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Characterization of 1,4‐dideoxy‐1,4‐imino‐ d ‐arabinitol (DAB) as an inhibitor of brain glycogen shunt activity
Author(s) -
Walls Anne B.,
Sickmann Helle M.,
Brown Angus,
Bouman Stephan D.,
Ransom Bruce,
Schousboe Arne,
Waagepetersen Helle S.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05250.x
Subject(s) - glycogen phosphorylase , glycogen , hexokinase , glycogen branching enzyme , glycogen synthase , biochemistry , glucose transporter , chemistry , glycolysis , enzyme , endocrinology , medicine , biology , insulin
The pharmacological properties of 1,4‐dideoxy‐1,4‐imino‐ d ‐arabinitol (DAB), a potent inhibitor of glycogen phosphorylase and synthase activity in liver preparations, were characterized in different brain tissue preparations as a prerequisite for using it as a tool to investigate brain glycogen metabolism. Its inhibitory effect on glycogen phosphorylase was studied in homogenates of brain tissue and astrocytes and IC 50 ‐values close to 400 nM were found. However, the concentration of DAB needed for inhibition of glycogen shunt activity, i.e. glucose metabolism via glycogen, in intact astrocytes was almost three orders of magnitude higher. Additionally, such complete inhibition required a pre‐incubation period, a finding possibly reflecting a limited permeability of the astrocytic membrane. DAB did not affect the accumulation of 2‐deoxyglucose‐6‐phosphate indicating that the transport of DAB is not mediated by the glucose transporter. DAB had no effect on enzymes involving glucose‐6‐phosphate, i.e. glucose‐6‐phosphate dehydrogenase, phosphoglucoisomerase and hexokinase. Furthermore, DAB was evaluated in a functional preparation of the isolated mouse optic nerve, in which its presence severely reduced the ability to sustain evoked compound action potentials in the absence of glucose, a condition in which glycogen serves as an important energy substrate. Based on the experimental findings, DAB can be used to evaluate glycogen shunt activity and its functional importance in intact brain tissue and cells at a concentration of 300–1000 μM and a pre‐incubation period of 1 h.