat hippocampal neurons by mood stabilizers.  Neuroscience. 2003;  117 949-955
• 4 Carmichael J, Sugars K L, Bao Y P, Rubinsztein D C. Glykogen synthase kinase-3β inhibitors prevent cellular polyglutamine toxicity caused by the Huntington's disease mutation.  J Biol Chem. 2002;  277 33 791-33 798
• 5 Chalecka-Franaszek E, Chuang D M. Lithium activates the serine/threonine kinase Akt-1 and suppresses glutamate-induced inhibition of Akt-1 activity in neurons.  Proc Natl Acad Sci USA. 1999;  96 8745-8750
• 6 Chen B, Dowlatshahi D, MacQueen G M, Wang J, Young L T. Increased hippocampal bdnf immunoreactivity in subjects treated with antidepressant medication.  Biol Psychiatry. 2001;  50 260-265
• 7 Chen G, Huang L D, Jiang Y M, Manji H K. The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3.  J Neurochem. 1999;  72 1327-1330
• 8 Chen G, Rajkowska G, Du F, Seraji-Bozorgzad Manji H K. Enhancement of hippocampal neurogenesis by lithium.  J Neurochem. 2000;  75 1729-1734
• 9 Chen R W, Qin Z H, Ren M, Kanai H, Chalecka-Franaszek E, Leeds P, Chuang D M. Regulation of c-Jun N-terminal kinase, p38 kinase and AP-1 DNA binding in cultured brain neurons: roles in glutamate excitotoxicity and lithium neuroprotection.  J Neurochem. 2003;  84 566-575
• 10 Coyle J T, Duman R S. Finding the intracellular signaling pathways affected by mood disorder treatments.  Neuron. 2003;  38 157-160
• 11 Cross D A, Alessi D R, Cohen P, Andjelkovich M, Hemmings B A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B.  Nature. 1995;  378 785-789
• 12 Datta S R, Brunet A, Greenberg M E. Cellular survival: a play in three Akts.  Genes Dev.. 1999;  13 2905-2927
• 13 Davis G W, Schuster C M, Goodman C S. Genetic dissection of structural and functional components of synaptic plasticity. III. CREB is necessary for presynaptic functional plasticity.  Neuron. 1996;  17 669-679
• 14 Deisseroth K, Bito H, Tsien R W. Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity.  Neuron. 1996;  16 89-101
• 15 Denicoff K D, Ali S O, Mirsky A F, Smith-Jackson E E, Leverich G S, Duncan C C, Connell E G, Post R M. Relationship between prior course of illness and neuropsychological functioning in patients with bipolar disorder.  J Affect Disord. 1999;  56 67-73
• 16 Deshauer D, Grof E, Alda M, Grof P. Patterns of DST positivity in remitted affective disorders.  Biol Psychiatry. 1999;  45 1023-1029
• 17 Dixon J F, Hokin L E. Lithium acutely inhibits and chronically up-regulates and stabilizes glutamate uptake by presynaptic nerve endings in mouse cerebral cortex.  Proc Natl Acad Sci USA. 1998;  95 8363-8367
• 18 Dong G X, Singh D K, Dendle P, Prasad R M. Regional expression of Bcl-2 mRNA and mitochondrial cytochrome c release after experimental brain injury in the rat.  Brain Res. 2001;  903 45-52
• 19 Drevets W C. Neuroimaging studies of mood disorders.  Biol Psychiatry. 2000;  488 13-828
• 20 Drevets W C, Ongur D, Price J L. Neuroimaging abnormalities in the subgenual prefrontal cortex: implications for the pathophysiology of familial mood disorders.  Mol Psychiatry. 1998;  3 220-6, 190 - 191
• 21 Frame S, Cohen P, Biondi R M. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation.  Mol Cell. 2001;  7 1321-1327
• 22 Ferrier I N, Stanton B R, Kelly T P, Scott J. Neuropsychological function in euthymic patients with bipolar disorder.  Br J Psychiatry. 1999;  175 246-251
• 23 Greil W, Ludwig-Mayerhofer W, Erazo N, Schochlin C, Schmidt S, Engel R R, Czernik A, Giedke H, Muller-Oerlinghausen B, Osterheider M, Rudolf G AE, Sauer H, Tegeler J, Wetterling T. Lithium versus carbamazepine in the maintenance treatment of bipolar disorders - a randomised study.  J Affect Disord. 1997;  43 151-161
• 24 Grimes C A, Jope R S. CREB DNA binding activity is inhibited by glycogen synthase kinase-3 beta and facilitated by lithium.  J Neurochem. 2001;  78 1219-1232
• 25 Grof P, Alda M, Grof E, Fox D, Cameron P. The challenge of predicting response to lithium stabilization. The importance of patient selection.  Br J Psychiatry. 1993;  163 ( 21) 16-19
• 26 Gyulai L, Bauer M, Bauer M S, García-España F, Cnaan A, Whybrow P C. Thyroid hypofunction in patients with rapid cycling bipolar disorder after lithium challenge.  Biol Psychiatry. 2003;  53 899-905
• 27 Harris E C, Barraclough B. Excess mortality of mental disorder.  Br J Psychiatry. 1998;  173 11-53
• 28 Hashimoto R, Fujimaki K, Jeong M R, Christ L, Chuang D M. Lithium-induced inhibition of Src tyrosine kinase in rat cerebral cortical neurons: a role in neuroprotection against N-methyl-D-aspartate receptor-mediated excitotoxicity.  FEBS Lett. 2003;  538 145-148
• 29 Hashimoto R, Hough C, Nakazawa T, Yamamoto T, Chuang D M. Lithium protection against glutamate excitotoxicity in rat cerebral cortical neurons: involvement of NMDA receptor inhibition possibly by decreasing NR2B tyrosine phosphorylation.  J Neurochem. 2002;  80 589-597
• 30 Hashimoto R, Senatorov V, Kanai H, Leeds P, Chuang D -M. Lithium stimulates progenitor proliferation in cultured brain neurons.  Neuroscience. 2003;  117 55-61
• 31 Hashimoto R, Takei N, Shimazu K, Christ L, Lu B, Chuang D M. Lithium induces brain-derived neurotrophic factor and activates TrkB in rodent cortical neurons: an essential step for neuroprotection against glutamate excitotoxicity.  Neuropharmacology. 2002;  43 1173-1179
• 32 Jope R S. Anti-bipolar therapy: mechanism of action of lithium.  Mol Psychiatry. 1999;  4 117-128
• 33 Kane D J, Sarafian T A, Anton , Hahn H, Gralla E B, Valentine J S, Ord T, Bredesen D E. Bcl-2 inhibition of neural death: decreased generation of reactive oxygen species.  Science. 1993;  262 1274-1277
• 34 Kessing L V. Cognitive impairment in the euthymic phase of affective disorder.  Psychol Med. 1998;  38 1027-1038
• 35 Klein P S, Melton D A. A molecular mechanism for the effect of lithium on development.  Proc Natl Acad Sci USA. 1996;  93 8455-8459
• 36 Kopnisky K L, Chalecka-Franaszek E, Gonzalez-Zulueta M, Chuang D M. Chronic lithium treatment antagonizes glutamate-induced decrease of phosphorylated CREB in neurons via reducing protein phosphatase 1 and increasing MEK activities.  Neuroscience. 2003;  116 425-435
• 37 Kowaltowski A J, Vercesi A E, Fiskum G. Bcl-2 prevents mitochondrial permeability transition and cytochrome c release via maintenance of reduced pyridine nucleotides.  Cell Death Differ. 2000;  7 903-910
• 38 MacQueen G M, Grof P, Alda M, Marriott M, Young L T, Duffy A. Backward masking task performance in affected versus unaffected children of parents with lithium responsive bipolar disorder. Submitted. 
• 39 Manji H K, Chen G. PKC, MAP kinases and the bcl-2 family of proteins as long-term targets for mood stabilizers.  Mol Psychiatry. 2002;  7 (Suppl 1) S46-56
• 40 Manji H K, Moore G J, Chen G. Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilizers.  Br J Psychiatry. 2001;  178 (Suppl 41) 107-119
• 41 Manji H K, Moore G J, Rajkowska G, Chen G. Neuroplasticity and cellular resilience in mood disorders.  Mol Psychiatry. 2000;  5 578-593
• 42 Manji H K, Quiroz J A, Sporn J, Payne J L, Denicoff K, A Gray N, Zarate CA J r, Charney D S. Enhancing neuronal plasticity and cellular resilience to develop novel, improved therapeutics for difficult-to-treat depression.  Biol Psychiatry. 2003;  53 707-742
• 43 Müller-Oerlinghausen B, Berghöfer A, Bauer M. Bipolar disorder.  Lancet. 2002;  359 241-247
• 44 Nemeth Z H, Deitch E A, Szabo C, Fekete Z, Hauser C J, Hasko G. Lithium induces NF-kappa B activation and interleukin-8 production in human intestinal epithelial cells.  J Biol Chem. 2002;  277 7713-7719
• 45 Nonaka S, Chuang D M. Neuroprotective effects of chronic lithium on focal cerebral ischemia in rats.  Neuroreport. 1998;  9 2081-2084
• 46 Nonaka S, Hough C J, Chuang D. Chronic lithium treatment robustly protects neurons in the central nervous system against excitotoxicity by inhibiting N-methyl-D-aspartate receptor-mediated calcium influx.  Proc Natl Acad Sci USA. 1998;  95 2642-2647
• 47 Nonaka S, Katsube N, Chuang D M. Lithium protects rat cerebellar granule cells against apoptosis induced by anticonvulsants, phenytoin and carbamazepine.  J Pharmacol Exp Ther. 1998;  286 39-47
• 48 Ongur D, Drevets W C, Price J L. Glial reduction in the subgenual prefrontal cortex in mood disorders.  Proc Natl Acad Sci USA. 1998;  95 13 290-13 295
• 49 Ozaki N, Chuang D M. Lithium increases transcription factor binding to AP-1 and cyclic AMP-responsive element in cultured neurons and rat brain.  J Neurochem. 1997;  69 2336-2344
• 50 Passmore M, Garnham J, Duffy A, MacDougall M, Munro A, Slaney C, Teehan A, Alda M. Phenotypic spectra of bipolar disorder in responders to lithium versus lamotrigine.  Bipol Disord. 2003;  5 110 - 114
• 51 Phiel C J, Klein P S. Molecular targets of lithium action.  Annu Rev Pharmacol Toxicol. 2001;  41 789-813
• 52 Phiel C J, Wilson C A, Lee V M-Y, Klein P S. GSK-3α regulates production of Alzheimer's disease amyloid-β peptides.  Nature. 2003;  423 435-439
• 53 Pilcher H R. Drug research: the ups and downs of lithium.  Nature. 2003;  425 118-120
• 54 Post R M, Uhde T W, Roy-Byrne P P, Joffe R T. Correlates of antimanic response to carbamazepine.  Psychiatr Res. 1987;  21 71-83
• 55 Post R M, Weiss S RB. Neurobiological models of recurrence in mood disorder. In: Charney DS, Nestler EJ, Bunney BS, eds Neurobiology of Mental Illness. New York; Oxford University Press 1999: 365-384
• 56 Rajkowska G, Halaris A, Selemon L D. Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder.  Biol Psychiatry. 2001;  49 741-752
• 57 Ren M, Senatorov V V, Chen R -W, Chuang D -M. Postinsult treatment with lithium reduces brain damage and facilitates neurological recovery in a rat ischemia/reperfusion model.  Proc Natl Acad Sci USA. 2003;  100 6210-6215
• 58 Ross E M. Signal sorting and amplification through G protein-coupled receptors.  Neuron. 1989;  3 141-152
• 59 Rubinsztein J S, Michael A, Paykel E S, Sahakian B J. Cognitive impairment in bipolar affective disorder.  Psychol Med. 2000;  30 1025-1036
• 60 Sapolsky R M. Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders.  Arch Gen Psychiatry. 2000;  57 925-935
• 61 Silva A J, Kogan J H, Frankland P W, Kida S. CREB and memory.  Annu Rev Neurosci. 1998;  21 127-148
• 62 Stambolic V, Ruel L, Woodgett J R. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells.  Curr Biol. 1996;  6 1664-1668
• 63 Strakowski S M, DelBello M P, Adler C, Cecil D M, Sax K W. Neuroimaging in bipolar disorder.  Bipol Disord. 2000;  2 148-164
• 64 Swann A C, Bowden C L, Morris D, Calabrese J R, Petty F, Small J, Dilsaver S C, Davis J M. Depression during mania. Treatment response to lithium or divalproex.  Arch Gen Psychiatry. 1997;  54 37-42
• 65 Tham A, Engelbrektson K, Mathe A A, Johnson L, Olsson E, Aberg-Wistedt A. Impaired neuropsychological performance in euthymic with recurring mood disorders.  J Clin Psychiatry. 1997;  58 26-29
• 66 vanGorp W G, Altshuler L, Theberge D C, Wilkins J, Dixon W. Cognitive impairment in euthymic bipolar patients with and without prior alcohol dependence.  Arch Gen Psychiatry. 1998;  55 41-46
• 67 Walton M R, Dragunow I. Is CREB a key to neuronal survival?.  Trends Neurosci. 2000;  23 48-53
• 68 Wang J F, Li P P, Warsh J J, Young L T. Signal transduction abnormalities in bipolar disorder. In: Young LT, Joffe RT, eds Bipolar disorder: biological models and their clinical application. New York; Marcel Dekker, Inc 1997: 41-79
• 69 Wei H, Qin Z -H, Senatorov V V, Wei W, Wang Y, Qian Y, Chuang D -M. Lithium suppresses excitotoxicity-induced striatal lesions in a rat model of Huntington's disease.  Neuroscience. 2001;  106 603-612
• 70 Young L T, Li P P, Kish S J, Warsh J J. Cerebral cortex beta-adrenoceptor binding in bipolar affective disorder.  J Affect Disord. 1994;  30 89-92
• 71 Young L T, Joffe R T. Bipolar disorder: biological models and their clinical application. New York, NY; Marcel Dekker 1997
• 72 Yuan P, Chen G, Manji H K. Lithium activates the c-Jun NH2-terminal kinases in vitro and in the CNS in vivo.  J Neurochem. 1999;  73 2299-2309
• 73 Yuan P X, Huang L D, Jiang Y M, Gutkind J S, Manji H K, Chen G. The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth.  J Biol Chem. 2001;  276 31 674-31 683