Midkine: a promising molecule for drug development to treat diseases of the central nervous system

Abstract

Midkine (MK) is a heparin-binding cytokine, and promotes growth, survival, migration and other activities of target cells. After describing the general properties of MK, this review focuses on MK and MK inhibitors as therapeutics for diseases in the central nervous system. MK is strongly expressed during embryogenesis especially at the midgestation period, but is expressed only at restricted sites in adults. MK expression is induced upon tissue injury such as ischemic brain damage. Since exogenously administered MK or the gene transfer of MK suppresses neuronal cell death in experimental systems, MK has the potential to treat cerebral infarction. MK might become important also in the treatment of neurodegenerative diseases such as Alzheimer's disease. MK is involved in inflammatory diseases by enhancing migration of leukocytes, inducing chemokine production and suppressing regulatory T cells. Since an aptamer to MK suppresses experimental autoimmune encephalitis, MK inhibitors are promising for the treatment of multiple sclerosis. MK is overexpressed in most malignant tumors including glioblastoma, and is involved in tumor invasion. MK inhibitors may be of value in the treatment of glioblastoma. Furthermore, an oncolytic adenovirus, whose replication is under the control of the MK promoter, inhibits the growth of glioblastoma xenografts. MK inhibitors under development include antibodies, aptamers, glycosaminoglycans, peptides and low molecular weight compounds. siRNA and antisense oligoDNA have proved effective against malignant tumors and inflammatory diseases in experimental systems. Practical information concerning the development of MK and MK inhibitors as therapeutics is described in the final part of the review.

Fig. (1)

Protein sequence of human MK. Amino acids conserved between MK of different species (human MK [18], Xenopus MK [20] and zebrafish Mdka [21, 194]) are shown by open boxes, while those conserved between MK and PTN (human MK and PTN [6], Xenopus MK and zebrafish Mdka) are shown by ★. Heparin binding sites Cluster 1 and 2 are shown by closed hexagons and open hexagons, respectively. Bars show β-sheets.

Fig. (2)

Domain structure of human MK. Homology to human PTN is more than 60 % (black color), between 40 – 60 % (grey color), or less than 40 % (white color).

Fig. (3)

Organization of the human MK gene (MDK). Closed boxes show coding sequences in exons, and open boxes show noncoding sequences in exons. There are 3 non-coding exons. Usually, an MK mRNA has one of the non-coding exons. Open star, a retinoic acid-responsive element [41]; closed star, a functional WT1-binding site [43].

Fig. (4)

Structures of two compounds initially selected as low molecularweight MK inhibitors [193]. Upper one, PubChem 4603792; lower one, a related compound.