Abstract
The cytotoxic effects of methamphetamine (MA) are well established to be caused via induced oxidative stress which in turn compromises the core function of the blood–brain barrier (BBB) by reducing its ability to regulate the homeostatic environment of the brain. While most studies were conducted over a period of 24–48 h, this study investigated the mechanisms by which chronic exposure of MA adversely affect the endothelial cells of BBB over an extended period of 96 h. MA induced significant depression of cell numbers at 96 h. This result was supported by flow cytometric data on the cell cycle which showed that brain endothelial cells (bEnd5) at 96 h were significantly suppressed in the S-phase of the cell cycle. In contrast, at 24–72 h control cell numbers for G1, S and G2-M phases were similar to MA-exposed cells. MA (0–1,000 µM) did not, however, statistically affect the viability and cytotoxicity of the bEnd5 cells, and the profile of ATP production and DNA synthesis (BrdU) across 96 h did not provide a rationale for the suppression of cell division. Our study reports for the first time that chronic exposure to MA results in long-term disruption of the cell cycle phases which eventuates in the attenuation of brain capillary endothelial cell growth after 96 h, compounding and contributing to the already well-known adverse short-term permeability effects of MA exposure on the BBB.
Similar content being viewed by others
References
Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37(1):13–25
Abdul Muneer PM, Alikunju S, Szlachetka AM, Murrin LC, Haorah J (2011) Impairment of brain endothelial glucose transporter by methamphetamine causes blood-brain barrier dysfunction. Mol Neurodegener. 6:23
Bowyer JF, Ali S (2006) High doses of methamphetamine that cause disruption of the blood-brain barrier in limbic regions produce extensive neuronal degeneration in mouse hippocampus. Synapse 60:521–532
Busu C, Li W, Caldito G, Aw TK (2013) Inhibition of glutathione synthesis in brain endothelial cells lengthens S-phase transit time in the cell cycle: implications for proliferation in recovery from oxidative stress and endothelial cell damage. Redox Biol 1:131–139
Culot M, Lundquist S, Vanuxeem D, Nion S, Landry C, Delplace Y, Dehouck MP, Berezowski V, Fenart L, Cecchelli R (2008) An in vitro blood-brain barrier model for high throughput (HTS) toxicological screening. Toxicology In Vitro 22:799–811
Dietrich JB (2009) Alteration of blood-brain barrier function by methamphetamine and cocaine. Cell Tissue Res 336:385–392
Ernst T, Chang L, Leonido-Yee M, Speck O (2000) Evidence for long-term neurotoxicity associated with methamphetamine abuse: a 1H MRS study. Neurology 54:1344–1349
Jedynak JP, Uslaner JM, Esteban JA, Robinson TE (2007) Methamphetamine-induced structural plasticity in the dorsal striatum. Eur J Neurosci 25(3):847–853
Li X, Wang H, Qiu P, Luo H (2008) Proteomic profiling of proteins associated with methamphetamine-induced neurotoxicity in different regions of rat brain. Neurochem Int 52(1–2):256–264
Mahajan SD, Aalinkeel R, Sykes DE, Reynolds JL, Bindukumar B, Adal A, Qi M, Toh J, Xu G, Prasad PN, Schwartz SA (2008) Methamphetamine alters blood brain barrier permeability via the modulation of tight junction expression: implication for HIV-1 neuropathogenesis in the context of drug abuse. Brain Res 1203:133–148
Martins T, Baptista S, Gonçalves J, Leal E, Milhazes N, Borges F, Ribeiro CF, Quintela O, Lendoiro E, López-Rivadulla M, Ambrósio AF, Silva AP (2011) Methamphetamine transiently increases the blood-brain barrier permeability in the hippocampus: role of tight junction proteins and matrix metalloproteinase-9. Brain Res 64(1441):28–40
Martins T, Burgoyne T, Kenny BA, Hudson N, Futter CE, Ambrósio AF, Silva AP, Greenwood J, Turowski P (2013) Methamphetamine-induced nitric oxide promotes vesicular transport in blood-brain barrier endothelial cells. Neuropharmacology 65:74–82
Melega WP, Cho AK, Harvey D, Lacan G (2007) Methamphetamine blood concentrations in human abusers: application to pharmacokinetic modeling. Synapse 61:216–220
Park M, Hennig B, Toborek M (2012) Methamphetamine alters occludin expression via NADPH oxidase-induced oxidative insult and intact caveolae. J Cell Mol Med 16(2):362–375
Ramirez SH, Potula R, Fan S, Eidem T, Papugani A, Reichenbach N, Dykstra H, Weksler BB, Romero IA, Couraud PO, Persidsky Y (2009) Methamphetamine disrupts blood-brain barrier function by induction of oxidative stress in brain endothelial cells. J Cereb Blood Flow Metab 29(12):1933–1945
Rau TF, Kothiwal AS, Rova AR, Brooks DM, Rhoderick JF, Poulsen AJ, Hutchinson J, Poulsen DJ (2011) Administration of low dose methamphetamine 12 h after a severe traumatic brain injury prevents neurological dysfunction and cognitive impairment in rats. Exp Neurol 253C:31–40
Robinson TE, Kolb B (2004) Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 1:33–46
Sharma HS, Kiyatkin EA (2009) Rapid morphological brain abnormalities during acute methamphetamine intoxication in the rat: an experimental study using light and electron microscopy. J Chem Neuroanat 37(1):18–32
Todd G, Noyes C, Flavel SC, DellaVedova CB, Spyropoulos P, Chatterton B, Berg D, White JM (2013) Illicit stimulant use is associated with abnormal substantia nigra morphology in humans. PLoS One 8(2):e56438
Van der Wouwer MV, Couzinié C, Serrano-Palero M, González-Fernández O, Galmés-Varela C, Menéndez-Antolí P, Grau L, Villalobo A (2012) Activation of the BRCA1/Chk1/p53/p21(Cip1/Waf1) pathway by nitric oxide and cell cycle arrest in human neuroblastoma NB69 cells. Nitric Oxide 26(3):182–191
Yuan CJ, Quiocho JMD, Kim A, Wee S, Mandyam CD (2011) Extended access methamphetamine decreases immature neurons in the hippocampus which results from loss and altered development of neuronal progenitors without altered dynamics of the S-phase of the cell cycle. Pharmocol Biochem Behav 100:98–108
Zhang X, Banerjee A, Banks WA, Ercal N (2009) N-Acetylcysteine amide protects against methamphetamine-induced oxidative stress and neurotoxicity in immortalized human brain endothelial cells. Brain Res 1275:87–95
Acknowledgments
The present study was supported by a Grant from the Senate Research Committee of University of the Western Cape, Cape Town South Africa. This study was ethically approved by UWC Senate Research Ethics Committee prior to execution of the research proposal.
Conflict of interest
The authors declare that there are no conflicts of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Fisher, D., Gamieldien, K. & Mafunda, P.S. Methamphetamine is not Toxic but Disrupts the Cell Cycle of Blood–Brain Barrier Endothelial Cells. Neurotox Res 28, 8–17 (2015). https://doi.org/10.1007/s12640-015-9520-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-015-9520-5