Peripheral ammonia and blood brain barrier structure and function after methamphetamine

Neuropharmacology. 2016 Aug:107:18-26. doi: 10.1016/j.neuropharm.2016.03.018. Epub 2016 Mar 10.


An effect of the widely abuse psychostimulant, methamphetamine (Meth), is blood-brain-barrier (BBB) disruption; however, the mechanism by which Meth causes BBB disruption remains unclear. Recently it has been shown that Meth produces liver damage and consequent increases in plasma ammonia. Ammonia can mediate oxidative stress and inflammation, both of which are known to cause BBB disruption. Therefore, the current studies examined the role of peripheral ammonia in Meth-induced disruption of BBB structure and function. A neurotoxic Meth regimen (10 mg/kg, ip, q 2 h, ×4) administered to rats increased plasma ammonia and active MMP-9 in the cortex 2 h after the last Meth injection, compared to saline treated rats. At 24 h after Meth treatment, decreased immunoreactivity of BBB structural proteins, occludin and claudin-5, and increased extravasation of 10,000 Da FITC-dextran were observed, as compared to saline controls. Pretreatment with lactulose (5.3 g/kg, po, q 12 h), a drug that remains in the lumen of the intestine and promotes ammonia excretion, prevented the Meth-induced increases in plasma ammonia. These results were paralleled by the prevention of decreases in BBB structural proteins, increases in extravasation of 10,000 Da FITC-dextran and increases in active MMP-9. The results indicate that Meth-induced increases in ammonia produce BBB disruption and suggest that MMP-9 activation mediates the BBB disruption. These findings identify a novel mechanism of Meth-induced BBB disruption that is mediated by plasma ammonia and are the first to identify a peripheral contribution to Meth-induced BBB disruption.

Keywords: Ammonia; Blood-brain barrier; Methamphetamine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Ammonia / blood*
  • Animals
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism*
  • Blood-Brain Barrier / pathology
  • Capillaries / drug effects
  • Capillaries / metabolism
  • Capillaries / pathology
  • Capillary Permeability / drug effects
  • Capillary Permeability / physiology
  • Central Nervous System Stimulants / toxicity*
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Claudin-5 / metabolism
  • Disease Models, Animal
  • Fever / chemically induced
  • Fever / drug therapy
  • Gastrointestinal Agents / pharmacology
  • Lactulose / pharmacology
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Methamphetamine / toxicity*
  • Occludin / metabolism
  • Rats, Sprague-Dawley


  • Central Nervous System Stimulants
  • Claudin-5
  • Cldn5 protein, rat
  • Gastrointestinal Agents
  • Occludin
  • Ocln protein, rat
  • Methamphetamine
  • Lactulose
  • Ammonia
  • Matrix Metalloproteinase 9
  • Mmp9 protein, rat