This review discusses the most recent data on the potential of quercetin to confer neuroprotection. Unfortunately, most of the in vitro studies have used quercetin aglycone, which is not detectable in the plasma or in the brain after oral intake. Moreover, quercetin metabolites and glycosides seem to be less neuroprotective and penetrate the BBB less efficiently than aglycone. Surprisingly, quercetin has beneficial effects on various in vivo models of neural disorders, particularly in cerebrovascular insults; contrasting data also do exist. This may be due to an increase of BBB permeability, described in many of these animal models, which would facilitate quercetin brain penetration. Although quercetin causes no significant toxicity in several animal studies, the risk for neurotoxicity is not negligible because of its narrow therapeutic dose-range in vitro. Notably, this risk may be even higher in the case of increased quercetin access to the brain, which may occur pathologically or artificially (e.g., by liposomal preparations). Based on the referred literature, we doubt that quercetin possesses any significant efficacy in neurodegenerative disorders. Instead, therapeutic trials should focus more on the quercetin efficacy in cerebrovascular insults rather than neurodegeneration.

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Prolyl oligopeptidase (PREP) inhibitors are potential drug candidates for the treatment of neurological disorders, but little is known about their ability to cross the blood-brain barrier and to reach the target site. This study characterizes brain pharmacokinetics of two potent PREP inhibitors, JTP-4819 and KYP-2047. Firstly, the in vitro permeability (P app ) of JTP-4819 and KYP-2047 through a bovine brain microvessel endothelial cell monolayer was assessed. Then, the in vivo brain ⁄ blood ratio was determined for the total brain and plasma concentrations and also for the unbound extracellular drug concentrations after a single dose (50 lmol ⁄ kg i.p.). KYP-2047 had a significantly higher P app than JTP-4819. In vivo, KYP-2047 had higher total and unbound brain ⁄ blood ratios. KYP-2047 was equally distributed between the cortex, hippocampus and striatum. In the case of JTP-4819, the unbound brain extracellular concentrations could not be readily predicted from the unbound blood levels, probably because of its poor membrane penetration properties. KYP-2047 displayed a better ability to reach the intracellularly located brain PREP, and it inhibited this enzyme more effectively than JTP-4819 after an equimolar single dose. In conclusion, KYP-2047 showed better brain penetration characteristics than JTP-4819 both in vitro and in vivo. KYP-2047 is a brain-penetrating, potent and long-acting PREP inhibitor; thus, it represents a convenient pharmacological tool for assessing the potential of PREP as a drug target.Prolyl oligopeptidase (PREP; EC 3.4.21.26) is an 80 kDa cytosolic enzyme, which belongs to the PREP family of serine proteases [1]. PREP preferentially hydrolyses small peptides at the carboxyl side of a proline residue. The enzyme is widely distributed in the mammalian body, but especially high amounts are found in the brain [2][3][4][5]. PREP is expressed in all regions of the brain except for the corpus callosum, but the distribution of the enzyme is not homogenous throughout the brain. In the rat, the most enriched brain areas for PREP immunoreactivity are the cerebellum, substantia nigra, cerebral cortex and hippocampus [3]. In humans, the highest PREP activities are found in those brain areas that are involved in memory and learning processes [4].Despite intensive research, the physiological role of PREP and the potential of PREP as a drug target are not fully understood. However, recent findings into the association of PREP with several intracellular processes, neuropeptide metabolism, learning and memory have markedly increased interest in PREP as a drug target [6][7][8][9][10][11][12][13][14][15][16][17][18]. Based on these findings, centrally acting PREP inhibitors have been suggested to have potential benefits, e.g., in the treatment of neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, and many potent PREP inhibitors have been developed. Perhaps, the most extensively studied PREP inhibitor is JTP-4819 fig. 1A), a compound that has an inhibitory constant (K i ) val...

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