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01-12-2008 | Original Paper

Effects of the HIV treatment drugs nevirapine and efavirenz on brain creatine kinase activity

Authors: Emilio L. Streck, Giselli Scaini, Gislaine T. Rezin, Jeverson Moreira, Celine M. Fochesato, Pedro R. T. Romão

Published in: Metabolic Brain Disease | Issue 4/2008

Abstract

Nevirapine (NVP) and efavirenz (EFV) are antiretroviral drugs belonging to potent class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) widely used for the treatment human immunodeficiency virus (HIV) infection. It has been demonstrated that NVP and EFV are able to cross the blood–brain barrier and arrive at the central nervous system (CNS), causing important adverse effects related to their presence within this tissue. Considering that the exact mechanisms responsible for CNS toxicity associated with NVP and EFV remain unknown and that creatine kinase (CK) plays an important role in cell energy homeostasis, in the present work we evaluated CK activity in brain of mice after chronic administration of these drugs. Our results demonstrated that NVP and EFV significantly inhibited CK activity in cerebellum, hippocampus, striatum and cortex of mice. Although it is difficult to extrapolate our findings to the human condition, the inhibition of brain CK activity by NVP and EFV may be associated with neurological adverse symptoms of these drugs.

Adkins JC, Noble S (1998) Efavirenz. Drugs 56:1055–1064PubMedCrossRef

Aksenov M, Butterfield DA, Markesbery WR (2000) Oxidative modification of creatine kinase BB in Alzheimer’s disease brain. J Neurochem 74:2520–2527PubMedCrossRef

Anthonypillai C, Sanderson RN, Gibbs JE, Thomas SA (2004) The distribution of the HIV protease inhibitor, ritonavir, to the brain, cerebrospinal fluid, and choroid plexuses of the guinea pig. J Pharmacol Exp Ther 308:912–920PubMedCrossRef

Anthonypillai C, Gibbs JE, Thomas SA (2006) The distribution of the anti-HIV drug, tenofovir (PMPA), into the brain, CSF and choroid plexuses. Cerebrospinal Fluid Res 3:1–10PubMedCrossRef

Arendt G, de Nocker D, von Giesen HJ, Nolting T (2007) Neuropsychiatric side effects of efavirenz therapy. Expert Opin Drug Saf 6:147–154PubMedCrossRef

Assis LC, Scaini G, Di-Pietro PB, Castro AA, Comim CM, Streck EL, Quevedo J (2007) Effect of antipsychotics on creatine kinase activity in rat brain. Basic Clin Pharmacol Toxicol 101:315–319PubMedCrossRef

Bessman SP, Carpenter CL (1985) The creatine–creatine phosphate energy shuttle. Annu Rev Biochem 54:831–865PubMedCrossRef

Bickel M, Stephan C, Rottmann C, Carlebach A, Haberl A, Kurowski M, Staszewski S (2005) Severe CNS side-effect and persistent high efavirenz plasma levels in a patient with HIV/HCV coinfection and liver cirrhosis. Scand J Infect Dis 37:520–522PubMedCrossRef

Blass JP (2001) Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia? J Neurosci Res 66:851–856PubMedCrossRef

Búrigo M, Roza CA, Bassani C, Feier G, Dal-Pizzol F, Quevedo J, Streck EL (2006) Decreased creatine kinase activity caused by electroconvulsive shock. Neurochem Res 31:877–881PubMedCrossRef

David S, Shoemaker M, Haley BE (1998) Abnormal properties of creatine kinase in Alzheimer’s disease brain: correlation of reduced enzyme activity and active site photolabeling with aberrant cytosol–membrane partitioning. Mol Brain Res 54:276–287PubMedCrossRef

Dore GJ, Correll PK, Li Y, Kaldor JM, Cooper DA, Brew BJ (1999) Changes to AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 13:1249–1253PubMedCrossRef

Dybul M, Fauci AS, Bartlett JG, Kaplan JE, Pau AK (2002) Panel on clinical practices for the treatment of HIV. Guidelines for using antiretroviral agents among HIV-infected adults and adolescents. Recommendations of the panel on clinical practices for treatment of HIV. MMWR Recomm Rep 51:1–55PubMed

Fumaz CR, Munõz-Moreno JA, Moltó J, Negredo E, Ferrer MJ, Sirera G, Pérez-Alvarez N, Gómez G, Burger D, Clotet B (2005) Long-term neuropsychiatric disorders on efavirenz-based approaches: quality of life, psychologic issues, and adherence. J Acquir Immune Defic Syndr 38:560–565PubMedCrossRef

Gibbs JE, Gaffen Z, Thomas SA (2006) Nevirapine uptake into the central nervous system of the Guinea pig: an in situ brain perfusion study. J Pharmacol Exp Ther 317:746–751PubMedCrossRef

Gross WL, Bak MI, Ingwall JS, Arstall MA, Smith TW, Balligand JL, Kelly RA (1996) Nitric oxide inhibits creatine kinase and regulates rat heart contractile reserve. Proc Natl Acad Sci USA 93:5604–5609PubMedCrossRef

Gutiérrez F, Navarro A, Padilla S, Antón R, Masiá M, Borrás J, Martín-Hidalgo A (2005) Prediction of neuropsychiatric adverse events associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin Infect Dis 41:1648–1653PubMedCrossRef

Haas DW, Ribaudo HJ, Kim RB, Tierney C, Wilkinson GR, Gulick RM Clifford DB, Hulgan T, Marzolini C, Acosta EP (2004) Pharmacogenetics of efavirenz and central nervous system side effects: an adult AIDS clinical trials group study. AIDS 18(18):2391–2400PubMed

Hawkins T, Geist C, Young B, Giblin A, Mercier RC, Thornton K, Haubrich R (2005) Comparison of neuropsychiatric side effects in an observational cohort of efavirenz- and protease inhibitor-treated patients. HIV Clin Trials 6:187–196PubMedCrossRef

Heales SJ, Bolaños JP, Stewart VC, Brookes PS, Land JM, Clark JB (1999) Nitric oxide, mitochondria and neurological disease. Biochim Biophys Acta 1410:215–228PubMedCrossRef

Hughes BP (1962) A method for estimation of serum creatine kinase and its use in comparing creatine kinase and aldolase activity in normal and pathologic sera. Clin Chim Acta 7:597–604PubMedCrossRef

Jost CR, Van der Zee CE, Zandt HJ, Oerlemans F, Verheij M, Streijger F, Fransen J, Heerschap A, Cools AR, Wieringa B (2002) Creatine kinase B-driven energy transfer in the brain is important for habituation and spatial learning behaviour, mossy fibre field size and determination of seizure susceptibility. Eur J Neurosci 15:1692–1706PubMedCrossRef

Khuchua ZA, Qin W, Boero J, Cheng J, Payne RM, Saks VA, Strauss AW (1998) Octamer formation and coupling of cardiac sarcomeric mitochondrial creatine kinase are mediated by charged N-terminal residues. J Biol Chem 273:22990–22996PubMedCrossRef

Lewis W, Kohler JJ, Hosseini SH, Haase CP, Copeland WC, Bienstock RJ Ludaway T, McNaught J, Russ R, Stuart T, Santoianni R (2006) Antiretroviral nucleosides, deoxynucleotide carrier and mitochondrial DNA: evidence supporting the DNA pol gamma hypothesis. AIDS 20:675–684PubMedCrossRef

Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–267PubMed

Maggiolo F (2007) Efavirenz. Expert Opin Pharmacoter 8(8):1137–1145CrossRef

Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T (2001) Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 15:71–75PubMedCrossRef

Piacenti FJ (2006) An update and review of antiretroviral therapy. Pharmacotherapy 26:1111–1133PubMedCrossRef

Rihs TA, Begley K, Smith DE, Sarangapany J, Callaghan A, Kelly M, Post JJ, Gold J (2006) Efavirenz and chronic neuropsychiatric symptoms: a cross-sectional case control study. HIV Med 7:544–548PubMedCrossRef

Sacktor N, Lyles RH, Skolasky R, Kleeberger C, Selnes OA, Miller EN, Becker JT, Cohen B, McArthur JC (2001) HIV-associated neurologic disease incidence changes: multicenter AIDS cohort study, 1990–1998. Neurology 56:257–260PubMed

Schlattner U, Wallimann T (2000) Octamers of mitochondrial creatine kinase isoenzymes differ in stability and membrane binding. J Biol Chem 275:17314–17320PubMedCrossRef

Schurr A (2002) Energy metabolism, stress hormones and neural recovery from cerebral ischemia/hypoxia. Neurochem Int 41:1–8PubMedCrossRef

Streck EL, Amboni G, Scaini G, Di-Pietro PB, Rezin GT, Valvassori SS, Luz G, Kapczinski F, Quevedo J (2008) Brain creatine kinase activity in an animal model of mania. Life Sci 82:424–429PubMedCrossRef

Streijger F, Jost CR, Oerlemans F, Ellenbroek BA, Cools AR, Wieringa B, Van der Zee CE (2004) Mice lacking the UbCKmit isoform of creatine kinase reveal slower spatial learning acquisition, diminished exploration and habituation, and reduced acoustic startle reflex responses. Mol Cell Biochem 256/257:305–318CrossRef

Streijger F, Oerlemans F, Ellenbroek BA, Jost CR, Wieringa B, Van der Zee CE (2005) Structural and behavioural consequences of double deficiency for creatine kinases BCK and UbCKmit. Behav Brain Res 157:219–234PubMedCrossRef

Tashima KT, Caliendo AM, Ahmad M, Gormley JM, Fiske WD, Brennan JM, Flanigan TP (1999) Cerebrospinal fluid human immunodeficiency virus type 1 (HIV-1) suppression and efavirenz drug concentrations in HIV-1-infected patients receiving combination therapy. J Infect Dis 180:862–864PubMedCrossRef

Tomimoto H, Yamamoto K, Homburger HA, Yanagihara T (1993) Immunoelectron microscopic investigation of creatine kinase BB-isoenzyme after cerebral ischemia in gerbils. Acta Neuropathol 86:447–455PubMed

Treisman GJ, Kaplin AI (2002) Neurologic and psychiatric complications of antiretroviral agents. AIDS 16:1201–1215PubMedCrossRef

van Praag RM, van Weert EC, van Heeswijk RP, Zhou XJ, Sommadossi JP, Jurriaans S, Lange JM, Hoetelmans RM, Prins JM (2002) Stable concentrations of zidovudine, stavudine, lamivudine, abacavir, and nevirapine in serum and cerebrospinal fluid during 2 years of therapy. Antimicrob Agents Chemother 46:896–899PubMedCrossRef

von Giesen HJ, Köller H, Theisen A, Arendt G (2002) Therapeutic effects of nonnucleoside reverse transcriptase inhibitors on the central nervous system in HIV-1-infected patients. J Acquir Immune Defic Syndr 29:363–367

Wallimann T, Wyss M, Brdiczka D, Nicolay K, Eppenberger HM (1992) Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem J 281:21–40PubMed

Wise ME, Mistry K, Reid S (2002) Drug points: neuropsychiatric complications of nevirapine treatment. BMJ 324:879PubMedCrossRef

Wynn HE, Brundage RC, Fletcher CV (2002) Clinical implications of CNS penetration of antiretroviral drugs. CNS Drugs 16:595–609PubMedCrossRef

Zanette F, Victor EG, Scaini G, Di-Pietro PB, Cardoso DC, Cristiano MP, Dal-Pizzol F, Paula MM, Streck EL (2007) Modulation of creatine kinase activity by ruthenium complexes. J Inorg Biochem 101:267–273PubMedCrossRef

Title: Effects of the HIV treatment drugs nevirapine and efavirenz on brain creatine kinase activity
Authors: Emilio L. Streck
Giselli Scaini
Gislaine T. Rezin
Jeverson Moreira
Celine M. Fochesato
Pedro R. T. Romão
Publication date: 01-12-2008
Publisher: Springer US
Published in: Metabolic Brain Disease / Issue 4/2008
Print ISSN: 0885-7490
Electronic ISSN: 1573-7365
DOI: https://doi.org/10.1007/s11011-008-9109-2

At a glance: The STEP trials

Springer Medicine

Effects of the HIV treatment drugs nevirapine and efavirenz on brain creatine kinase activity

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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