Research report
N
1
-Dansyl-spermine: a potent polyamine antagonist
Brian P. Kirby
a,
*
, Sheila A. Ryder
a
, Nikolaus Seiler
b
, Jacques Renault
c
, Graham G. Shaw
a
a
Department of Pharmacology, School of Pharmacy, Trinity College, Dublin 2, Ireland
b
Laboratory of Nutritional Oncology INSERM U-392, Institut de Recherche contre les Cancers de l’Appareil Digestif (IRCAD), 1,
Place de l’hoˆpital B.P. 426, 67091 Strasbourg Cedex, France
c
Laboratoire de Chimie Pharmaceutique, 2, U.P.R. des Sciences Pharmaceutiques et Biologiques, Universite
´
de Rennes 1,
Avenue du Professeur Le
´
on Bernard 35045, Rennes Cedex, France
Accepted 21 February 2004
Available online 27 April 2004
Abstract
The potential polyamine antagonist action of N
1
-dansyl-spermine (a potent NMDA antagonist) was assessed in two in vivo mouse models
of polyamine action. Co-administration of N
1
-dansyl-spermine (2 –10 Ag, i.c.v.) with spermine (100 Ag, i.c.v.) resulted in a dose-dependent
antagonism of the spermine-induced CNS excitation (body tremor and fatal tonic convulsions). In addition, the same dose of N
1
-dansyl-
spermine antagonised spermine’s enhancement of NMDA-induced convulsions. These results suggest that N
1
-dansyl-spermine is in vivo a
potent antagonist of the CNS effects of spermine and of its action at the positive polyamine modulatory site on the NMDA receptor.
D 2004 Elsevier B.V. All rights reserved.
Theme: Neurotransmitters, modulators, transporters and receptors
Topic: Excitatory amino acids: excitotoxicity
Keywords: Spermine; N-Methyl-
D
-aspartate; N
1
-dansyl-spermine; Convulsion; Intracerebroventricular
1. Introduction
The polyamines (putrescine, spermidine and spermine) are
a family of di-, tri- and tetra-amines found in heterogeneous
concentrations throughout the body, including within the
brain [16]. Intense research over recent years has elucidated
a number of physiological roles for the polyamines within the
body [5,13]. They interact, among others, with different ion
channels, and are likely to control membrane excitability by
inward rectification of ion channels (for review see Ref. [20]).
The N-methyl-
D
-aspartate (NMDA) receptor, one of the
ionotropic glutamate receptors made up of two different
subunit groups (NR1 and NR2), is responsible for slow
excitatory neurotransmission. Two polyamine recognition
sites have been identified on the NMDA receptor macro-
complex, a positive modulatory and negative modulatory site
[11,12]. At physiological concentrations, spermine and sper-
midine act mainly as activators of the NMDA receptor
[18,21]. In agreement with these observations, spermidine
has been shown to enhance N-methyl-
DL
-aspartate
(NMDLA)-induced convulsions [4,17]. Thus, the antago-
nism of polyamine enhancement of NMDA-induced seizures
provides an in vivo model for examination of polyamine
antagonists.
The injection of spermine (100 Ag) into the cerebral
ventricles of mice (i.c.v.) results in the development of
CNS excitation and convulsions [7]. The initial behavioural
response consists of hypothermia, sedation, scratching and
face washing and, occasionally, clonic convulsions. This first
phase of effects lasts for approximately 1 h with a second
distinct phase commencing about 2 h after injection. During
this second phase, CNS excitation is manifest in all animals
as a tremor, which increases in intensity with time, culmi-
nating in a fatal tonic convulsion, usually within 6 –8 h [7].
While these excitatory effects of spermine are well recog-
nised [1], their underlying mechanism still remains to be
fully understood. The presence of polyamine binding sites on
the NMDA receptor macrocomplex [11,12] suggests that
0006-8993/$ - see front matter D 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.brainres.2004.02.075
* Corresponding author. Current address: School of Pharmacy, Royal
College of Surgeons, 123 St. Stephens Green, Dublin 2, Ireland. Tel.: +353-
1-4022727; fax: +353-1-4022765.
E-mail address: bkirby@rcsi.ie (B.P. Kirby).
www.elsevier.com/locate/brainres
Brain Research 1011 (2004) 69 –73