Plasma pharmacokinetics, nervous system biodistribution and biostability, and spinal cord permeability at the blood-brain barrier of putrescine-modified catalase in the adult rat

Free radical-mediated oxidative damage has been proposed to be an underlyin g mechanism in several neurodegenerative disorders. Previous investigations in our laboratory have shown that putrescine-modified catalase (PUT-CAT) h as increased permeability at the blood-brain (BBB) and blood-nerve barriers with retained enzymatic activity after parenteral administration when comp ared to native catalase (CAT). The goals of the present study were to exami ne the plasma stability, spinal cord BBB permeability, nervous system biodi stribution, and spinal cord enzyme activity of CAT and PUT-CAT after parent eral administration in the adult rat. TCA precipitation and chromatographic analyses revealed that CAT and PUT-CAT were found intact in the plasma and in the central nervous system (CNS) after iv, ip, or sc bolus injections. The highest percentages of intact CAT or PUT-CAT proteins mere found in the plasma after iv administration, and similar percentages of intact CAT or P UT-CAT were found in the CNS following all three types of administration. I ncreases of 2.4- to 4.7-fold in permeability at the BBB and similar increas es in the levels of intact PUT-CAT were found in different brain regions co mpared to the levels of CAT. A 2.4-fold higher level of intact PUT-CAT comp ared to that of CAT (P < 0.05) was found in the spinal cord 60 min after a sc bolus injection. CAT enzyme activity in the spinal cord was 50% higher ( P < 0.05) in rats treated with PUT-CAT continuously for 1 week by subcutane ously implanted, osmotic pumps than the activity found in rats treated with PBS. These results provide evidence that intact, enzymatically active PUT- CAT is efficiently delivered to the nervous system following iv, ip, and sc administration and suggest that sc administration of PUT-CAT may be effect ive in treating neurodegenerative disorders in which the underlying mechani sms involve the action of free radicals and oxidative damage, (C) 1999 Acad emic Press.