Comparative analysis of methamphetamine’s metabolic effects onblood-brain barrier endothelial cells: an in vitro recreational versus addictive simulation

Abstract

Methamphetamine (Meth) neurotoxicity has traditionally been attributed to monoaminergicdisruption, yet growing evidence implicates early injury at the blood-brain barrier (BBB). the brainmicrovascular endothelial cells (BMVecs), which are the core cell type of the BBB and form thecerebral capillaries, contain the highest mitochondrial density of any endothelial population. thishigh mitochondrial density is essential for maintaining the highly selectively permeable propertiesof the BBB, leaving the BMVecs and the BBB susceptible to metabolic stress. to model the twostereotypical types of Meth users, recreational and addictive, bend.5 cells were exposed to Methat physiological (0.1, 1, 10, and 20 µM) and supraphysiological (100 µM) concentrations for 24 h only(acute exposure) or daily for 96 h (chronic exposure). succinate dehydrogenase (sDh) activity,mitochondrial membrane potential (ΔΨm), intracellular reactive oxygen species (ROs) levels, andendothelial monolayer integrity were assessed. acute Meth caused transient metabolic dysfunctionin BMVecs, marked by reduced sDh activity, ΔΨm depolarization, and increased intracellular ROsproduction with subsequent metabolic recovery, however, endothelial monolayer integrity remainedimpaired long-term. chronic Meth exposure, induced sustained ΔΨm depolarization, persistent ROselevation, and prolonged decreased endothelial monolayer integrity. these findings demonstratedistinct responses to acute and chronic Meth exposure and implicate mitochondrial dysfunction asa central mechanism driving BBB endothelium disruption, potential neuroinflammation, andincreased neurological vulnerability, shifting the focus beyond classical monoaminergic toxicity andhighlight the BBB endothelium as the central contributor to Meth-induced neuropathology.