Quantitative targeted absolute proteomics (QTAP) has provided a rational strategy to determine the protein expression amounts of transporters which are involved in the highly regulated drug transport across the blood-brain barrier(BBB). This enables us to clarify the functional differences in the BBB transport between in vitro and in vivo, human and experimental animals such as monkeys and rodents, normal and disease conditions. The reconstruction of in vivo BBB transport function has been achieved by integrating the absolute amount of transporter proteins and the in vitro intrinsic transport activity for individual transporter, leading to the appropriate prediction of the human BBB central nervous system-acting drug transport.

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Epithelial tissues divide external environment and internal milieu to maintain homeostasis. Tight junctions (TJ) are one mode of cell to cell contacts apparatus in epithelia, which control paracellular permeability of epithelial cellular sheets. The major components of TJ are claudins, that have tour transmembrane proteins and consist of multi-gene family. The blood- brain barrier (BBB) has a crucial role for maintaining homeostasis of CNS. TJs that exist in endothelial cells in brain microcapillary characterize barrier function of the BBB. To date, it is suggested that dysfunction of the BBB is involved in many neurogenic disorders. In developing drug delivery strategies, BBB- forming endothelial cells are promising therapeutic targets.

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The central nervous system(CNS) diseases or disorders including Alzheimer's disease have been classified into a group in which their medicinal treatment remains ineffective. Thus, effective pharmacotherapy is highly required for such diseases. Recently, in addition to the conventional medicines based on low-molecular-weight compounds, biopharmaceuticals such as endogenous proteins and monoclonal antibodies targeted to specific sites is expected as a new class of medicines for treatment of CNS diseases. However, the poor permeability of drugs through blood-brain barrier(BBB) following peripheral administration has to be overcome to ensure the pharmacological activities of biopharmaceuticals in CNS, by means of permeation enhancement or alternative administration route to circumvent BBB. In this review, the recent progress in brain delivery researches to achieve the effective pharmacotherapy of CNS diseases is discussed.

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Galanin-like peptide(GALP) was discovered in the porcine hypothalamus in 1999 and it was found to be a 60 amino-acid peptide. Administration of GALP is well known to decrease food intake and body weight. In addition, it is also shown to increase core body temperature and energy metabolism after intraventricular infusion. Therefore, GALP may be a potential therapeutic medicine to be sued for the treatment of life-related diseases. This review summarizes the current evidence regarding the function of GALP, particularly in relation to feeding and energy metabolism. Moreover, intranasal administration of GALP is an effective route for delivery to the brain. We have examined the effect of GALP on food intake, body weight and energy metabolism after intranasal infusion which is a clinically viable route of delivery. We will present here that GALP may be used for obese people and also be helpful to overcome life-style-related diseases in the near future.

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We have previously demonstrated that CD38, a transmembrane protein with ADP-ribosyl cyclase activity, plays a critical role in mouse social behavior by regulating the release of oxytocin(OXT), which is essential for mutual recognition. When CD38 was disrupted, social amnesia was observed in CD38 knockout mice. The autism spectrum disorders(ASDs), characterized by defects in reciprocal social interaction and communication, occur either sporadically or in a familial pattern. The etiology of ASDs remains largely unknown and pharmacological treatments are needed. Therefore, we investigated single nucleotide polymorphisms(SNPs) in the human CD38 gene in ASD subjects. We found several SNPs in this gene. The SNP rs3796863 was associated with high-functioning autism(HFA) in American samples from the Autism Gene Resource Exchange. Although this finding was partially confirmed in low-functioning autism subjects in Israel, it has not been replicated in Japanese HFA subjects. The second SNP of interest, rs1800561, leads to the substitution of an arginine(R) at codon 140 by tryptophan(W; R140W) in CD38. This mutation was found in 4 probands of ASD and in family members of 3 pedigrees with variable levels of ASD or ASD traits. The plasma levels of OXT in ASD subjects with the R140W allele were lower than those in ASD subjects lacking this allele. Our preliminary study reveals that one proband with the R140W allele or 3 other ASD patients out of 6 receiving intranasal OXT for 0.5-3 years showed improvement in areas of social approach, eye contact and communication behaviors, emotion, irritability, and aggression. These results suggest that SNPs in CD38 may be possible risk factors for ASD by abrogating OXT function and that some ASD subjects can be treated with OXT in preliminary clinical trials. Further studies are necessary how intranasal OXT gets into the brain bypassing the blood-brain barrier.

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Intranasal administration is a promising effective and non-invasive drug delivery to the brain without passing through the blood-brain barrier (BBB). Cell penetrating peptide-modified block copolymer micelles (MPEG-PCL-Tat) have potential for improvement of mucosal permeability and nose-to-brain transport efficiency. Here we review the advantages of our MPEG-PCL-Tat micelles for intranasal drug and gene delivery.

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In vivo molecular imaging is a key technology for an innovative drug development. In particular, positron emission tomography(PET) has been applied to many studies in diagnosis, PK/PD, and DDS, since PET has superior sensitivity, quantitativity, and molecular multiplicity among other molecular imaging modalities. The brain is known to be kept its homeostasis by the blood-brain barrier that strictly limits the penetration of both endogenous and exogenous substances from the systemic circulation. In the development of drug targeting to the brain, molecular imaging technique is highly useful, because it enables the analysis of drug biodistribution in the brain, non-invasively in vivo. Here we introduced PET studies for the analysis of drug transporters in the blood-brain barrier, the visualization and evaluation of pharmacokinetics and pharmacodynamics of drugs in the brain as examples in effective use of molecular imaging technique for the drug development.

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