Increased Plasma Ammonia Concentration Contributes To Methamphetamine-Induced Blood-Brain Barrier Damage

Recently our lab has shown that the psychostimulant, methamphetamine (Meth), produces liver damage. In models of acute liver failure, increases in plasma ammonia mediate brain edema and disruption of tight junction proteins of the blood‐brain barrier (BBB). Neurotoxic doses of Meth that produce liver damage also disrupt the structure and function of tight junction proteins, occludin and claudin‐5. Therefore, we hypothesized that Meth‐induced increases in plasma ammonia will disrupt BBB structure and function. A neurotoxic Meth regimen (10 mg/kg, ip, q 2hr, ×4) produced an 86±12% increase in plasma ammonia 2 hr after the last Meth injection, compared to saline treated controls. Pretreatment with lactulose (5.3 g/kg, po, q 12hr), a drug that increases the excretion of ammonia, prevented these increases. Meth significantly decreased expression of occludin by 51±8% and claudin‐5 by 51±7%, and increased BBB permeability as measured by FITC‐dextran extravasation, compared to saline treated controls 24 hr after treatment. Meth‐induced BBB disruption was prevented by lactulose pretreatment. These data indicate that Meth‐induced increases in plasma ammonia contribute to the disruption of BBB structure and function. These findings identify a novel mechanism through which Meth disrupts the BBB and a novel consequence of Meth‐induced liver damage. Supported by NIH DA07606.