The blood-brain barrier efficiently controls the entry of drug molecules into the brain. We describe a feasible means to achieve carrier-mediated drug transport into the rat brain via the specific, large neutral amino acid transporter (LAT1) by conjugating a model compound to L-tyrosine. A hydrophilic drug, ketoprofen, that is not a substrate for LAT1 was chosen as a model compound. The mechanism and the kinetics of the brain uptake of the prodrug were determined with an in situ rat brain perfusion technique. The brain uptake of the prodrug was found to be concentration-dependent. In addition, a specific LAT1 inhibitor significantly decreased the brain uptake of the prodrug. Therefore, our results reveal for the first time that a drug-substrate conjugate is able to transport drugs into the brain via LAT1.

The effects of a novel prolyl oligopeptidase (POP) inhibitor KYP-2047 on spatial memory of young (3-monthold) and old (8-to 9-month-old) scopolamine-treated rats (0.4 mg/kg intraperitoneally) was investigated in the Morris water maze. In addition, the concentrations of promnesic neuropeptide substrates of POP, substance P and neurotensin in various brain areas after acute and chronic POP inhibition were measured in young rats. In addition, inositol-1,4,5-trisphosphate (IP 3 ) levels were assayed in rat cortex and hippocampus after effective 2.5-day POP inhibition. KYP-2047 (1 or 5 mg/kg 30 min. before daily testing) dose-dependently improved the escape performance (i.e. latency to find the hidden platform and swimming path length) of the young but not the old rats in the water maze. POP inhibition had no consistent effect on substance P levels in cortex, hippocampus or hypothalamus, and only a modest increase in neurotensin concentration was observed in the hypothalamus after a single dose of KYP-2047. Moreover, IP 3 concentrations remained unaffected in cortex and hippocampus after POP inhibition. In conclusion, the behavioural data support the earlier findings of the promnesic action of POP inhibitors, but the mechanism of the memory-enhancing action remains unclear.In addition to the cholinergic neurones, many neuropeptides may play a role in cognitive functions such as learning and memory. These peptides include vasopressin, neurotensin, oxytocin, substance P and bradykinin [1,2]. A common feature of the above-mentioned promnesic neuropeptides is their sensitivity to prolyl oligopeptidase (POP, EC 3.4.21.26), also known as prolyl endopeptidase [1]. POP is a member of the serine protease family that hydrolyses peptide bonds at the carboxy terminal of  -proline. The effects of POP in memory disorders are somewhat conflicting. On one hand, some findings suggest that a decrease in POP activity is characteristic of a generalized process of neurodegeneration, including Alzheimer's disease and dementia [3]. However, for example in Alzheimer's disease, the changes in POP activities depend on which brain areas are being investigated. In cerebral cortex, a reduction in POP activity has been observed, whereas in occipital cortex, the POP activity seems to increase [4]. It has been proposed but not proved that these alterations in POP activity in Alzheimer's disease and dementia account for some of the observed changes in neuropeptide levels. In Alzheimer's disease, vasopressin and substance P levels decrease in cortical areas and hippocampus [5], areas implicated in cognitive processes. Furthermore, increased levels of neuropeptides have been shown to improve cognitive function in experimental animals [6,7].These observations would seem to indicate that manipulations of POP activity and its secondary effects on neuropeptide levels could represent a potential therapeutic target for treatment of cognitive disorders. Several POP inhibitors have been studied in animals. Studies with rats have demonstrated memo...

This study shows that ketoprofen is able to enter the CSF of children, which enables central analgesic effects of ketoprofen. However, the slow distribution of ketoprofen into the CSF and the apparently low absolute concentrations has to be taken into account when central analgesic effects are desired.

Metformin is a potent antidiabetic agent and currently used as a first-line treatment for patients with type 2 diabetes. Unfortunately, the moderate absorption and uncomfortable gastrointestinal adverse effects associated with metformin therapy impair its use. In this study, two novel prodrugs of a biguanidine functionality containing antidiabetic agent, metformin, were designed, synthesized, and evaluated in vitro and in vivo to accomplish improved lipophilicity and, consequently, enhanced oral absorption of this highly water-soluble drug. These results represent that the more lipophilic prodrug 2a biotransformed quantitatively to metformin mainly after absorption. The enhanced oral absorption consequently promoted the bioavailability of metformin from 43% to 65% in rats. Thus, this novel prodrug may offer a solution to reduce the required daily doses of metformin, which may decrease the uncomfortable adverse effects associated with metformin therapy.

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