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The Journal of Neuroscience, December 1, 1998, 18(23):10070-10077
Galanin Modulation of Seizures and Seizure Modulation of
Hippocampal Galanin in Animal Models of Status Epilepticus
Andrey M.
Mazarati1, 4,
Hantao
Liu1, 4,
Ursel
Soomets5, 6,
Raman
Sankar1, 2,
Don
Shin1, 2, 4,
Hiroshi
Katsumori1, 4,
Ülo
Langel5, and
Claude G.
Wasterlain1, 3, 4
Departments of 1 Neurology and 2 Pediatrics
and the 3 Brain Research Institute, University of
California, Los Angeles, School of Medicine, Los Angeles, California,
4 Neurology Service Veterans Administration Medical Center,
Sepulveda, California, 5 Department of Neurochemistry and
Neurotoxicology, Arrhenius Laboratories, Stockholm University,
Stockholm, Sweden, and 6 Department of Neurochemistry,
Tartu University, Tartu, Estonia
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ABSTRACT |
We examined the role of hippocampal galanin in an animal model of
status epilepticus (SE). Control rats showed abundant
galanin-immunoreactive (Gal-IR) fibers in the dentate hilus,
whereas no Gal-IR neurons were observed. Three hours after the onset of
self-sustaining SE (SSSE), induced either by intermittent stimulation
of the perforant path for 30 min (PPS) or by injection of lithium and
pilocarpine, Gal-IR fibers disappeared in the hilus and remained absent
for up to 1 week afterward. Twelve hours after the induction of SE by
PPS or 3 hr after pilocarpine administration, Gal-IR neurons appeared
in the hilus; these neurons increased in number after 1 d and
gradually declined 3 and 7 d later. Galanin concentration in the
hippocampus, measured by ELISA, significantly decreased on the
plateau of SSSE and increased 24 hr after PPS. Galanin (0.05 nmol)
injected into the hilus prevented the induction of SSSE, and 0.5 nmol
of galanin stopped established SSSE. These effects were attenuated by
galanin receptor antagonists (M35 > M40  M15).
2-Ala-galanin (5 nmol), a putative agonist of galanin type 2 receptors,
prevented but was unable to stop SSSE. M35 facilitated the development
of SSSE when given before PPS. We suggest that hippocampal galanin acts
as an endogenous anticonvulsant via galanin receptors. SE-induced
galanin depletion in the hippocampus may contribute to the maintenance
of seizure activity, whereas the increase of galanin concentration and
the appearance of galanin-immunoreactive neurons may favor the
cessation of SSSE. The seizure-protecting action of galanin SSSE opens
new perspectives in the treatment of SE.
Key words:
status epilepticus; hippocampus; galanin; immunocytochemistry; galanin receptor ligands; anticonvulsant
effects
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INTRODUCTION |
Galanin, a bioactive peptide
containing 29 or 30 amino acid residues, is widely distributed
throughout the CNS (Skofitsch and Jacobowitz, 1985 , 1986;
Melander et al., 1986a-d; Bartfai et al., 1993; Merchenthaler
et al., 1993), where it coexists with classical neurotransmitters
(Melander et al., 1985, 1986b,c; Fisone et al., 1987; Bartfai et al.,
1988; Senut et al., 1989) and often inhibits their release (Kask et
al., 1995). Three subtypes of galanin receptors (GalR) that have been
cloned, GalR1 (Habert-Ortoli et al., 1994; Burgevin et al., 1995),
GalR2 (Howard et al., 1997; Smith et al., 1997; Wang et al., 1997a),
and GalR3 (Wang et al., 1997b), belong to a superfamily of
G-protein-linked receptors. Activation of galanin receptors results in
the opening of K+ channels, in the inhibition of
cAMP synthesis (GalR1 and GalR2) (Chen et al., 1992; Karelson et al.,
1995; Wang et al., 1997a), and probably in the activation of
phospholipase C (GalR2) (Smith et al., 1997).
Galanin is abundant in several brain structures, including septum
in which it coexists with acetylcholine and locus coeruleus in which it
is colocalized with norepinephrine. The axons of the neurons located in
these structures project diffusely to the hippocampus (Melander et al.,
1985; Lamour et al., 1989; Senut et al., 1989; Cortes et al.,
1990; Merchenthaler et al., 1993) where the density of galanin
receptors is high (Melander et al., 1986a,d; Skofitsch et al.,
1986; Servin et al., 1987; Fisone et al., 1989a,b). Sparse hippocampal
galanin-immunoreactive (Gal-IR) neurons and those expressing
preprogalanin mRNA are revealed after intrahippocampal administration
of colchicine (Skofitsch and Jacobowitz, 1985; Cortes et al.,
1990). Physiological studies suggest that the action of galanin in the
hippocampus is predominantly inhibitory. Thus, galanin inhibited EPSP
in pyramidal neurons of CA1 (Dutar et al., 1989) and inhibited
long-term potentiation at Schaffer collateral-CA1 synapses in
hippocampal slices (Sakurai et al., 1996). Galanin decreased the
release of excitatory amino acids in hippocampal slices under both
normal and ischemic conditions (Ben-Ari and Lazdunski, 1989; Zini et
al., 1993a,b). The mentioned physiological properties of galanin
suggest that it may have modulatory effects on seizures. However,
although the role of galanin in memory function (Mastropaolo et al.,
1988; Sundström et al., 1988) in the regulation of the secretion
of hypothalamopituitary hormones (Bartfai et al., 1993) is well
established, its involvement in seizure mechanisms has received little
attention (Mazarati et al., 1992; Chepurnov et al., 1997). In the
present report, we show that status epilepticus (SE) induces distinct
time-dependent changes in hippocampal galanin. We also provide evidence
of a strong, receptor-mediated anticonvulsant effect of
intrahippocampal galanin application and of the facilitation of SE
resulting from the blockade of hippocampal galanin receptors.
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MATERIALS AND METHODS |
Animals and surgery. The experiments were performed
on male Wistar rats, 8-10 weeks old (Simonsen Labs, Gilroy,
CA). Animals were kept at room temperature with a 12 hr
artificial dark/light cycle and access to standard diet and tap water
ad libitum. All experiments were performed according to the
protocol approved by the Animal Care Committee of Sepulveda Veterans
Administration Medical Center.
Under ketamine (60 mg/kg) and xylazine (15 mg/kg) anesthesia, animals
were implanted with a bipolar stimulating electrode into the angular
bundle of the perforant path (4.5 mm left of and 0.5 mm posterior to
lambda) and with a bipolar recording electrode combined with a guide
cannula (internal diameter, 0.6 mm) into the granule cell layer of the
ipsilateral dentate gyrus (2.2 mm left of and 3.5 mm anterior to
lambda). The depth of both electrodes was optimized by finding the
population spike of maximal amplitude evoked from the dentate gyrus by
the stimulation of the perforant path (single square-wave monophasic
stimuli; 20 V; 0.1 msec). To standardize the conditions of perforant
path stimulation (PPS) and of the site of electrographic recording, we
used only those animals in which population spike amplitude was 2 mV.
Some animals were additionally injected during surgery with colchicine
(100 µg in 10 µl) into the medial septum (MS) (0.8 mm
anterior to bregma and 8.3 mm deep from the cortical surface) by means
of a Hamilton microsyringe to block axonal transport of galanin
(Skofitsch and Jacobowitz, 1985). These animals were not used for the
induction of SE but were killed 3 d after the surgery for immunostaining.
Induction and analysis of SE. To induce self-sustaining SE
(SSSE), animals were stimulated in the awake state for 30 min with 10 sec, 20 Hz trains (1 msec square wave; 20 V) delivered every minute,
together with 2 Hz continuous stimulation (Mazarati et al., 1998). Some
animals underwent 7 min of PPS using the same parameters. Another
protocol for the induction of SE used intraperitoneal administration of
LiCl (3 meq/kg) followed 18 hr later by intraperitoneal injection of
pilocarpine HCl (60 mg/kg) (Sankar et al., 1997). Electrographic
activity from the dentate gyrus was monitored and recorded during PPS
and for 24 hr after the end of PPS using the Monitor 8.1 computer
program (Stellate Systems). The software was configured for automatic
detection and saving of seizures and spikes. EEG was analyzed off-line
using the same software. After the end of PPS, EEGs were recorded for
10 min to verify the presence of SSSE, before any treatment was
initiated. The duration of SSSE was determined as the time between the
end of PPS and the last paroxysmal event (seizure or spike). The
severity of behavioral seizures was evaluated using the Racine (1972)
scale. Control animals underwent surgery and received sham PPS or
injection of 0.9% NaCl instead of pilocarpine.
Studies of galanin-like immunoreactivity. Three, 12, or 24 hr or 3 or 7 d after the end of PPS or pilocarpine
administration, animals were deeply anesthetized with sodium
pentobarbital (60 mg/kg) and perfused through the ascending aorta with
200 ml of 0.1 M sodium PBS, pH 7.4, followed by 0.1 M sodium PBS containing 4% paraformaldehyde. The
brains were post-fixed in the same solution for 4 hr and placed in
Tris-PBS and 30% sucrose, pH 7.4 (4°C), for 24 hr and then serially
sectioned in 40-µm-thick coronal sections on a cryotome. The sections
were blocked in Tris-PBS containing 10% normal goat serum (NGS)
and 0.3% Triton X-100 for 1 hr, incubated in the rabbit anti-galanin
antiserum (Peninsula Laboratories) at a concentration of 1:5000
overnight at room temperature, washed with Tris-PBS containing 1% NGS
and 0.3% Triton X-100 for 30 min at room temperature, incubated in
biotinylated goat anti-rabbit IgG (Vector Laboratories, Burlingame, CA)
for 1 hr at room temperature, and washed with Tris-PBS for 30 min and
an avidin-biotin-peroxidase complex (Vicastain; Vector Laboratories)
for 1 hr. To identify the immunoreaction product, we visualized the
horseradish peroxidase with diaminobenzidine and glucose oxidase, with
nickel intensification. The specificity of the anti-galanin antiserum
was confirmed by the absence of staining in the hippocampus when the
primary antiserum was replaced with nonimmune serum and by the absence
of labeling when the primary antiserum was omitted.
Gal-IR was quantified by a blinded investigator in the hilus and in the
granule cell layer of the dentate gyrus, in CA3 and in MS. For the
quantification of Gal-IR fibers, the sections were captured with a 10×
objective and a Sony DKC 5000 camera (Tokyo, Japan), converted
to digital images, and analyzed by means of the Image-Pro Plus
software. The optical density of Gal-IR fibers was measured by manually
outlining the region of the hilus and CA3. Background values were
obtained from the stratum radiatum of CA1. The optical density was
measured in five sections from each brain and was expressed as absolute
values, with higher numbers corresponding to a higher density of
Gal-IR. The number of Gal-IR neurons in five sections from each brain
was counted on an Olympus AX-70 microscope with a 10× objective.
Galanin concentration in the hippocampus. The hippocampal
galanin concentration was examined by means of competitive
ELISA. Six or twenty-four hours after PPS, animals were deeply
anesthetized with methoxyflurane. The brains were quickly removed; the
whole hippocampi were dissected on ice, homogenized in 2 M
acetic acid containing 10 µg/ml aprotinin (Sigma, St. Louis, MO), and
centrifuged for 15 min at 4°C. The supernatant was stored at
 70°C. For the preparation of conjugate, 200 µg of rat galanin was
coupled to 2 mg of bovine serum albumin with glutaraldehyde (both from
Sigma) (Folkesson and Terenius, 1985). The conjugate was dialyzed for 2 d at 4°C with three changes of PBS, diluted to 0.4 mg of
protein per milliliter, brought to 0.02% in sodium azide, and coated
to the 96 well plate. For ELISA, the samples and the standards (eight concentrations from 800 to 0.05 ng of galanin/ml of PBS) were added in
12.5 µl of PBS/bovine serum albumin with 87.5 µl of galanin antibodies at 1:50,000 (Chemicon, Temecula, CA) to the conjugate-coated plates. The plates were incubated overnight at 4°C, repeatedly rinsed
with PBS, and incubated with peroxidase-labeled goat anti-rabbit IgG at
1:1500 (Sigma) for 2 hr at room temperature. This was followed by
addition of 100 µl of substrate solution (O-phenylenediamine HCl with
H2O2; both from Sigma). The reaction was
stopped in 30 min with 100 µl of 2.5 M
H2SO4. The results were analyzed on an ELISA
plate reader (Titertek) at 490 nm.
Administration of galanin receptor ligands. The following
ligands of galanin receptors were used: rat galanin (0.01, 0.05, and
0.5 nmol), which is a mixed GalR1/GalR2 agonist; the putative GalR2
agonist 2-Ala-Galanin (0.5 and 5 nmol); and the antagonists M15, M35,
and M40 (0.5 and 5 nmol) (Bartfai et al., 1992; McDonald et al., 1997).
Galanin and M15 were purchased from American Peptide Company. Other
peptides were synthesized on an ABI peptide synthesizer using
the t-Boc strategy of solid-phase peptide synthesis according to the
protocol described previously (Langel et al., 1992). The purity of the
peptides was >99% as demonstrated by HPLC on an analytical
nucleosil 120-3 C18 reverse-phase HPLC column (0.4 × 10 cm). The molecular masses of the peptides were determined with a
Plasma Desorption Mass Spectrometer (Bioion 20; Applied Biosystems,
Foster City, CA), and the calculated values were obtained in each case.
The peptide solutions were prepared extempore by dissolving
in 0.9% NaCl and were injected, in a volume of 0.5 µl, into the
hilus of freely moving rats by a Hamilton microsyringe connected to the
guide cannula for 5 min. Peptides were injected either 10 min before
the beginning or 10 min after the end of PPS. Control animals were
treated with 0.9% NaCl.
Statistics. Data were analyzed by one-way ANOVA followed by
Newman-Keuls test or by Kruskal-Wallis test followed by Mann-Whitney test, where appropriate; p < 0.05 was accepted to be
statistically significant.
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RESULTS |
Gal-IR in control animals
In controls, a fine dense network of Gal-IR fibers was observed in
all hippocampal areas. No Gal-IR neurons were present (Figs. 1A,
2). MS was characterized by a high degree
of immunostaining of Gal-IR fibers. In the animals injected with
colchicine into the MS, the density of galanin-positive fibers in both
the hilus and area CA3 was significantly lower than that in controls.
The decline in optical density was more pronounced in CA3 than in the
hilus (6 and 26% of control values, respectively). No Gal-IR neurons
were observed in the hippocampus in colchicine-treated animals (Figs.
1B, 2).
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Figure 1.
SE-induced changes in galanin-like
immunoreactivity in the hippocampus. A, Control.
Abundant galanin-immunoreactive fibers are present in the hilus and
CA3. B, Three days after injection of colchicine into
the medial septum. No Gal-IR fibers are visualized. h,
Hilus. C, Twelve hours after PPS. D,
Twenty-four hours after PPS. E, Seven days after PPS.
F, Three hours after the induction of Li-pilocarpine SE.
Note the absence of Gal-IR fibers and the presence of Gal-IR neurons.
Scale bar, 200 µm.
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Figure 2.
Changes in galanin-like immunoreactivity and
galanin content in the hippocampus induced by self-sustaining SE.
A, B, Optical density of Gal-IR fibers
(A) and the number of Gal-IR neurons per section
(B) in the hilus (open bars) and
CA3 (black bars). Colch, Colchicine. Time
is hours and days after SSSE, which was induced by 30 min of PPS.
Because there were no differences between stimulated and contralateral
sides, data from both hippocampi were pooled. C, Galanin
content in the hippocampus, measured by ELISA 6 and 24 hr after PPS.
Data for the left and the right hippocampi were pooled together in the
control. Error bars indicate SD. *p < 0.05 versus
controls; #p < 0.05 versus 24 hr (one-way ANOVA
plus Newman-Keuls test). Controls included four animals, and all other
groups had three animals.
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Description of SE
Thirty minutes of PPS induced behavioral and electrographic
seizures in all animals, starting after 5-10 min of stimulation. The
seizures were initially facial myoclonus (stage 1), which progressed
through the head and forelimb clonic seizures (stage 3) to rearing
(stage 4) or rearing and falling (stage 5). Stage 4-5 convulsions were
accompanied by high-frequency, high-amplitude paroxysmal activity in
the dentate gyrus (Fig. 3A),
which recurred at intervals of 3-30 min and was recognized as seizures
by the software. Stage 4-5 seizures alternated with stage 1-3
behavior, accompanied by spike-and-wave complexes in the EEG.
Behavioral and electrographic seizure activity (stage 1-5) was
observed for 6-18 hr after the end of PPS in different animals (Fig.
3A). In the Li-pilocarpine model, seizures started 10-15
min after injection of pilocarpine. Repetitive stage 3-5 seizures were
observed for 4-8 hr after their onset.
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Figure 3.
Electrographic activity during SSSE in
control and galanin ligand-treated animals. A,
Representative time course of SSSE. Top, Each
line represents 2 hr of monitoring. The duration of PPS
is indicated by the large horizontal gray bar. Each
electrographic event recognized as a seizure (usually corresponding to
stage 4-5 behavioral convulsions) is indicated by a small
horizontal black bar. Seizures recurred for 18 hr in this
animal. Bottom, Sample EEG indicates electrographic
activity before and 8 hr after PPS. The event recognized as a seizure
by the software is underlined. Between the seizures,
frequent spikes occurred (accompanied by stage 1-3 behavioral
convulsions). B, Representative tracing from a rat
injected with intrahippocampal galanin 10 min after the end of PPS
(arrow). Note the presence of seizures (as indicated in
A) during PPS and between the end of PPS and galanin
administration and their disappearance after galanin injection. Sample
electrographic recordings show seizure activity 10 min after the end of
PPS (just before galanin injection) and the absence of seizure activity
30 min after administration of galanin. C, Recording
during and after 7 min of PPS in a control animal. Only a single
seizure occurred several minutes after PPS. Sample EEG taken 30 min
after PPS shows no paroxysmal activity. D, The effects
of pretreatment with M35 on the ability of the animal to establish
SSSE. In contrast to control animals, this rat developed
self-sustaining seizures, which lasted for 3 hr.
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Changes in hippocampal Gal-IR and galanin concentration during and
after SE
In the animals killed 3 hr after the end of PPS, during
steady-state SSSE, Gal-IR fibers were absent in all hippocampal areas (Fig. 2). Gal-IR fibers were still absent 12 hr after PPS, as well as 1 and 3 d later (Figs. 1C,D,
2A). One week after SSSE, some Gal-IR fibers
reappeared in the hilus, although their density was still significantly
lower than that in control animals (Figs. 1E, 2).
Starting from 12 hr after PPS, Gal-IR neuronal bodies, located mostly
in the hilus on the border of the granule cell layer, appeared (Fig.
1C). Twenty-four hours after PPS, the number of
galanin-positive neurons further increased, and they were distributed evenly on the border of the dentate granule cell layer and in the
middle of the hilus (Fig. 1D). Three and 7 d
after PPS, the number of Gal-IR neurons gradually decreased (Figs.
1E, 2B). No Gal-IR neurons were
observed in the dentate granule cell layer and in CA3. These changes
occurred on both the stimulated and the contralateral sides. After SE
induced by Li-pilocarpine, the decline in hippocampal fibers was
similar to that observed after SSSE. However, Gal-IR neurons in the
hilus appeared as early as 3 hr after pilocarpine administration (Fig.
1F) and were present at 1, 3, and 7 d. In both
models of SE, no significant changes in Gal-IR were seen in MS.
Six hours after PPS, on the plateau of SSSE, galanin
concentration in both stimulated and contralateral hippocampi was
significantly lower than that in controls. On the next day after PPS,
galanin content returned to the initial level in the contralateral
hippocampus, whereas in the stimulated hippocampus it significantly
exceeded the concentration in control animals (Fig. 2C).
Effects of galanin receptor ligands on SSSE
Perihilar injection of 0.05 nmol (n = 5) and 0.5 nmol (n = 6) of galanin before 30 min of PPS
significantly shortened the duration of self-sustaining seizures (Fig.
4A). After PPS, stage 4 seizures continued for only a few minutes, and spikes were observed for
another 10-20 min, after which no electrographic or behavioral seizure
was seen (Fig. 3B). 2-Ala-galanin did not affect the course of SSSE, when given before PPS in a dose of 0.5 nmol (n = 4). A dose of 5 nmol (n = 4) significantly decreased
the duration of self-sustaining seizures, which lasted for 2-4 hr
(Fig. 4A).
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Figure 4.
The effects of galanin receptor ligands on SSSE.
A, Effects of peptides injected before 30 min of PPS.
B, Effects of peptides injected after the end of PPS.
Galanin (Gal), but not 2-Ala-galanin
(2-Ala-Gal), stopped established SSSE when
administered after PPS. These effects were abolished by all three
galanin receptor antagonists. C, Effects of galanin
receptor antagonists injected before 7 min of PPS. M35, but not two
other galanin receptor antagonists, favored the establishment of SSSE
when given before 7 min of PPS. Error bars indicate SD of the mean
ratio of SSSE duration in the peptide-treated to control animals in
which SSSE duration is presented as 1 and indicated by the
dashed line. Absolute values (mean + SD; in minutes) of
SSSE duration in control rats are indicated above the
dashed line. *p < 0.05 versus
control (Kruskal-Wallis test followed by Mann-Whitney post
hoc test).
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In the next set of the experiments, we injected galanin 10 min after
the end of PPS, a time sufficient to document that seizures are
self-sustaining (Mazarati et al., 1998). Perihilar administration of
0.5 nmol (n = 5) but not 0.05 nmol (n = 3) of galanin stopped self-sustaining seizures within 25 min (Fig.
4B). 2-Ala-galanin in a dose that prevented the
establishment of SSSE (5 nmol) did not stop previously established SSSE
(n = 3). The seizure-blocking effects of galanin were
canceled by its coadministration with any of the three galanin receptor
antagonists, given in doses that did not alter seizures (Fig. 4,
n = 4 in each group)
Because galanin displayed anticonvulsant effects, we examined the
consequences of administration of galanin receptor antagonists before
our experiments. In this set of experiments, the animals received PPS
for 7 min after the administration of placebos or galanin antagonists.
As shown earlier (Mazarati et al., 1998), 7 min of PPS never induced
SSSE in control animals (n = 4) (Fig. 3C). No SSSE was observed in the rats pretreated with either
M15 or M40 (Fig. 4C, 0.5 and 5 nmol; n = 4 in each group). However, animals (n = 4) that received
5 nmol of M35 developed SSSE and continued to seize for 180-250 min
after PPS (Figs. 3D, 4C).
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DISCUSSION |
Our studies show that both SSSE induced by 30 min of PPS and SE
induced by Li-pilocarpine were accompanied by time-dependent changes of
galanin stores in the hilus and CA3. Gal-IR, which was confined to
fibers in the hippocampi of normal animals, dramatically declined after
colchicine administration into the MS, confirming that the bulk of
those fibers are the axons of MS neurons (Lamour et al., 1989).
The rest of the fibers come from different sources, such as locus
coeruleus (Xu et al., 1998) and hypothalamus (Skofitsch and Jacobowitz,
1985). SE was accompanied by the rapid disappearance of galanin from
hilar and CA3 fibers, which lasted for at least 1 week. The mechanism
of this disappearance is the subject of further studies. However,
considering the importance of MS neurons as a source of galanin
delivered to the hilus and the functional anatomy of the
septohippocampal complex, we can suggest a sequence of events that may
underlie these changes. The glutamatergic pathway originating from the
hippocampus provides excitation for GABAergic neurons in the lateral
septum (LS) (Malthe-Sorenssen et al., 1980; Stevens and
Cotman, 1986). Those LS neurons in turn inhibit
galanin-containing MS neurons (McLennan and Miller, 1974). The neurons
from the MS project back to the hippocampus. There is also a less
abundant direct glutamatergic projection from the hippocampus to the MS (Gaykema et al., 1991). Therefore, galanin-containing neurons in the MS
experience a dual hippocampal feedback, inhibitory via the
hippocampo-lateral septum-MS loop and excitatory via the
hippocampo-MS projection. With continuous hippocampal activation, the
first circuit may decrease the outflow of galanin to the hippocampus. The second circuit might initially have the opposite effect, but because SE lasts, the increased release of galanin because of continuous firing of MS axons and synapses may exhaust their galanin stores. Either tonic inhibition of galanin-containing MS neurons via
the lateral septum or galanin fatigue via the hippocampo-MS projection
could result in the disappearance of galanin fibers in the hippocampus.
Finally, the inhibition of polypeptide synthesis during SE (Dwyer and
Wasterlain, 1984) and the reported inhibition of axonal transport by
seizures (Divac et al., 1984) may also play a role in inhibiting the
replenishment of presynaptic hippocampal galanin stores.
Another change induced by SE was the expression of galanin by hilar
neurons, which were completely devoid of Gal-IR in the control rats.
This phenomenon probably was not a compensatory response to the
depletion of galanin from the septohippocampal fibers. First, the
depletion of galanin from hilar fibers in colchicine-treated animals
was not accompanied by its appearance in hilar neurons. Second, in SE,
no Gal-IR neurons were seen in CA3, although galanin fibers projecting
to that area also lost their immunoreactivity. These data suggest that
the observed changes specifically relate to the effects of SE on the
hilus. Alternatively, galanin might be expressed in neurons that are
degenerating as a result of excitotoxic damage. However, SSSE-induced
neuronal injury spreads far beyond the hilus of the dentate gyrus, to
other hippocampal as well as extrahippocampal areas (Mazarati et al.,
1998), and therefore the distribution of Gal-IR neurons and that of
neuronal injury are quite different. The earlier appearance of Gal-IR
neurons in Li-pilocarpine SE compared with SSSE may reflect differences in seizure intensity in these two models. Li-pilocarpine SE was characterized by continuous severe stage 4-5 seizures, whereas during
SSSE, such convulsions alternated with less severe (stage 1-3)
seizures. Thus, the earlier expression of Gal-IR seems to correlate
with greater seizure severity. The nature of Gal-IR neurons appearing
as a result of SE is uncertain and is a matter of future studies. The
fact that these cells appear initially at the edge of the granule cell
layer suggests that at least some of these neurons may be basket cells.
However, later Gal-IR neurons are distributed evenly throughout the
hilus and thus may belong to other subpopulations of hilar interneurons.
Changes in hippocampal Gal-IR correlated with galanin content. On the
plateau of SSSE, when galanin disappeared from hippocampal fibers,
peptide concentration went down in both stimulated and contralateral
hippocampi, suggesting that the decrease of Gal-IR during seizures
reflects profound depletion of hippocampal galanin. Recovery of galanin
concentration soon after SSSE may reflect the accumulation of galanin
in hippocampal neurons, evidenced by the appearance of
galanin-immunopositive neurons at this time point.
Changes resembling those observed in our study were described earlier
for neuropeptide Y (NPY), which appeared de novo in mossy
fibers (Marksteiner et al., 1990; Lurton et al., 1996; Vezzani et al.,
1996), and for the GAD67 isoform of glutamic acid decarboxylase (Schwarzer and Sperk, 1995), which appeared in dentate granule cells.
Although the significance of such changes is uncertain, they may
represent endogenous adaptive mechanisms that counteract seizure
activity. Both GABA (the product of GAD) and NPY (Klapstein and
Colmers, 1997; Sperk and Herzog, 1997), as well as galanin (Dutar et
al., 1989; Sakurai et al., 1996), may reduce hippocampal excitability
under most circumstances, and their increased expression may function
as a braking mechanism on SE.
The significance of the changes in hippocampal galanin in the course of
SE was confirmed in pharmacological experiments. We found that galanin,
a natural nonselective agonist for all types of galanin receptors
(Habert-Ortoli et al., 1994; Burgevin et al., 1995; Howard et al.,
1997; Smith et al., 1997; Wang et al., 1997a,b), had a potent
seizure-protecting effect when injected into the dentate gyrus. Galanin
was not only able to prevent the initiation of SSSE but, when given
after PPS, it effectively and irreversibly aborted the maintenance
phase of established SSSE. This effect seems even more spectacular,
considering that the standard anticonvulsant drug diazepam failed to
abort the maintenance of SSSE, as was shown earlier (Mazarati and
Wasterlain, 1997). The anticonvulsant effect of galanin was mediated
via galanin receptors, because it was abolished by coinjection of any
of the three galanin receptor antagonists in doses that correspond to their affinity for GalR1 receptors: M35 equimolar to galanin, and M15
or M40 in a 10-fold excess dose (Smith et al., 1997). Moreover, M35,
the most potent of the three and a preferential antagonist of GalR1
(Smith et al., 1997), facilitated the development of SSSE when
administered before PPS. The mechanism by which exogenously applied
galanin counteracts seizures more likely includes presynaptic inhibition of glutamate release via opening of ATP-dependent
K+ channels, the effect that has been reported
earlier (Ben-Ari and Lazdunski, 1989; Zini et al., 1993a,b). It is
worth mentioning that the compounds acting as K+
channel openers are considered a promising class of anticonvulsants (Meldrum, 1997).
The evidence from this study suggests that both GalR1 and GalR2
receptors may play a role in SSSE but that they may affect different
phases of its pathophysiology to different degrees. Both M35, which has
a higher affinity for GalR1, and M15 and M40, which show some
preference for GalR2 (Smith et al., 1997), blocked the effects of
galanin on the maintenance of SSSE, suggesting that the maintenance
phase depends on both receptor types. It has been reported (Smith et
al., 1997) that modifications of the galanin sequence in position 2 may
reduce its affinity for GalR1 receptors more severely than that for
GalR2. 2-Ala-galanin, a putative GalR2 agonist, showed much weaker
seizure-preventing effect than did galanin in spite of its 10-fold
higher dose and the greater abundance of GalR2 compared with GalR1 in
the hippocampus (Gustafson et al., 1996; Xu et al., 1998). This
suggests that the role of GalR2 receptors in the endogenous
anticonvulsant effects of galanin in the initiation phase of SSSE may
be relatively weak. On the other hand, the effects of M35 suggest an
important role of GalR1 in the initiation phase of SSSE. Further
pharmacological analysis using more selective ligands is needed to
clarify the role of GalR1 and GalR2 in the seizing hippocampus.
Most of the studies on the effects of galanin in the hippocampus have
concentrated on the ventral rather than the dorsal hippocampus. However, the latter, including the hilus, receives abundant innervation from MS galanin-containing neurons (Lamour et al., 1989). Our data indicate the importance of galanin in the dorsal hippocampus in
the control of hippocampal excitability.
In conclusion, our data suggest that hippocampal galanin is
dramatically altered by SE. Depletion of galanin from the hippocampus soon after the onset of SE observed in both immunocytochemical and
immunobiochemical studies may reflect the failure of normal functioning
of the hippocampal galanin system and may contribute to the
establishment of a vicious cycle, which favors self-maintenance of
seizure activity. On the other hand, increased galanin concentration in
the hippocampus soon after SSSE, which probably reflects de novo or increased peptide synthesis in hippocampal neurons, may be
a compensatory response to prolonged ictal activity and depletion of
galanin from septal efferents. The high efficacy of exogenously applied
galanin in protecting the animals from SE, together with recent
progress in the development of potent specific and stable ligands for
galanin receptors (Pooga et al., 1998), opens an intriguing opportunity
for the development of novel drugs for the treatment of SE.
| |
FOOTNOTES |
Received July 15, 1998; revised Sept. 9, 1998; accepted Sept. 14, 1998.
C.G.W. is supported by National Institute of Neurological Disorders and
Stroke (NINDS) Grant NS 11315 and by the research service of Veteran
Health Administration. R.S. is supported by NINDS Grant NS
01792. U.L. is supported by a grant from the Swedish Research Council.
U.S. is supported by a stipend from the Swedish Institute.
Correspondence should be addressed to Dr. Andrey M. Mazarati,
Department of Neurology, University of California, Los Angeles, School
of Medicine, Veterans Administration Medical Center (111N1), 16111 Plummer Street, Sepulveda, CA 91343-2099.
| |
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Abstract
Introduction
