Permeability of blood–brain barrier in macaque model of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine‐induced Parkinson disease

Abstract

Brain bioavailability of drugs developed to address central nervous system diseases is classically documented through cerebrospinal fluid collected in normal animals, i.e., through an approximation as there are fundamental differences between cerebrospinal fluid and tissue contents. The fact that disease might affect brain availability of drugs is almost never considered at this stage although several conditions are associated with blood-brain barrier damage. Building upon our expertise in Parkinson's disease translational research, the present study addressed this gap comparing plasma and cerebrospinal fluid bioavailability of l-3,4-dihydroxyphenylalanine, carbamazepine, quinidine, lovastatin, and simvastatin, in healthy and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated macaques, the gold standard model of Parkinson's disease. The drugs were selected based upon their differential transport across the blood-brain barrier. Interestingly, brain bioavailability of quinidine was decreased while others were unaffected. Pharmacokinetics and pharmacodynamics experiments of drugs addressing Parkinson's disease might thus be performed in healthy animals unless the drugs are known to interact with the organic cation transporter.

Peripheral-Central Neuroimmune Crosstalk in Parkinson's Disease: What Do Patients and Animal Models Tell Us?

“…Increased number of blood vessels and endothelial cells have been described in proximity of degenerating neurons in MPTP-treated NHP (112). Changes in phospho-glycoprotein functionality suggestive of BBB alterations have also been observed in MPTP-treated NHP (113). Therapeutic strategies that prevent BBB leakage through activation of CB2 receptors have been shown to reduce dopamine neuron loss in the MPTP model (114).…”

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

“…The brain distribution of compounds with different transport mechanisms across the BBB (l-3,4-dihydroxyphenylalanine, carbamazepine, quinidine, lovastatin, and simvastatin) in healthy and MPTP-treated macaques have been studied. 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.…”

Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease

“…While the OFF state is very interesting and informative 1477 Parkinsonism, however, does not seem to modulate the L-dopa 1478 cerebral bioavailability. The plasma and cerebrospinal fluid 1479 bioavailability of L-dopa was found comparable in healthy and 1480 MPTP-treated macaques (Thiollier et al, 2015). Pharmacokinetics 1481 and pharmacodynamics experiments of drugs addressing PD might 1482 thus be performed in healthy animals unless the drugs are known 1483 to interact with the organic cation transporter (Thiollier et al, 1484(Thiollier et al, 2015.…”

“…The plasma and cerebrospinal fluid 1479 bioavailability of L-dopa was found comparable in healthy and 1480 MPTP-treated macaques (Thiollier et al, 2015). Pharmacokinetics 1481 and pharmacodynamics experiments of drugs addressing PD might 1482 thus be performed in healthy animals unless the drugs are known 1483 to interact with the organic cation transporter (Thiollier et al, 1484(Thiollier et al, 2015. 1513 Traditional measures of presynaptic DAergic integrity give only 1514 a rough estimate of striatal DA nerve terminal density.…”