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Metab Brain Dis (2008) 23:485–492DOI 10.1007/s11011-008-9109-2 Effects of the HIV treatment drugs nevirapineand efavirenz on brain creatine kinase activity Emilio L. Streck & Giselli Scaini & Gislaine T. Rezin &Jeverson Moreira & Celine M. Fochesato &Pedro R. T. Romão Received: 2 June 2008 / Accepted: 15 August 2008 /Published online: 24 September 2008 # Springer Science + Business Media, LLC 2008 Abstract Nevirapine (NVP) and efavirenz (EFV) are antiretroviral drugsbelonging 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 theblood–brain barrier and arrive at the central nervous system (CNS), causingimportant adverse effects related to their presence within this tissue. Consid-ering that the exact mechanisms responsible for CNS toxicity associated withNVP and EFV remain unknown and that creatine kinase (CK) plays animportant role in cell energy homeostasis, in the present work we evaluated CKactivity in brain of mice after chronic administration of these drugs. Our resultsdemonstrated that NVP and EFV significantly inhibited CK activity incerebellum, hippocampus, striatum and cortex of mice. Although it is difficultto extrapolate our findings to the human condition, the inhibition of brain CKactivity by NVP and EFV may be associated with neurological adversesymptoms of these drugs.
Keywords Antiretroviral drugs . Efavirenz . Nevirapine . Creatine kinase E. L. Streck G. Scaini G. T. RezinLaboratório de Fisiopatologia Experimental, Unidade Acadêmica de Ciências da Saúde,Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense,Criciúma, SC, Brazil J. Moreira C. M. Fochesato P. R. T. Romão (*)Laboratório de Imunologia e Mutagênese, Unidade Acadêmica de Ciências da Saúde,Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense,Criciúma, SC, Brazile-mail: ptr@unesc.net Nevirapine (NVP) and efavirenz (EFV) are antiretroviral drugs belonging to potentclass of non-nucleoside reverse transcriptase inhibitors (NNRTIs), drugs currentlyused as part of highly active antiretroviral therapy (HAART) regimen. They arerecommended at initial therapy for asymptomatic HIV patients or in advanceddisease and also in patients presenting with failure of antiretroviral therapy (Dybul etal. The HAART completely changed the clinical evolution of HIV infection,reducing the morbidity and mortality among HIV-1 infected patients and changingthe incidence of neurological complications in acquired immunodeficiency syn-drome (AIDS) patients (Dore et al. ; Sacktor et al. ). Nevertheless, drugrelated toxicity is one of the obstacles in the fight against AIDS (von Giesen et al.
).
It was well demonstrated that both NNRTIs, NVP and EFV, are able to cross the blood–brain barrier and enter the central nervous system (CNS) (von Giesen et al.
; Treisman and Kaplin and possibly cause important adverse effectsrelated to their presence within this tissue, especially EFV (Bickel et al. ;Arendt et al. ; Maggiolo ).
NVP is the oldest NNRTI offering a better treatment compliance due to its once daily initial dosage (only for the first 2 weeks, after that the dosage goes to twicedaily). Despite this advantage, side effects such as hypersensitivity reaction, gastriccomplications and hepatotoxicity can be frequently observed. Futhermore, neuro-psychiatry complications have been associated with its use (Wise et al. ).
EFV is known by its efficacy and easy treatment compliance. However, it was observed that more than 50% of patients receiving EFV reported neurologicaladverse symptoms which are very specific of this NNRTI. CNS side effectsincluding insomnia, dizziness, impaired concentration, vertigo, depression, abnormaldreams and hallucinations are very frequent during the first week of therapy(Treisman and Kaplin ; Bickel et al. Adkins and Noble ; Gutiérrez etal. ). Recent studies have demonstrated that neuropsychiatry disorders maypersist in patients chronically treated with EFV (Fumaz et al. ; Rihs et al. The exact mechanism responsible for CNS toxicity associated with EFV remainsunknown, but plasma and intracellular drug concentrations and CYP2B6 genotypehave been found to be predictors of early neuropsychological disturbances inpatients starting antiretroviral therapy regimens containing EFV (Haas et al. ;Gutiérrez et al. Although HAART regimen represents a very important role in the treatment of HIV/AIDS, its side effects can be responsible for patients’ non adherence to drugs,contributing to the treatment failure and development of resistant HIV strains(Piacenti Creatine kinase (CK; E.C. 2.7.3.2) catalyzes the reversible transfer of a phosphoryl group from ATP to creatine, producing phosphocreatine and ADP(Bessman and Carpenter Wallimann et al. ). This enzyme plays animportant role in the rapid regeneration of ATP in high–energy consuming tissuessuch as brain, skeletal muscle and heart, where it functions as an effective bufferingsystem of cellular ATP levels. In this context, it has been widely shown that adecrease in CK activity is associated with a neurodegenerative pathway that results in neuronal loss following brain ischemia (Tomimoto et al. neurodegenerativediseases (David et al. ; Aksenov et al. and other pathological states(Gross et al. ; Streck et al. ). Moreover, we have recently demonstrated thatbrain CK activity is altered by antipsychotic (Assis et al. electroconvulsiveschock (Búrigo et al. and ruthenium compounds (Zanette et al. ).
Therefore, considering that CK plays an important role in cell energy homeostasis, that impairment of brain metabolism is linked to neuronal death andthat NVP and mainly EFV-treated patients present important CNS adverse effects, inthe present work we evaluated CK activity in brain of mice after chronicadministration of these drugs.
Animals Male CF-1 mice (age 60–90 days; weight 30–40 g) were obtained from theState Foundation for Health Science Research (FEPPS-RS, Porto Alegre, Brazil),and maintained in the animal facility of Universidade do Extremo Sul Catarinense(UNESC) for at least 2 weeks before drug treatment. The animals were housed inplastic cages, eight per cage, under 12 h light/dark cycle (lights on 7:00 A.M.) atconstant room temperature of 23±1°C; with water and food ad libitum. Allexperimental procedures were carried out in accordance with the National Institutesof Health Guide for the Care and Use of Laboratory Animals and the BrazilianSociety for Neuroscience and Behavior (SBNeC) recommendations for animal care,with the approval of local Ethics Committee.
Drugs and treatment Two NNRTIs were employed in this study: efavirenz (EFV-Patheon Inc., Mississauga, Ontario, Canada) and nevirapine (NVP-BoehringerIngelheim Roxane, Inc. Columbus, Ohio, USA). Normal mice were treated orally,once a day for 36 days, with EFV 10 mg/kg, NVP 3.3 mg/kg or vehicle in a volumeof 1 mL/kg. The doses employed in this study were based on the doses used forhuman therapy (Lewis et al. ). EFV and NVP were dissolved in distillated waterslightly warmed with Tween 80 1%. The control group received a solution consistingof distillated water with Tween 80 1%. Drug solutions were prepared daily justbefore the oral administration. The animals were killed by decapitation 3 h after thelast administration of the drugs. The brain was immediately removed andhippocampus, striatum, cerebellum, cortex and prefrontal cortex were isolated.
Tissue and homogenate preparation These brain areas were homogenized (1:10,w/v) in SETH buffer, pH 7.4 (250 mM sucrose, 2 mM EDTA, 10 mM Trizmabase, 50 IU/ml heparin). The homogenates were centrifuged at 800×g for 10 minand the supernatants kept at 70°C until used for CK activity determination. Themaximal period between homogenate preparation and enzyme analysis wasalways less than 5 days. Protein content was determined by the method describedby Lowry et al. (using bovine serum albumin as standard.
Creatine kinase (CK) activity assay Creatine kinase activity was measured in brainhomogenates pre-treated with 0.625 mM lauryl maltoside. The reaction mixture consisted of 60 mM Tris-HCl, pH 7.5, containing 7 mM phosphocreatine, 9 mMMgSO4 and approximately 0.4–1.2 μg protein in a final volume of 100 μL. After15 min of pre-incubation at 37°C, the reaction was started by the addition of0.3 μmol of ADP plus 0.08 μmol of reduced glutathione. The reaction was stoppedafter 10 min by the addition of 1 μmol of p-hydroxymercuribenzoic acid. Thecreatine formed was estimated according to the colorimetric method of Hughes). The color was developed by the addition of 100 μL 2% α-naphtol and100 μL 0.05% diacetyl in a final volume of 1 mL and read spectrophotometricallyafter 20 min at 540 nm. Results were expressed as nmol/min.mg protein.
Statistical analysis Data were analyzed by one-way analysis of variance (ANOVA)followed by the Tukey test when F was significant and are expressed as mean ±standard deviation. All analyses were performed using the Statistical Package for theSocial Science (SPSS) software.
In this study we treated mice for 36 days with antiretroviral drugs at doses similar tothose administrated in humans. As seen in Fig. , our results demonstrated that EFVand NVP significantly inhibited creatine kinase activity in cerebellum (F(2,12)=328.9; p<0.01), hippocampus (F(2,12) =38.2; p<0.01), striatum (F(2,12) =103.7; p<0.01) and cortex (F(2,12) =296.9; p<0.01) of mice. Futhermore, we observed thatanimals treated with EFV presented more intense inhibition on CK in cortex andcerebellum when compared to the group treated with NVP. We also observed thatNVP-treated group showed a reduction of approximately 17% in body weight at theend of treatment, when compared to the beginning (data not shown).
Fig. 1 Creatine kinase (CK) activity in the cerebellum, hippocampus, striatum and cerebral cortex of micesubmitted to chronic administration of efavirenz and nevirapine. Data are expressed as units per milligramprotein, for five independent experiments (n=5) performed in duplicate. Different from control (vehicle)*p<0.01 (Tukey test). Different from EFV-treated group ap<0.05 (Tukey test) Although non-nucleoside analogue inhibitors of HIV-1 reverse transcriptase (RT)have become a cornerstone of antiretroviral combination regimens during HAART,adverse events CNS-related can be responsible for patients’ non-adherence tomedications (Piacenti ).
There are some reports suggesting that neuropsychiatric features like anxiety, hostility and depression seen in patients with long-term EFV use were associatedwith high serum drug concentration (Gutiérrez et al. Rihs et al. ;Marzolini et al. ; Hawkins et al. ). On the other hand, indirect evidencesuggests that NVP reaches the CNS comes from the headaches and neuropsychiatriccomplications sometimes associated with its use (Wise et al. Drugs must cross the blood–brain and blood–cerebrospinal fluid (CSF) barriers to reach the CNS. In this context, there are direct clinical evidences that the NNRTIsare able to penetrate the CSF, and for NVP, the CSF/plasma ratio has been reportedto range from 15 to 40% (von Giesen et al. ; van Praag et al. ). Gibbs et al.
) have demonstrated that NVP accumulates in the brain, CSF, choroid plexusand brain parenchyma of guinea pig. In addition, both EFV and NVP can be detectedin the cerebrospinal fluid in concentrations effective in suppressing HIV viral levels(Tashima et al. ; Wynn et al. ), which might be a prerequesite for theproven CNS efficacy or for the manifestations of CNS side effects. The degree ofNVP brain uptake was higher for an antiviral HIV drug. In fact, NVP has the highestbrain accumulation of any of the antiretroviral drugs tested, including abacavir,amprenavir and ritonavir (Anthonypillai et al. ; Anthonypillai et al. ).
In the present paper, we demonstrated that EFV and NVP significantly inhibited CK activity in cerebellum, hippocampus, striatum and cortex of mice. Moreover, CKactivity in cortex and in cerebellum was significantly lower in EFV-treated groupwhen compared to NVP-treated group. This could explain a diference in neurologictolerability of the two drugs. In order to ellucidate this hypothesis further studiesneed to be done. We did not investigate the plasmatic or cerebrospinal fluidconcentrations of NNRTIs, but as commented above, both drugs have a good CNSpenetration (Tashima et al. Wynn et al. ; Gibbs et al. ).
CK is important for normal energy homeostasis by exerting several integrated functions, such as temporary energy buffering, metabolic capacity, energy transferand metabolic control (Wallimann et al. The brain, like other tissues withhigh and variable rates of ATP metabolism, presents high phosphocreatineconcentration and CK activity. It is well described that inhibition of CK activityhas been implicated in the pathogenesis of a number of diseases, especially in brain(Khuchua et al. ; Schlattner and Wallimann Energy impairment has beenlinked to neuronal death and neurodegeneration (Heales et al. ; Blass ;Schurr ). In this context, it has also been demonstrated that the creatine/phosphocreatine/CK circuit is involved in processes that involve habituation,spatial learning and seizure susceptibility (Jost et al. Streijger et al. ;Streijger et al. The mechanisms underlying NNRTIs side effects are still poorly understood. In the present work, we demonstrated, for the first time, that brain CK activity wasinhibited in cerebellum, hippocampus, striatum and cortex when mice were chronically treated with any of the NNRTIs, EFV or NVP. The clinical correlationwith activity and behavior of mice should be further more investigated.
This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Apoio à Pesquisa Científica e Tecnológica do Estado deSanta Catarina (FAPESC) and Universidade do Extremo Sul Catarinense (UNESC).
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