2′‐Deoxycoformycin Inhibition of Adenosine Deaminase in Rat Brain

In Vivo and In Vitro Analysis of Specificity, Potency, and Enzyme Recovery

R. Padua, Jonathan Geiger, S. Dambock, J. I. Nagy

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

2′‐Deoxycoformycin (DCF), a potent inhibitor of adenosine deaminase (ADA), is increasingly used as a tool to investigate adenosine metabolism and neuromodulation. To advance further the usefulness of DCF for studies of purines in the CNS, we determined the inhibitory potency of this compound against ADA and adenylate deaminase (AMPDA) in brain, the rate of ADA recovery in various brain regions after single or repeated intraperitoneal DCF administrations, and the effect of DCF on several neurotransmitter synthetic enzymes. In vitro, the Ki values for inhibition of ADA and AMPDA were found to be 23 pM and 233 μM, respectively. In vivo, DCF inhibited ADA with ED50 values ranging from 155 to 280 μg/kg at 2 h posttreatment, and 98% inhibition was achieved with 1 mg/kg. AMPDA activity was not affected by doses up to 5.0 mg/kg. In contrast to the >95% inhibition of ADA seen 1 day after DCF at 5 mg/kg, the effectiveness of a second similar DCF treatment on the activity that had recovered by 14 days was dramatically reduced. Eight days after DCF treatment with doses of 5–50 mg/kg, the degree of ADA activity recovery in 10 brain regions examined was similar; it averaged 35% of control values at the low dose but showed some heterogeneity, ranging from 15 to 54% of control values, at the higher doses. Forty days after treatment with a single dose of 5 mg/kg, ADA activity recovered by 68–78% of control values in brain regions with normally high levels of activity and by 44–59% of control values in other regions. The activities of choline acetyltransferase, glutamic acid decarboxylase, and histidine decarboxylase (an enzyme colocalized with ADA in hypothalamic neurons) were unaffected by DCF treatment, a result suggesting the lack of a generalized neurotoxic effect. The very low doses of DCF required for ADA inhibition in vivo are consistent with the high potency of this drug against ADA in vitro, and any physiological effects observed at low doses might therefore be ascribed to inhibition of ADA.

Original languageEnglish (US)
Pages (from-to)1169-1178
Number of pages10
JournalJournal of Neurochemistry
Volume54
Issue number4
DOIs
StatePublished - Jan 1 1990

Fingerprint

Adenosine Deaminase
Rats
Brain
Recovery
Enzymes
In Vitro Techniques
rat Ada protein
Adenosine Deaminase Inhibitors
AMP Deaminase
Histidine Decarboxylase
Purines
Glutamate Decarboxylase
Choline O-Acetyltransferase
Metabolism
Adenosine
Neurons
Neurotransmitter Agents

Keywords

  • 2′‐Deoxycoformycin
  • Adenosine
  • Adenosine deaminase
  • Adenylate deaminase
  • Brain
  • Neuromodulation
  • Purine metabolism

ASJC Scopus subject areas

  • Biochemistry
  • Medicine(all)
  • Cellular and Molecular Neuroscience

Cite this

2′‐Deoxycoformycin Inhibition of Adenosine Deaminase in Rat Brain : In Vivo and In Vitro Analysis of Specificity, Potency, and Enzyme Recovery. / Padua, R.; Geiger, Jonathan; Dambock, S.; Nagy, J. I.

In: Journal of Neurochemistry, Vol. 54, No. 4, 01.01.1990, p. 1169-1178.

Research output: Contribution to journalArticle

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abstract = "2′‐Deoxycoformycin (DCF), a potent inhibitor of adenosine deaminase (ADA), is increasingly used as a tool to investigate adenosine metabolism and neuromodulation. To advance further the usefulness of DCF for studies of purines in the CNS, we determined the inhibitory potency of this compound against ADA and adenylate deaminase (AMPDA) in brain, the rate of ADA recovery in various brain regions after single or repeated intraperitoneal DCF administrations, and the effect of DCF on several neurotransmitter synthetic enzymes. In vitro, the Ki values for inhibition of ADA and AMPDA were found to be 23 pM and 233 μM, respectively. In vivo, DCF inhibited ADA with ED50 values ranging from 155 to 280 μg/kg at 2 h posttreatment, and 98{\%} inhibition was achieved with 1 mg/kg. AMPDA activity was not affected by doses up to 5.0 mg/kg. In contrast to the >95{\%} inhibition of ADA seen 1 day after DCF at 5 mg/kg, the effectiveness of a second similar DCF treatment on the activity that had recovered by 14 days was dramatically reduced. Eight days after DCF treatment with doses of 5–50 mg/kg, the degree of ADA activity recovery in 10 brain regions examined was similar; it averaged 35{\%} of control values at the low dose but showed some heterogeneity, ranging from 15 to 54{\%} of control values, at the higher doses. Forty days after treatment with a single dose of 5 mg/kg, ADA activity recovered by 68–78{\%} of control values in brain regions with normally high levels of activity and by 44–59{\%} of control values in other regions. The activities of choline acetyltransferase, glutamic acid decarboxylase, and histidine decarboxylase (an enzyme colocalized with ADA in hypothalamic neurons) were unaffected by DCF treatment, a result suggesting the lack of a generalized neurotoxic effect. The very low doses of DCF required for ADA inhibition in vivo are consistent with the high potency of this drug against ADA in vitro, and any physiological effects observed at low doses might therefore be ascribed to inhibition of ADA.",
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AB - 2′‐Deoxycoformycin (DCF), a potent inhibitor of adenosine deaminase (ADA), is increasingly used as a tool to investigate adenosine metabolism and neuromodulation. To advance further the usefulness of DCF for studies of purines in the CNS, we determined the inhibitory potency of this compound against ADA and adenylate deaminase (AMPDA) in brain, the rate of ADA recovery in various brain regions after single or repeated intraperitoneal DCF administrations, and the effect of DCF on several neurotransmitter synthetic enzymes. In vitro, the Ki values for inhibition of ADA and AMPDA were found to be 23 pM and 233 μM, respectively. In vivo, DCF inhibited ADA with ED50 values ranging from 155 to 280 μg/kg at 2 h posttreatment, and 98% inhibition was achieved with 1 mg/kg. AMPDA activity was not affected by doses up to 5.0 mg/kg. In contrast to the >95% inhibition of ADA seen 1 day after DCF at 5 mg/kg, the effectiveness of a second similar DCF treatment on the activity that had recovered by 14 days was dramatically reduced. Eight days after DCF treatment with doses of 5–50 mg/kg, the degree of ADA activity recovery in 10 brain regions examined was similar; it averaged 35% of control values at the low dose but showed some heterogeneity, ranging from 15 to 54% of control values, at the higher doses. Forty days after treatment with a single dose of 5 mg/kg, ADA activity recovered by 68–78% of control values in brain regions with normally high levels of activity and by 44–59% of control values in other regions. The activities of choline acetyltransferase, glutamic acid decarboxylase, and histidine decarboxylase (an enzyme colocalized with ADA in hypothalamic neurons) were unaffected by DCF treatment, a result suggesting the lack of a generalized neurotoxic effect. The very low doses of DCF required for ADA inhibition in vivo are consistent with the high potency of this drug against ADA in vitro, and any physiological effects observed at low doses might therefore be ascribed to inhibition of ADA.

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