AnIn VivoMicrodialysis Study of FLZ Penetration through the Blood-Brain Barrier in Normal and 6-Hydroxydopamine Induced Parkinson’s Disease Model Rats

Abstract

FLZ (N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic squamosamide derivative and a potential anti-Parkinson's disease (PD) agent. The objective of the present study was to investigate the penetration of free FLZ across the BBB and the effects of P-gp inhibition on FLZ transport in normal and 6-hydroxydopamine (6-OHDA) induced PD model rats. In vivo microdialysis was used to collect FLZ containing brain and blood dialysates following intravenous (i.v.) drug administration either with or without pretreatment with the specific P-gp inhibitor, zosuquidar trihydrochloride (zosuquidar·3HCl). A sensitive, rapid, and reliable ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was developed and validated to quantitate free FLZ levels in the dialysates. No significant differences were observed in the brain/blood FLZ area under the concentration-time curve (AUC) ratio between normal and PD model rats. However, pretreatment with zosuquidar·3HCl markedly increased the AUC ratio in both rat models. In addition, FLZ penetration was similar in zosuquidar·3HCl-pretreated normal and PD rats. These results suggest that P-gp inhibition increases BBB permeability to FLZ, thereby supporting the hypothesis that P-gp normally restricts FLZ transfer to the brain. These findings could provide reference data for future clinical trials and may aid investigation of the BBB permeability of other CNS-active substances.

RETRACTED: Icariin Reduces Dopaminergic Neuronal Loss and Microglia-Mediated Inflammation in Vivo and in Vitro

“…LPS (5 μg in 5 μl of sterile saline) was injected into the right side of rat midbrain SN with the coordinates 4.8 mm posterior to bregma, 1.7 mm lateral to the midline and 8.2 mm ventral to the skull surface ( Zhang et al, 2010 ). 6-OHDA (8 μg in 5 μl of saline with 0.2% vitamin C) was injected into the right side of SN with the coordinates 5.2 mm posterior to bregma, 2.4 mm lateral to the midline and 8.0 mm ventral to the skull surface ( Hou et al, 2014 ). Daily intragastric administration of ICA (10 and 20 mg/kg) for 7 and 14 consecutive days was given beginning 24 h before LPS and 6-OHDA injection, respectively.…”

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

“…This has been found for highly protein-bound drugs, while drugs with lower degree of protein binding do not seem to be influenced (unpublished observations). The same phenomenon has been found by others (59,60). It can thus be concluded that albumin present in the dialysate will likely influence recovery of highly protein-bound drugs but not be of importance for drugs that bind to a lower extent to proteins.…”

Age-Related Functional and Expressional Changes in Efflux Pathways at the Blood-Brain Barrier

“…Thiollier et al (2016) found only changes in the distribution of quinidine, indicating changes in P-gp functionality. In contrast, studies performed by Hou et al (2014) suggest that P-gp inhibition increases BBB permeability to N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxyphenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide (FLZ), a novel synthetic squamosamide derivative and potential anti-PD agent. No significant differences were observed, however, in the brain distribution of FLZ between normal and PD model rats, suggesting no significant change in P-gp in PD (Hou et al, 2014).…”