SYNTHESIS AND EVALUATION OF BRAIN-TARGETED CHEMICAL DELIVERY SYSTEMS FOR THE NEUROTROPHOMODULATOR 4-METHYLCATECHOL

Since various 4-alkylcatechols stimulate nerve growth factor (NGF) bio synthesis both in-vitro and in-vivo, delivery of these agents to the b rain may provide beneficial effect for the treatment of neurodegenerat ive diseases such as Alzheimer's. Several dihydropyridine-pyridinium s alt type redox chemical delivery systems (CDS) of 4-methylcatechol (4- methylcatechol) were prepared as potential brain selective targetry fo rms for 4-methylcatechol. After preliminary evaluation by in-vitro sta bility studies in various buffer solutions and biological media, a sel ected CDS was further investigated in the rat to determine its in-vivo distribution. Selective and sustained delivery of the compound of int erest to the rat brain was achieved. Furthermore, the NGF stimulatory activity in the rat brain after peripheral administration of the selec ted CDS was evaluated by measuring the levels of pre-pro-NGF mRNA in t he rat hippocampus and frontal cortex, by dot blot hybridization and a nalysis. Results showed the peripheral administration of the CDS to ac hieve a 1.7-fold increase in NGF mRNA compared to control in the rat h ippocampus, and an approximately 1.4-fold increase in the frontal cort ex.