Skip to main content
Erschienen in: Metabolic Brain Disease 3/2018

29.12.2017 | Original Article

Methylphenidate disrupts cytoskeletal homeostasis and reduces membrane-associated lipid content in juvenile rat hippocampus

verfasst von: Felipe Schmitz, Paula Pierozan, Helena Biasibetti-Brendler, Fernanda Silva Ferreira, Fernanda dos Santos Petry, Vera Maria Treis Trindade, Regina Pessoa-Pureur, Angela T. S. Wyse

Erschienen in: Metabolic Brain Disease | Ausgabe 3/2018

Einloggen, um Zugang zu erhalten

Abstract

Although methylphenidate (MPH) is ubiquitously prescribed to children and adolescents, the consequences of chronic utilization of this psychostimulant are poorly understood. In this study, we investigated the effects of MPH on cytoskeletal homeostasis and lipid content in rat hippocampus. Wistar rats received intraperitoneal injections of MPH (2.0 mg/kg) or saline solution (controls), once a day, from the 15th to the 44th day of age. Results showed that MPH provoked hypophosphorylation of glial fibrillary acidic protein (GFAP) and reduced its immunocontent. Middle and high molecular weight neurofilament subunits (NF-M, NF-H) were hypophosphorylated by MPH on KSP repeat tail domains, while NFL, NFM and NFH immunocontents were not altered. MPH increased protein phosphatase 1 (PP1) and 2A (PP2A) immunocontents. MPH also decreased the total content of ganglioside and phospholipid, as well as the main brain gangliosides (GM1, GD1a, and GD1b) and the major brain phospholipids (sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositol, and phosphatidylserine). Total cholesterol content was also reduced in the hippocampi of juvenile rats treated with MPH. These results provide evidence that disruptions of cytoskeletal and lipid homeostasis in hippocampus of juvenile rats are triggers by chronic MPH treatment and present a new basis for understanding the effects and consequences associated with chronic use of this psychostimulant during the development of the central nervous system.
Literatur
Zurück zum Zitat Akay AP, Kaya GÇ, Emiroglu NI, Aydin A, Monkul ES, Tasçi C et al (2006) Effects of long-term methylphenidate treatment: a pilot follow-up clinical and SPECT study. Prog Neuropsychopharmacol Biol Psychiatry 30:1219–1224CrossRefPubMed Akay AP, Kaya GÇ, Emiroglu NI, Aydin A, Monkul ES, Tasçi C et al (2006) Effects of long-term methylphenidate treatment: a pilot follow-up clinical and SPECT study. Prog Neuropsychopharmacol Biol Psychiatry 30:1219–1224CrossRefPubMed
Zurück zum Zitat Bartlett GR (1959) Phosphorus assay in column chromatography. J Biol Chem 234(3):466–468PubMed Bartlett GR (1959) Phosphorus assay in column chromatography. J Biol Chem 234(3):466–468PubMed
Zurück zum Zitat Brownlees J, Yates A, Bajaj NP, Davis D, Anderton BH, Leigh PN, Shaw CE, Miller CC (2000) Phosphorylation of neurofilament heavy chain side-arms by stress activated protein kinase-1b/Jun N-terminal kinase-3. J Cell Sci 113:401–407PubMed Brownlees J, Yates A, Bajaj NP, Davis D, Anderton BH, Leigh PN, Shaw CE, Miller CC (2000) Phosphorylation of neurofilament heavy chain side-arms by stress activated protein kinase-1b/Jun N-terminal kinase-3. J Cell Sci 113:401–407PubMed
Zurück zum Zitat de Almeida LM, Funchal C, Pde Pelaez L, Pessutto FD, Loureiro SO, Vivian L, Wajner M, Pessoa-Pureur R (2003) Effect of propionic and methylmalonic acids on the in vitro phosphorylation of intermediate filaments from cerebral cortex of rats during development. Metab Brain Dis 18(3):207–219. https://doi.org/10.1023/A:1025555132675 CrossRefPubMed de Almeida LM, Funchal C, Pde Pelaez L, Pessutto FD, Loureiro SO, Vivian L, Wajner M, Pessoa-Pureur R (2003) Effect of propionic and methylmalonic acids on the in vitro phosphorylation of intermediate filaments from cerebral cortex of rats during development. Metab Brain Dis 18(3):207–219. https://​doi.​org/​10.​1023/​A:​1025555132675 CrossRefPubMed
Zurück zum Zitat Fagundes AO, Scaini G, Santos PM, Sachet MU, Bernhardt NM, Rezin GT, Valvassori SS, Schuck PF, Quevedo J, Streck EL (2010b) Inhibition of mitochondrial respiratory chain in the brain of adult rats after acute and chronic administration of methylphenidate. Neurochem Res 35(3):405–411. https://doi.org/10.1007/s11064-009-0069-7 CrossRefPubMed Fagundes AO, Scaini G, Santos PM, Sachet MU, Bernhardt NM, Rezin GT, Valvassori SS, Schuck PF, Quevedo J, Streck EL (2010b) Inhibition of mitochondrial respiratory chain in the brain of adult rats after acute and chronic administration of methylphenidate. Neurochem Res 35(3):405–411. https://​doi.​org/​10.​1007/​s11064-009-0069-7 CrossRefPubMed
Zurück zum Zitat Folch J, Lees M, Sloane-Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226(1):497–509PubMed Folch J, Lees M, Sloane-Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226(1):497–509PubMed
Zurück zum Zitat Fragoso ALR, Trindade VMT (2015) Resorcinol-HCl method adaption for N-acetyl neuraminic acid measurement in an aqueous medium, oral and poster communication. In: XXVII SALÃO DE INICIAÇÃO CIENTÍFICA DA UFRGS, Porto Alegre, RS, Brazil Fragoso ALR, Trindade VMT (2015) Resorcinol-HCl method adaption for N-acetyl neuraminic acid measurement in an aqueous medium, oral and poster communication. In: XXVII SALÃO DE INICIAÇÃO CIENTÍFICA DA UFRGS, Porto Alegre, RS, Brazil
Zurück zum Zitat Gerasimov MR, Franceschi M, Volkow ND, Gifford A, Gatley SJ, Marsteller D et al (2000) Comparison between intraperitoneal and oral methylphenidate administration: a microdialysis and locomotor activity study. J Pharmacol Exp Ther 295:51–57PubMed Gerasimov MR, Franceschi M, Volkow ND, Gifford A, Gatley SJ, Marsteller D et al (2000) Comparison between intraperitoneal and oral methylphenidate administration: a microdialysis and locomotor activity study. J Pharmacol Exp Ther 295:51–57PubMed
Zurück zum Zitat Heimfarth L, Loureiro SO, Reis KP, de Lima BO, Zamboni F, Lacerda S, Soska AK, Wild L, da Rocha JB, Pessoa-Pureur R (2012) Diphenyl ditelluride induces hypophosphorylation of intermediate filaments through modulation of DARPP-32-dependent pathways in cerebral cortex of young rats. Arch Toxicol 86(2):217–230. https://doi.org/10.1007/s00204-011-0746-6 CrossRefPubMed Heimfarth L, Loureiro SO, Reis KP, de Lima BO, Zamboni F, Lacerda S, Soska AK, Wild L, da Rocha JB, Pessoa-Pureur R (2012) Diphenyl ditelluride induces hypophosphorylation of intermediate filaments through modulation of DARPP-32-dependent pathways in cerebral cortex of young rats. Arch Toxicol 86(2):217–230. https://​doi.​org/​10.​1007/​s00204-011-0746-6 CrossRefPubMed
Zurück zum Zitat Kuczenski R, Segal DS (2001) Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: relative roles of dopamine and norepinephrine. J Pharmacol Exp Ther 296(3):876–883PubMed Kuczenski R, Segal DS (2001) Locomotor effects of acute and repeated threshold doses of amphetamine and methylphenidate: relative roles of dopamine and norepinephrine. J Pharmacol Exp Ther 296(3):876–883PubMed
Zurück zum Zitat Kuczenski R, Segal DS (2002) Exposure of adolescent rats to oral methylphenidate: preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci 22(16):7264–7271CrossRefPubMed Kuczenski R, Segal DS (2002) Exposure of adolescent rats to oral methylphenidate: preferential effects on extracellular norepinephrine and absence of sensitization and cross-sensitization to methamphetamine. J Neurosci 22(16):7264–7271CrossRefPubMed
Zurück zum Zitat Lake BD, Goodwin HJ (1976) Lipids. In: Smith I, Seakings JWT (eds) Chromatographic and Eletrophoretic techniques, Paper and thin layer chromatography, vol 1. William Heinemann Medical Books Ltd, London, pp 345–366 Lake BD, Goodwin HJ (1976) Lipids. In: Smith I, Seakings JWT (eds) Chromatographic and Eletrophoretic techniques, Paper and thin layer chromatography, vol 1. William Heinemann Medical Books Ltd, London, pp 345–366
Zurück zum Zitat Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275PubMed Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275PubMed
Zurück zum Zitat Pfrieger FW (2003) Cholesterol homeostasis and function in neurons of the central nervous system. Cell Mol Life Sci 60:1158–1171CrossRefPubMed Pfrieger FW (2003) Cholesterol homeostasis and function in neurons of the central nervous system. Cell Mol Life Sci 60:1158–1171CrossRefPubMed
Zurück zum Zitat Röschlau P, Bernt E, Gruber W (1974) Cholesterol and esterified cholesterol, in: Bergmeyer, H.U., Gawehn, K. (Eds.), Methods of Enzymatic Analysis (Second English Edition): Academic, New York, pp. 1890-1893 Röschlau P, Bernt E, Gruber W (1974) Cholesterol and esterified cholesterol, in: Bergmeyer, H.U., Gawehn, K. (Eds.), Methods of Enzymatic Analysis (Second English Edition): Academic, New York, pp. 1890-1893
Zurück zum Zitat Schmitz F, Scherer EB, da Cunha MJ, da Cunha AA, Lima DD, Delwing D et al (2012b) Chronic methylphenidate administration alters antioxidant defenses and butyrylcholinesterase activity in blood of juvenile rats. Mol Cell Biochem 36:281–288CrossRef Schmitz F, Scherer EB, da Cunha MJ, da Cunha AA, Lima DD, Delwing D et al (2012b) Chronic methylphenidate administration alters antioxidant defenses and butyrylcholinesterase activity in blood of juvenile rats. Mol Cell Biochem 36:281–288CrossRef
Zurück zum Zitat Schmitz F, Pierozan P, Rodrigues AF, Biasibetti H, Coelho DM, Mussulini BH, Pereira MS, Parisi MM, Barbé-Tuana F, Oliveira DL, Vargas CR, Wyse AT (2016c) Chronic treatment with a clinically relevant dose of methylphenidate increases glutamate levels in cerebrospinal fluid and impairs glutamatergic homeostasis in prefrontal cortex of juvenile rats. Mol Neurobiol 53:2385–2396 Schmitz F, Pierozan P, Rodrigues AF, Biasibetti H, Coelho DM, Mussulini BH, Pereira MS, Parisi MM, Barbé-Tuana F, Oliveira DL, Vargas CR, Wyse AT (2016c) Chronic treatment with a clinically relevant dose of methylphenidate increases glutamate levels in cerebrospinal fluid and impairs glutamatergic homeostasis in prefrontal cortex of juvenile rats. Mol Neurobiol 53:2385–2396
Zurück zum Zitat Veeranna GJ, Amin ND, Ahn NG, Jaffe H, Winters CA, Grant P, Pant HC (1998) Mitogen-activated protein kinases (Erk1,2) phosphorylate lys-ser-pro (KSP) repeats in neurofilament proteins NF-H and NF-M. J Neurosci 18(11):4008–4021CrossRefPubMed Veeranna GJ, Amin ND, Ahn NG, Jaffe H, Winters CA, Grant P, Pant HC (1998) Mitogen-activated protein kinases (Erk1,2) phosphorylate lys-ser-pro (KSP) repeats in neurofilament proteins NF-H and NF-M. J Neurosci 18(11):4008–4021CrossRefPubMed
Zurück zum Zitat Volkow ND, Wang GJ, Fowler JS, Logan J, Gerasimov M, Maynard L, Ding Y, Gatley SJ, Gifford A, Franseschi D (2001) Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci 21:1–5CrossRef Volkow ND, Wang GJ, Fowler JS, Logan J, Gerasimov M, Maynard L, Ding Y, Gatley SJ, Gifford A, Franseschi D (2001) Therapeutic doses of oral methylphenidate significantly increase extracellular dopamine in the human brain. J Neurosci 21:1–5CrossRef
Zurück zum Zitat Zanatta L, Goulart PB, Gonçalves R, Pierozan P, Winkelmann-Duarte EC, Woehl VM, Pessoa-Pureur R, Silva FR, Zamoner A (2012) 1α,25-dihydroxyvitamin D(3) mechanism of action: modulation of L-type calcium channels leading to calcium uptake and intermediate filament phosphorylation in cerebral cortex of young rats. Biochim Biophys Acta 1823(10):1708–1719. https://doi.org/10.1016/j.bbamcr.2012.06.023 CrossRefPubMed Zanatta L, Goulart PB, Gonçalves R, Pierozan P, Winkelmann-Duarte EC, Woehl VM, Pessoa-Pureur R, Silva FR, Zamoner A (2012) 1α,25-dihydroxyvitamin D(3) mechanism of action: modulation of L-type calcium channels leading to calcium uptake and intermediate filament phosphorylation in cerebral cortex of young rats. Biochim Biophys Acta 1823(10):1708–1719. https://​doi.​org/​10.​1016/​j.​bbamcr.​2012.​06.​023 CrossRefPubMed
Metadaten
Titel
Methylphenidate disrupts cytoskeletal homeostasis and reduces membrane-associated lipid content in juvenile rat hippocampus
verfasst von
Felipe Schmitz
Paula Pierozan
Helena Biasibetti-Brendler
Fernanda Silva Ferreira
Fernanda dos Santos Petry
Vera Maria Treis Trindade
Regina Pessoa-Pureur
Angela T. S. Wyse
Publikationsdatum
29.12.2017
Verlag
Springer US
Erschienen in
Metabolic Brain Disease / Ausgabe 3/2018
Print ISSN: 0885-7490
Elektronische ISSN: 1573-7365
DOI
https://doi.org/10.1007/s11011-017-0177-z

Weitere Artikel der Ausgabe 3/2018

Metabolic Brain Disease 3/2018 Zur Ausgabe

Leitlinien kompakt für die Neurologie

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Neurologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.