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Peripheral ammonia and blood brain barrier structure and function after methamphetamine.

Nicole A Northrop1, Laura E Halpin1, Bryan K Yamamoto2

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Methamphetamine (Meth) disrupts the blood-brain barrier (BBB) by increasing plasma ammonia levels. This study shows ammonia activates MMP-9, damaging BBB structure and function, a mechanism preventable with lactulose.

Keywords:
AmmoniaBlood-brain barrierMethamphetamine

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Area of Science:

  • Neuroscience
  • Toxicology
  • Pharmacology

Background:

  • Methamphetamine (Meth) abuse is linked to blood-brain barrier (BBB) disruption.
  • The precise mechanisms underlying Meth-induced BBB disruption are not fully understood.
  • Methamphetamine can cause liver damage, leading to elevated plasma ammonia levels, which are implicated in BBB dysfunction.

Purpose of the Study:

  • To investigate the role of peripheral ammonia in Methamphetamine-induced BBB disruption.
  • To determine if elevated ammonia levels mediate BBB structural and functional damage caused by Methamphetamine.
  • To explore the potential involvement of matrix metalloproteinase-9 (MMP-9) in this process.

Main Methods:

  • Rats were administered a neurotoxic regimen of Methamphetamine.
  • Plasma ammonia levels, cortical MMP-9 activity, BBB structural protein integrity (occludin, claudin-5), and BBB permeability (FITC-dextran extravasation) were measured.
  • Lactulose, an ammonia-reducing agent, was used as a pretreatment in some groups.

Main Results:

  • Methamphetamine administration significantly increased plasma ammonia and active MMP-9 in the cortex.
  • Methamphetamine treatment led to decreased expression of BBB structural proteins and increased BBB permeability.
  • Lactulose pretreatment prevented Methamphetamine-induced increases in plasma ammonia, MMP-9 activation, and BBB disruption.

Conclusions:

  • Elevated plasma ammonia levels contribute significantly to Methamphetamine-induced blood-brain barrier disruption.
  • Matrix metalloproteinase-9 (MMP-9) activation appears to be a key mediator of this ammonia-driven BBB damage.
  • These findings reveal a novel peripheral mechanism underlying Methamphetamine's neurotoxic effects on the BBB.