British journal of pharmacology · 2025
Increased ATP production and P-glycoprotein activity underlie the marked changes in blood-brain barrier transport of drugs in a mouse model of amyotrophic lateral sclerosis.
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Pan Yijun, Spiteri Alanna G, Runwal Pranav, Sun Jiaqi, Hutchinson Dana S, Kagawa Yoshiteru, Turner Bradley J, Huang Cheng, Shah Anup D, Schittenhelm Ralf B, Nicolazzo Joseph A
Аннотация
BACKGROUND AND PURPOSE: Patients with amyotrophic lateral sclerosis (ALS) are prescribed many medications for symptomatic relief. However, how potential alterations to the blood-brain barrier (BBB) affect the brain exposure of drugs in ALS remains under-investigated.
EXPERIMENTAL APPROACH: We used high-dimensional proteomic analysis, cellular metabolism, and mitochondrial functional assays to characterise isolated brain microvascular endothelial cells (BMECs) from wildtype and SOD1G93A transgenic mice, a mouse model of familial ALS, at a late-symptomatic age (P115-120), together with a transcardiac brain perfusion technique to assess BBB function in situ.
KEY RESULTS: The BBB of the SOD1G93A transgenic (TG) mice was significantly altered, including a 1.3-fold decrease in apparent brain microvascular volume, and decreased BBB transport of 3H-diazepam (1.4-fold) and 3H-2-deoxy-D-glucose (1.2-fold). BMEC proteomic analysis revealed multiple changes in TG mice including altered transmembrane activity, metabolism, and mitochondrial function, as revealed by gene set enrichment analysis, alongside altered glucose transporter (Glut1) abundance. These proteomic findings supported the identified increase in mitochondrial basal/ATP-linked respiration, mitochondrial action potential, ATP production, and intracellular ATP levels in SOD1G93A mouse BMECs. The BBB transport of 3H-digoxin, a specific ATP-binding cassette efflux P-glycoprotein (P-gp) substrate, was reduced by 11.0% in SOD1G93A mice. This was confirmed by a 46.7% reduction in BMEC uptake of 3H-digoxin, an observation that was reversed by resolving the hypermetabolic state of SOD1G93A BMECs.
CONCLUSION AND IMPLICATIONS: These findings open possible therapeutic avenues that could be exploited to overcome P-gp-mediated CNS drug resistance in ALS.
EXPERIMENTAL APPROACH: We used high-dimensional proteomic analysis, cellular metabolism, and mitochondrial functional assays to characterise isolated brain microvascular endothelial cells (BMECs) from wildtype and SOD1G93A transgenic mice, a mouse model of familial ALS, at a late-symptomatic age (P115-120), together with a transcardiac brain perfusion technique to assess BBB function in situ.
KEY RESULTS: The BBB of the SOD1G93A transgenic (TG) mice was significantly altered, including a 1.3-fold decrease in apparent brain microvascular volume, and decreased BBB transport of 3H-diazepam (1.4-fold) and 3H-2-deoxy-D-glucose (1.2-fold). BMEC proteomic analysis revealed multiple changes in TG mice including altered transmembrane activity, metabolism, and mitochondrial function, as revealed by gene set enrichment analysis, alongside altered glucose transporter (Glut1) abundance. These proteomic findings supported the identified increase in mitochondrial basal/ATP-linked respiration, mitochondrial action potential, ATP production, and intracellular ATP levels in SOD1G93A mouse BMECs. The BBB transport of 3H-digoxin, a specific ATP-binding cassette efflux P-glycoprotein (P-gp) substrate, was reduced by 11.0% in SOD1G93A mice. This was confirmed by a 46.7% reduction in BMEC uptake of 3H-digoxin, an observation that was reversed by resolving the hypermetabolic state of SOD1G93A BMECs.
CONCLUSION AND IMPLICATIONS: These findings open possible therapeutic avenues that could be exploited to overcome P-gp-mediated CNS drug resistance in ALS.