Vol. 275, Issue 2, R509-R514, August 1998
Epidermal growth factor enhances spontaneous sleep in rabbits
Tetsuya
Kushikata1,
Jidong
Fang1,
Zutang
Chen1,
Ying
Wang2, and
James M.
Krueger1
1 Department of Veterinary and
Comparative Anatomy, Pharmacology and Physiology, Washington State
University, Pullman, Washington 99164-6520; and
2 Department of Physiology, The
University of Tennessee-Memphis, Memphis, Tennessee 38163
 |
ABSTRACT |
Several
growth factors are implicated in sleep regulation. Epidermal growth
factor (EGF) is found in the brain, and it influences the production of
several sleep-promoting substances. We determined, therefore, whether
administration of exogenous EGF affected spontaneous sleep in rabbits.
Twenty-five rabbits were implanted with electroencephalographic electrodes, a brain thermistor, and an intracerebroventricular guide
cannula. Three doses of EGF (0.5, 5, and 25 µg) were used. The
animals were injected intracerebroventricularly with saline as control
and one dose of EGF on 2 separate days. Five and twenty-five micrograms
of EGF enhanced non-rapid eye movement sleep and increased brain
temperature. The 25-µg dose of EGF also inhibited rapid eye movement
sleep across the 23-h postinjection recording period. Results are
consistent with the hypothesis that EGF, like other growth factors,
could be involved in sleep regulation.
fever; rapid eye movement sleep; slow-wave sleep; cytokine; electroencephalogram
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INTRODUCTION |
A VARIETY OF GROWTH FACTORS are implicated
in sleep regulation; the list includes endocrine
secretions such as growth hormone (GH), GH-releasing
hormone (GHRH), prolactin (PRL), and insulin and autocrine or exocrine
secretions such as interleukin (IL)-1
, tumor necrosis factor-
(TNF-), acidic fibroblast growth factor (aFGF), and nerve growth
factor (NGF) (reviewed in Refs. 6, 13, 14, 16, 18, 22, 25). All of
these substances, if injected, have the capacity to enhance either
non-rapid eye movement sleep (NREMS) (insulin, IL-1, TNF, aFGF) or
rapid eye movement sleep (REMS) (GH, PRL) or both (GHRH, NGF).
Inhibition of GH, IL-1, TNF, NGF, and GHRH inhibits spontaneous sleep,
and in the case of GHRH, IL-1, and TNF, sleep rebound after sleep deprivation (reviewed in Ref. 19).
All of these substances are in the brain, and for some (i.e., GHRH,
IL-1, and TNF) a diurnal rhythm and/or sleep-wake-related production in brain has been demonstrated (3, 9, 35). Consistent with
these findings, it is hypothesized that sleep is regulated, in part, by
growth factors whose rate of production is synaptic-use dependent.
These growth factors are likely involved locally in the synaptic
sculpturing process, which is hypothesized to represent a central
nervous system manifestation of a wider growth function of sleep
(reviewed in Ref. 20).
Epidermal growth factor (EGF) is one of the growth factors that has the
ability to coordinate cell growth, proliferation, differentiation and
multifunctional maintenance by inducing DNA synthesis and cell division
(4). EGF has been isolated from the brain (7, 33), and its receptors
are widely distributed in brain (36). EGF also acts as a neurotrophic
survival and maintenance factor for neurons (31). EGF stimulates GH
secretion (11), IL-1 biological activity, and IL-1 mRNA levels (23). EGF also stimulates nitric oxide (NO) production (29); NO is also
implicated in sleep regulation (15). The ability of EGF to influence
substances known to be involved in sleep regulation and its general
involvement in growth suggest that EGF may play a role in sleep
regulation. We now report that administration of exogenous EGF to
rabbits is associated with an enhancement of NREMS.
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MATERIALS AND METHODS |
Recombinant human EGF was purchased from Calbiochem Biochemicals (La
Jolla, CA). This EGF is a single-chain polypeptide containing 54 amino
acids identical to human EGF except for an additional NH2-terminal methionine. This
material is mitogenic for a wide range of ectoderm-derived cells from
various tissues, and it also acts as a survival factor in preventing
apoptosis (24). Substances were dissolved in pyrogen-free isotonic NaCl
(PFS; Abbott Laboratories, North Chicago, IL). Injections were done in
a volume of 25 µl.
Animals. Male New Zealand White
Pasteurella-free rabbits (4.0-5.0 kg) were implanted with a
lateral ventricular guide cannula, stainless steel
electroencephalographic (EEG) electrodes, and a brain thermistor using
ketamine-xylazine (35 and 5 mg/kg ip) anesthesia as previously
described (17). In brief, the guide cannula was placed in left lateral
ventricle for intracerebroventricular injection. The EEG electrodes
were placed over the frontal and parietal cortexes. A calibrated
30-k
thermistor (model no. 44008; Omega Engineering, Stamford, CT)
was implanted on the dura mater over the parietal cortex to measure
brain temperature (Tbr). The leads from EEG electrodes and the thermistor were routed to a Teflon
pedestal (Plastics One, Roanoke, VA). The pedestal and the guide
cannula were attached to the skull with dental acrylic (Duz-All;
Cordite Dental Product, Skokie, IL). After a 2-wk recovery period, the
animals were placed in sleep-recording chambers (Hot Pack 352600, Philadelphia, PA) for at least one 24-h habituation. The rabbits were
kept on a 12:12-h light-dark cycle (lights on at 0600) at 21 ± 1°C ambient temperature. Water and food were available ad libitum
throughout the experiment.
Experimental protocols. A total of 25 rabbits were used in these experiments. Each rabbit received an
injection of 25 µl of PFS intracerebroventricularly on a separate day
to obtain control values. The same animals were then injected
intracerebroventricularly with one of three doses of EGF:
group
1, 0.5 µg
(n = 8);
group 2, 5 µg
(n = 9);
group
3, 25 µg
(n = 8). The injections took place between 0840 and 0915. After injections, EEG,
Tbr, and motor activity were
recorded for the next 23 h as described previously (17).
Recording and analysis. The rabbits
were allowed relatively unrestricted movement inside the recording
cages. A flexible tether connecting the electrodes and thermistor led
to an electronic swivel (SL6C, Plastics One). Body movements were
detected by ultrasonic detectors (Biomedical Instrumentation,
University of Tennessee). The leads from the electronic swivel and
movement detectors were routed to Grass 7D polygraphs (Grass, Quincy,
MA) in an adjacent room. The EEG was filtered below 0.1 Hz and above 35 Hz. The amplified signals were digitized at the frequency of 128 Hz for
the EEG and at 2 Hz for Tbr and
motor activity. Tbr data were
saved on the computer in 10-s intervals.
Tbr values, averaged in 3-h
intervals, were used for statistical analysis. Some of the
Tbr data were lost because of
technical problems; therefore, the sample sizes for
Tbr were lower than for sleep
data. Online Fourier analysis of the EEG was performed. The vigilance
states were determined offline in 10-s epochs. The vigilance states of
wakefulness (W), NREMS, and REMS were visually identified in 10-s
epochs using criteria previously reported (34). Briefly, W was
characterized by fast low-amplitude EEG waves, gradually increasing
Tbr, and high incidence of gross
body movements. NREMS was associated with slow (0.5-4 Hz)
high-amplitude EEG waves, slowly decreasing
Tbr, and lack of body movements.
In contrast, REMS was characterized by fast low-amplitude EEG waves,
the appearance of rhythmic theta activity in the EEG, rapidly
increasing Tbr at REMS onset, and a lack of motor activity. The amount of time spent in each vigilance state was calculated for 1-h intervals and for the entire recording period. The percent of time spent in sleep for 3-h intervals was used
for statistical analyses. In addition, the number of NREMS and REMS
episodes, the mean episode lengths, and the mean lengths of sleep
cycles (REMS-REMS interval) were determined using a computer program
with the criterion that each episode lasted at least 30 s. The EEG
power density values were summed in four frequency bands for each 10-s
epoch; delta (0.5-4.0 Hz)-, theta (4.5-8.0 Hz)-, alpha (8.5- 12.0 Hz)-, and beta (12.5-30 Hz)-wave activity were calculated.
Hourly averages of the EEG power density values in the four frequency
bands were determined for W, NREMS, and REMS separately.
Statistical analysis. All analyses
were performed with two-way ANOVA for repeated measures across the
entire recording period followed by Student-Newman-Keuls test. A
significance level of P < 0.05 was
accepted.
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RESULTS |
Intracerebroventricular administration of the lowest dose of EGF tested
in these experiments, 0.5 µg, did not affect NREMS, REMS, and
Tbr. In contrast,
intracerebroventricular administration of 5 µg of EGF significantly
increased the amount of time spent in NREMS [ANOVA, treatment
effect: F(1,8) = 6.30;
P < 0.05] and elevated
Tbr [ANOVA; treatment
effect; F(1,5) = 14.47;
P < 0.05] (Table
1, Fig. 1). The increase in
NREMS occurred during the first 12 h postinjection, but did not persist
into hours
13-23 postinjection (Table 1). In
contrast, EGF-induced hyperthermia persisted across the 23-h recording
period (Table 1). REMS was not affected by the 5-µg dose. Neither of
the lower two doses of EGF significantly affected the number or
duration of NREMS or REMS episodes (Table
2). The highest dose of EGF (25 µg)
significantly increased the amount of time spent in NREMS [ANOVA;
treatment effect: F(1,7) = 16.89; P < 0.01], the number
of NREMS episodes [ANOVA; treatment effect:
F(1,8) = 15.36;
P < 0.01], and
Tbr [ANOVA; treatment
effect: F(1,5) = 20.70;
P < 0.01]. The time course of EGF-induced NREMS and Tbr effects
after the high dose was similar to that observed after the middle dose;
NREMS was increased during the first 12 h postinjection and
Tbr was increased across the 23-h
recording period. The high dose also inhibited REMS across the 23-h
recording period. The decrease in REMS resulted from a significant
decrease in the number of REMS episodes [ANOVA; treatment effect:
F(1,8) = 5.469;
P < 0.05] (Table 2). All doses of EGF failed to affect EEG power density in the four frequency bands
of the EEG during any of the vigilance states; results obtained after
the 5-µg dose are shown on Fig. 2.
Although not systematically quantified, EGF did not induce abnormal
behavior in the sense that animals continued to cycle through
sleep-wake episodes (Table 2), they were easily aroused if disturbed,
and they failed to exhibit any gross abnormal motor behavior.
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Fig. 1.
Effects of intracerebroventricular injection of 0.5 (A), 5 (B), and 25 µg
(C) epidermal growth factor (EGF) on
time spent in non-rapid eye movement sleep (NREMS) and rapid eye
movement sleep (REMS), slow wave activity (SWA), and brain temperature
(Tbr) during the first 12 h
postinjection. Error bars indicate SE. Five and twenty-five micrograms
of EGF enhanced NREMS and increased
Tbr.
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Fig. 2.
Effects of intracerebroventricular injection of EGF on
electroencephalogram (EEG) power density values in 4 frequency bands
during wakefulness (W), NREMS, and REMS. EEG power density values were
summed in 4 frequency bands for each 10-s epoch; delta (0.5-4.0
Hz; A)-, theta (4.5-8.0 Hz;
B)-, alpha (8.5- 12.0 Hz;
C)-, and beta (12.5-30 Hz;
D)-wave activity were calculated.
Error bars indicate SE. All doses of EGF failed to affect EEG power
density values during any vigilance state; results shown are those
obtained after 5.0-µg EGF dose.
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| |
DISCUSSION |
Current results clearly indicate that administration of exogenous EGF
has the capacity to promote NREMS. Nevertheless, whether EGF normally
plays a role in sleep regulation remains unknown. It is unlikely that
EGF-induced sleep effects were secondary to EGF-induced changes in
Tbr. There is a rather extensive
literature describing the multiple links between thermoregulation and
sleep. For example, there is a regulated decrease in
Tbr during the entry into NREMS,
and an acute mild increase in ambient temperature is a
well-characterized somnogen. Nevertheless, under a variety of
circumstances, thermoregulation can be separated from sleep regulation
(reviewed in Ref. 21). For example, some substances enhance both NREMS
and Tbr (e.g., TNF, IL-1, and
PGD2), yet the pyrogenic actions
of IL-1 can be pharmacologically blocked without affecting sleep
responses (22). In contrast, the somnogenic actions of IL-1, but not
its pyrogenic actions, are blocked by central administration of nitric
oxide synthase inhibitors (15). Other substances increase
Tbr yet decrease NREMS (e.g.,
corticotropin-releasing hormone,
PGE2). Yet other substances
decrease Tbr and inhibit sleep
(e.g., -melanocyte-stimulating hormone). Collectively, such
considerations clearly indicate separate, yet linked, mechanisms for
sleep and body temperature.
EGF failed to enhance EEG delta-wave activity, also called EEG slow
wave activity (SWA), during NREMS. In contrast, other somnogenic growth
factors, such as IL-1, TNF-, GHRH, aFGF, and NGF, all enhance EEG
SWA at doses that also enhance duration of NREMS. The mechanisms
responsible for EEG SWAs remain unknown, although there is extensive
literature describing the separation of EEG SWA from state regulation
and, conversely, the separation of the association of amplitudes of EEG
slow waves with the intensity of NREMS. For example, systemic injection
of atropine (32) or hyperventilation (37) in adolescents induces
high-amplitude EEG slow waves during waking states. In contrast, after
sleep deprivation, "supranormal" EEG slow waves characterize
NREMS (30) and are associated with higher arousal thresholds (28).
Experimental manipulation can induce separation of duration of NREMS
and amplitudes of EEG slow waves. For example, intraperitoneal
injections of IL-1 or TNF induce increases in NREMS and decreases in
EEG SWA in rats (10) and mice (8), whereas intracerebroventricular injections of IL-1 or TNF enhance both (11, 27). EGF also failed to
affect EEG power density values in any of the other frequency bands
measured. Some hypnotics, such as benzodiazepine derivatives, decrease
low-frequency activity (0.25-10.0 Hz) while increasing
high-frequency activity (17-25 Hz) during sleep (2).
Microbial products such as endotoxin are common contaminants of
recombinant products. Endotoxin induces production of a variety of
somnogenic cytokines and is itself somnogenic. It is thus possible that
the observed EGF-induced sleep responses were due to endotoxin contaminants in the EGF preparation. Because EGF, like endotoxin, is
heat stable (4), the often used, heat-inactivation control was not an
experimental option. Nevertheless, it seems unlikely that results were
due to endotoxin. Endotoxin induces increases in NREMS, EEG SWA, and
Tbr at all somnogenic doses thus
far tested. EGF induced increases in NREMS but not EEG SWA.
Furthermore, after bolus intracerebroventricular injection of
endotoxin, the duration of the somnogenic actions is only ~3 h; the
effects of EGF were more prolonged.
Perspectives
The mechanisms by which EGF promotes NREMS are unknown. However, that
EGF stimulates nuclear factor kappa B (NF
B) activation (26) was a
motivating factor for these studies. Several substances implicated in
physiological sleep regulation activate NFB; the list includes
IL-1, TNF-, NGF, and FGF. Furthermore, some substances that
inhibit spontaneous sleep, such as IL-4 and IL-10, inhibit NFB
activation (1). NFB activation enhances production of yet other
substances that have been linked to sleep regulation, such as NO
synthase and IL-2. Finally, preliminary data from our laboratory
suggest that NFB is activated in the cerebral cortex by sleep
deprivation (5). The hypothesis that NFB is involved in the actions
of EGF and in sleep regulation is attractive because, at least
superficially, it provides a common mechanism for the actions of
several sleep-promoting substances. However, it seems unlikely that
there is any single central mechanism that, by itself, is necessary and
sufficient for sleep regulation. Regardless of such speculation,
results provided here and the previous findings that EGF is a brain
product and that it stimulates production of other substances known to
be involved in physiological sleep regulation provide reasons to
further characterize the potential role of EGF in sleep regulation.
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ACKNOWLEDGEMENTS |
This work was supported, in part, by National Institute of
Neurological Disorders and Stroke Grants NS-25378, NS-27250, and NS-31453 and by Office of Naval Research Grant N00014-90-J-1069.
| |
FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests: J. M. Krueger, Dept. of Veterinary and
Comparative Anatomy, Pharmacology and Physiology, Washington State
Univ., 205 Wegner Hall, Pullman, WA 99164-6520.
Received 9 February 1998; accepted in final form 30 April 1998.
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Abstract
Introduction
