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

Monica M. Reinholz, Jill J. Haggard, Geoffry L. Curran, Joseph F. Poduslo

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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 rain 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.

Original languageEnglish (US)
Pages (from-to)191-203
Number of pages13
JournalExperimental Neurology
Volume159
Issue number1
DOIs
StatePublished - Sep 1999

Fingerprint

Putrescine
Blood-Brain Barrier
Catalase
Nervous System
Permeability
Spinal Cord
Pharmacokinetics
Neurodegenerative Diseases
Free Radicals
Blood-Nerve Barrier
Central Nervous System
Injections
Rain
Brain

Keywords

  • Antioxidant
  • Blood-brain barrier
  • Catalase
  • Permeability
  • Putrescine

ASJC Scopus subject areas

  • Neurology
  • Neuroscience(all)

Cite this

Plasma pharmacokinetics, nervous system biodistribution and biostability, and spinal cord permeability at the blood-brain barrier of putrescine-modified catalase in the adult rat. / Reinholz, Monica M.; Haggard, Jill J.; Curran, Geoffry L.; Poduslo, Joseph F.

In: Experimental Neurology, Vol. 159, No. 1, 09.1999, p. 191-203.

Research output: Contribution to journalArticle

@article{a1df73736b7e4324b2bd2d9ce7cd842a,
title = "Plasma pharmacokinetics, nervous system biodistribution and biostability, and spinal cord permeability at the blood-brain barrier of putrescine-modified catalase in the adult rat",
abstract = "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 rain 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.",
keywords = "Antioxidant, Blood-brain barrier, Catalase, Permeability, Putrescine",
author = "Reinholz, {Monica M.} and Haggard, {Jill J.} and Curran, {Geoffry L.} and Poduslo, {Joseph F.}",
year = "1999",
month = "9",
doi = "10.1006/exnr.1999.7117",
language = "English (US)",
volume = "159",
pages = "191--203",
journal = "Experimental Neurology",
issn = "0014-4886",
publisher = "Academic Press Inc.",
number = "1",

}

TY - JOUR

T1 - Plasma pharmacokinetics, nervous system biodistribution and biostability, and spinal cord permeability at the blood-brain barrier of putrescine-modified catalase in the adult rat

AU - Reinholz, Monica M.

AU - Haggard, Jill J.

AU - Curran, Geoffry L.

AU - Poduslo, Joseph F.

PY - 1999/9

Y1 - 1999/9

N2 - 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 rain 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.

AB - 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 rain 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.

KW - Antioxidant

KW - Blood-brain barrier

KW - Catalase

KW - Permeability

KW - Putrescine

UR - http://www.scopus.com/inward/record.url?scp=0032826921&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032826921&partnerID=8YFLogxK

U2 - 10.1006/exnr.1999.7117

DO - 10.1006/exnr.1999.7117

M3 - Article

C2 - 10486187

AN - SCOPUS:0032826921

VL - 159

SP - 191

EP - 203

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

IS - 1

ER -