Abstract
Lithium, which is approved for treating patients with bipolar disorder, is reported to inhibit 3′(2′)-phosphoadenosine-5′-phosphate (PAP) phosphatase activity. In yeast, deletion of PAP phosphatase results in elevated PAP levels and in inhibition of sulfation and of growth. The effect of lithium on PAP phosphatase is remarkable for the low Ki (~0.2 mM), suggesting that this system would be almost completely shut down in vivo with therapeutic levels of 1 mM lithium, thereby elevating PAP levels. To test the hypothesis that lithium inhibition of PAP phosphatase is pharmacologically relevant to bipolar disorder, we fed rats LiCl for 6 weeks, and assayed brain PAP levels after subjecting the brain to high-energy microwaving. We also measured PAP phosphatase mRNA and protein levels in frozen brain tissue of lithium-treated mice. Brain adenosine phosphates were extracted by trichloroacetic acid and assayed by HPLC with a gradient system of two phases. PAP phosphatase mRNA was measured by RT-PCR, and PAP phosphatase protein was measured by Western blotting. Brain PAP levels were below detection limit of 2 nmol/g wet weight, even following lithium treatment. Lithium treatment also did not significantly change brain PAP phosphatase mRNA or protein levels. These results question the relevance of PAP phosphatase to the therapeutic mechanism of lithium. A statistically significant 25% reduced brain ADP/ATP ratio was found following lithium treatment in line with lithium’s suggested neuroprotective effects.
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References
Agam G, Shaltiel G (2003) Possible role of 3′(2′)-phosphoadenosine-5′-phosphate phosphatase in the etiology and therapy of bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry 27:723–727
Agam G, Shaltiel G, Kozlovsky N, Shimon H, Belmaker RH (2003) Lithium inhibitable enzymes in postmortem brain of bipolar patients. J Psychiatr Res 37:433–442
Basselin M, Chang L, Rapoport SI (2006) Chronic lithium chloride administration to rats elevates glucose metabolism in wide areas of brain, while potentiating negative effects on metabolism of dopamine D2-like receptor stimulation. Psychopharmacology (Berl) 187:303–311
Bosetti F, Rintala J, Seemann R, Rosenberger TA, Contreras MA, Rapoport SI, Chang MC (2002) Chronic lithium downregulates cyclooxygenase-2 activity and prostaglandin E(2) concentration in rat brain. Mol Psychiatry 7:845–850
Brzeznicka EA, Hazelton GA, Klaassen CD (1987) Comparison of adenosine 3′-phosphate 5′-phosphosulfate concentrations in tissues from different laboratory animals. Drug Metab Dispos 15:133–135
Chang MC, Jones CR (1998) Chronic lithium treatment decreases brain phospholipase A2 activity. Neurochem Res 23:887–892
Chen Y, Xing D, Wang W, Ding Y, Du L (2007) Development of an ion-pair HPLC method for investigation of energy charge changes in cerebral ischemia of mice and hypoxia of Neuro-2a cell line. Biomed Chromatogr 21:628–634
Deutsch J, Rapoport SI, Rosenberger TA (2002) Coenzyme A and short-chain acyl-CoA species in control and ischemic rat brain. Neurochem Res 27:1577–1582
Dichtl B, Stevens A, Tollervey D (1997) Lithium toxicity in yeast is due to the inhibition of RNA-processing enzymes. EMBO J 16:7184–7195
Folbergrova J, Ingvar M, Siesjo BK (1981) Metabolic changes in cerebral cortex, hippocampus, and cerebellum during sustained bicuculline-induced seizures. J Neurochem 37:1228–1238
Hallcher LM, Sherman WR (1980) The effects of lithium ion and other agents on the activity of myo-inositol-1-phosphatase from bovine brain. J Biol Chem 255:10896–10901
Kim HJ, Madhu C, Cho JH, Klaassen CD (1995) In vivo modification of 3′-phosphoadenosine 5′-phosphosulfate and sulfate by infusion of sodium sulfate, cysteine, and methionine. Drug Metab Dispos 23:840–845
Klaassen CD, Boles JW (1997) Sulfation and sulfotransferases 5: the importance of 3′-phosphoadenosine 5′-phosphosulfate (PAPS) in the regulation of sulfation. FASEB J 11:404–418
Klein PS, Melton DA (1996) A molecular mechanism for the effect of lithium on development. Proc Natl Acad Sci USA 93:8455–8459
Kozlovsky N, Belmaker RH, Agam G (2000) Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients. Am J Psychiatry 157:831–833
Lopez-Coronado JM, Belles JM, Lesage F, Serrano R, Rodriguez PL (1999) A novel mammalian lithium-sensitive enzyme with a dual enzymatic activity, 3′-phosphoadenosine 5′-phosphate phosphatase and inositol-polyphosphate 1-phosphatase. J Biol Chem 274:16034–16039
Maayan R, Shaltiel G, Poyurovsky M, Ramadan E, Morad O, Nechmad A, Weizman A, Agam G (2004) Chronic lithium treatment affects rat brain and serum dehydroepiandrosterone (DHEA) and DHEA-sulphate (DHEA-S) levels. Int J Neuropsychopharmacol 7:71–75
Macko AR, Beneze AN, Teachey MK, Henriksen EJ (2008) Roles of insulin signalling and p38 MAPK in the activation by lithium of glucose transport in insulin-resistant rat skeletal muscle. Arch Physiol Biochem 114:331–339
McQuillin A, Rizig M, Gurling HM (2007) A microarray gene expression study of the molecular pharmacology of lithium carbonate on mouse brain mRNA to understand the neurobiology of mood stabilization and treatment of bipolar affective disorder. Pharmacogenet Genomics 17:605–617
Nemanov L, Ebstein R, Belmaker R, Osher Y, Agam G (1999) Effect of bipolar disorder on lymphocyte inositol monophosphatase mRNA levels. Int J Neuropsychopharmacol 2:25–29
Rowe MK, Chuang DM (2004) Lithium neuroprotection: molecular mechanisms and clinical implications. Expert Rev Mol Med 6:1–18
Shaldubina A, Agam G, Belmaker RH (2001) The mechanism of lithium action: state of the art, ten years later. Prog Neuropsychopharmacol Biol Psychiatry 25:855–866
Shaltiel G, Kozlovsky N, Belmaker RH, Agam G (2002) 3′(2′)-Phosphoadenosine 5′-phosphate phosphatase is reduced in postmortem frontal cortex of bipolar patients. Bipolar Disord 4:302–306
Shamir A, Shaltiel G, Greenberg ML, Belmaker RH, Agam G (2003) The effect of lithium on expression of genes for inositol biosynthetic enzymes in mouse hippocampus; a comparison with the yeast model. Brain Res Mol Brain Res 115:104–110
Spiegelberg BD, Dela Cruz J, Law TH, York JD (2005) Alteration of lithium pharmacology through manipulation of phosphoadenosine phosphate metabolism. J Biol Chem 280:5400–5405
Spiegelberg BD, Xiong JP, Smith JJ, Gu RF, York JD (1999) Cloning and characterization of a mammalian lithium-sensitive bisphosphate 3′-nucleotidase inhibited by inositol 1, 4-bisphosphate. J Biol Chem 274:13619–13628
Yenush L, Belles JM, Lopez-Coronado JM, Gil-Mascarell R, Serrano R, Rodriguez PL (2000) A novel target of lithium therapy. FEBS Lett 467:321–325
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The experiments performed on rats were entirely supported by the Intramural Program of the National Institute on Aging, National Institutes of Health.
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Invited manuscript from 1st Inter-Academic Symposium, Jerusalem 2008
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Shaltiel, G., Deutsch, J., Rapoport, S.I. et al. Is phosphoadenosine phosphate phosphatase a target of lithium’s therapeutic effect?. J Neural Transm 116, 1543–1549 (2009). https://doi.org/10.1007/s00702-009-0298-6
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DOI: https://doi.org/10.1007/s00702-009-0298-6