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 underlying mechanism in several neurodegenerative disorders. Previous investigations in our laboratory have shown that putrescine-modified catalase (PUT-CAT) has increased permeability at the blood-brain (BBB) and blood-nerve barriers with retained enzymatic activity after parenteral administration when compared to native catalase (CAT). The goals of the present study were to examine the plasma stability, spinal cord BBB permeability, nervous system biodistribution, and spinal cord enzyme activity of CAT and PUT-CAT after parenteral 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 were found in the plasma after iv administration, and similar percentages of intact CAT or PUT-CAT were found in the CNS following all three types of administration. Increases of 2.4- to 4.7-fold in permeability at the BBB and similar increases in the levels of intact PUT-CAT were found in different brain regions compared to the levels of CAT. A 2.4-fold higher level of intact PUT-CAT compared 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 subcutaneously 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 effective in treating neurodegenerative disorders in which the underlying mechanisms involve the action of free radicals and oxidative damage.
Reinholz
M M
MM
Departments of Neurology and Biochemistry/Molecular Biology, Mayo Clinic and Foundation, Rochester, Minnesota, 55905, USA.
Haggard
J J
JJ
Curran
G L
GL
Poduslo
J F
JF
D000367:Age Factors; D000818:Animals; D000975:Antioxidants / Q000493:pharmacokinetics; D001812:Blood-Brain Barrier; D002374:Catalase / Q000097:blood / Q000493:pharmacokinetics*; D002490:Central Nervous System / Q000098:blood supply / Q000201:enzymology; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D009410:Nerve Degeneration / Q000188:drug therapy; D011700:Putrescine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000975:Antioxidants; D007457:Iodine Radioisotopes; D002374:Catalase; D011700:Putrescine