N-Acetylcysteine Modulation of Mitochondrial Respiration and Blood Brain Barrier Permeability Is Time Dependent and Cell Type Specific
One common symptom of most neurodegenerative diseases related to aging is the presence of blood-brain barrier disruption and mitochondrial disfunction. N-acetylcysteine (NAC) is an FDA approved drug commonly utilized for a variety of neuropsychiatric and neurodegenerative diseases; however, while studies have shown that NAC can improve mitochondrial function in mouse models of some of these diseases, the mechanism(s) of action have yet to be fully defined. Our previous studies have shown that NAC treatment can alter blood-brain barrier (BBB) permeability in mice via changes in reactive oxygen species (ROS). To further examine the effects of NAC on both cell-specificity and the mitochondrial respiration of brain vascular endothelial cells and astrocytes that make up the blood-brain barrier, we utilized brain microvascular endothelial and cerebrum astrocytic cells and an in vitro mouse BBB model. We show that NAC caused time- and dose-dependent changes in BBB permeability that were correlated to significant changes in tight and gap junction proteins, change in endothelial nNOS, and downregulation of mitochondrial complex proteins in endothelial cells. Extracellular flux analysis revealed a significant reduction in endothelial cell mitochondrial maximal respiration after 48hrs. In contrast, astrocyte respiration showed no change after 48hours but was significantly increased after 24hours of NAC treatment corresponding to the decreased permeability noted at this time. These changes paralleled alterations in NOS in endothelial cells but not astrocytes. We conclude that murine astrocytes and endothelial cells respond to NAC treatment in a cell-specific fashion, altering their perspective metabolic profiles and ultimately the tight and gap junctions that determine the permeability of the BBB. Given the current theory that mitochondrial dysfunction and BBB leakiness are predisposing, possibly causative symptoms, for most neurodegenerative diseases associated with aging, our findings suggest that NAC’s cell-specific effects upon both metabolism and BBB permeability may be concurrent mechanisms by which this drug is effective.
Amouri, A. S.,
Waker, C. A.,
Smith, C. L.,
& Mayes, D. A.
(2018). N-Acetylcysteine Modulation of Mitochondrial Respiration and Blood Brain Barrier Permeability Is Time Dependent and Cell Type Specific. Molecular Biology, 3 (6), 266-276.