title: Methamphetamine transiently increases the blood-brain barrier permeability in the hippocampus: role of tight junction proteins and matrix metalloproteinase-9.
abstract: Methamphetamine (METH) is a powerful stimulant drug of abuse that has steadily gained popularity worldwide. It is known that METH is highly neurotoxic and causes irreversible damage of brain cells leading to neurological and psychiatric abnormalities. Recent studies suggested that METH-induced neurotoxicity might also result from its ability to compromise blood-brain barrier (BBB) function. Due to the crucial role of BBB in the maintenance of brain homeostasis and protection against toxic molecules and pathogenic organisms, its dysfunction could have severe consequences. In this study, we investigated the effect of an acute high dose of METH (30mg/kg) on BBB permeability after different time points and in different brain regions. For that, young adult mice were sacrificed 1h, 24h or 72h post-METH administration. METH increased BBB permeability, but this effect was detected only at 24h after administration, being therefore a transitory effect. Interestingly, we also found that the hippocampus was the most susceptible brain region to METH, comparing to frontal cortex and striatum. Moreover, in an attempt to identify the key players in METH-induced BBB dysfunction we further investigated potential alterations in tight junction (TJ) proteins and matrix metalloproteinase-9 (MMP-9). METH was able to decrease the protein levels of zonula occludens (ZO)-1, claudin-5 and occludin in the hippocampus 24h post-injection, and increased the activity and immunoreactivity of MMP-9. The pre-treatment with BB-94 (30mg/kg), a matrix metalloproteinase inhibitor, prevented the METH-induced increase in MMP-9 immunoreactivity in the hippocampus. Overall, the present data demonstrate that METH transiently increases the BBB permeability in the hippocampus, which can be explained by alterations on TJ proteins and MMP-9.
authors.affiliation: Laboratory of Pharmacology and Experimental Therapeutics, Faculty of Medicine, University of Coimbra, 3004-548 Coimbra, Portugal.
authors.forename: Tânia
authors.initials: T
authors.lastname: Martins
authors.forename: Sofia
authors.initials: S
authors.lastname: Baptista
authors.forename: Joana
authors.initials: J
authors.lastname: Gonçalves
authors.forename: Ermelindo
authors.initials: E
authors.lastname: Leal
authors.forename: Nuno
authors.initials: N
authors.lastname: Milhazes
authors.forename: Fernanda
authors.initials: F
authors.lastname: Borges
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Ribeiro
authors.forename: Oscar
authors.initials: O
authors.lastname: Quintela
authors.forename: Elena
authors.initials: E
authors.lastname: Lendoiro
authors.forename: Manuel
authors.initials: M
authors.lastname: López-Rivadulla
authors.forename: António F
authors.initials: AF
authors.lastname: Ambrósio
authors.forename: Ana P
authors.initials: AP
authors.lastname: Silva
mesh_terms: D000661:Amphetamine / Q000032:analysis / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000201:enzymology; D015153:Blotting, Western; D000697:Central Nervous System Stimulants / Q000032:analysis / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D005070:Evans Blue; D007839:Functional Laterality / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology; D007150:Immunohistochemistry; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D008694:Methamphetamine / Q000032:analysis / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000502:physiology*; D010539:Permeability / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D053719:Tandem Mass Spectrometry; D019108:Tight Junctions / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*
chemical_list: D000697:Central Nervous System Stimulants; D009419:Nerve Tissue Proteins; D008694:Methamphetamine; D005070:Evans Blue; D000661:Amphetamine; D020780:Matrix Metalloproteinase 9