222 Research report
Cerebral ischemia-induced difference in sensitivity
to depression and potential therapeutics in rats
Miao-Kun Sun and Daniel L. Alkon
The ‘vascular depression’ hypothesis has recently attracted
significant research attention, although the causal
relationship between vascular-related injuries and
depression has not been established. Here, we show that
one episode of cerebral ischemia was sufficient to greatly
increase the sensitivity of rats to potentially depressogenic
events, evaluated at below-threshold intensities in the
c 2013
open space swim test. The induced ‘ischemic depression’
was lasting and sensitive to an acute administration of
brain-derived neurotrophic factor or bryostatin-1,
a relatively selective activator of protein kinase Ce, during
the induction phase. Chronic treatment with bryostatin-1
(5 weeks) after the induction of depressive behavior
reversed the depressive immobility and produced a lasting
therapeutic effect, which remained effective 3 weeks after
discontinuation of the treatment. Similar treatment with
alaproclate, a selective serotonin reuptake inhibitor, in
contrast, produced temporary relief from the depressive
Introduction
Vascular disease and depression constitute two of the most
prevalent health problems in the world today, and there is
interest in their interaction and potential causal relation-
ship (Liebetrau et al., 2008; Wouts et al., 2008). Evidence is
accumulating that depressive behavior increases the risk
for cerebrovascular and cardiovascular abnormalities as well
as stroke (Roose, 2003; Neu et al., 2004; Isingrini et al.,
2011; Pan et al., 2011; Majed et al., 2012). In contrast,
insufficient cortical circulation and impaired cerebrovas-
cular integrity may play an important role in the etiology of
depression, thus, vascular depression (Krishnan et al.,
2009; Santos et al., 2004; Chatterjee et al., 2010). There
is evidence that a high proportion of depressed patients,
especially those who are older, exhibit characteristic
microvascular white matter ischemic lesions, as measured
by the occurrence of white matter hyperintensities within
the cerebral white matter that appear as ‘bright signals’ on
brain MRIs (Kim et al., 2011; Disabato and Sheline,
2012; Mettenburg et al., 2012). This clinical correlation has
led to the ‘vascular depression’ hypothesis (Krishnan and
McDonald, 1995; Alexopoulos et al., 1997; Mast et al.,
2004; Paranthaman et al., 2010; Andreescu and Reynolds,
2011; Naarding and Beekman, 2011; Sneed and Culang-
Reinlieb, 2011). Validation of the hypothesis would direct
therapeutic correction of vascular problems as an essential
part of behavioral therapies.
Depression is very common after stroke and ischemic
events and occurs in 20–60% of all stroke survivors
0955-8810
c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
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symptoms, with the therapeutic effect disappearing soon
after the end of the treatment. The results strongly suggest
that cerebral ischemia has a direct role in shaping the
sensitivity of an individual to depressogenic events and
that bryostatin-1-like agents may be developed as
therapeutics for treating ischemic depression in
humans. Behavioural Pharmacology 24:222–228
Wolters Kluwer Health | Lippincott Williams & Wilkins.
Behavioural Pharmacology 2013, 24:222–228
Keywords: antidepressant, brain-derived neurotrophic factor, bryostatin,
cerebral ischemia, depression, hypoxia, rat
Blanchette Rockefeller Neurosciences Institute, Rockville, Maryland, USA
Correspondence to Miao-Kun Sun, PhD, Blanchette Rockefeller Neuroscience
Institute, 9601 Medical Center Drive, Academic & Research Building, Room 319,
Rockville, MD 20850, USA
E-mails: mksun@brni-jhu.org, masun@brni.org
Received 14 December 2011 Accepted as revised 5 March 2013
(Kauhanen et al., 1999; Dam, 2001; Robinson, 2003;
Hackett et al., 2005). The vascular depression hypothesis
proposes that cerebrovascular diseases cause ischemic
lesions in the brain structures involved in mood control
(Alexopoulos et al., 1997). Cerebrovascular diseases are
indeed associated with increased risk for depression, with
the frequency of poststroke/ischemic depression remain-
ing high during the first month and even after several
years (Gothe et al., 2012; Husseini et al., 2012). There is
evidence that vascular risk factors and white matter
ischemic lesions are independent risk factors for post-
stroke depression (Chatterjee et al., 2010; Tang et al.,
2010). The existence of white matter hyperintensities,
however, is not necessarily associated with behavioral
or cognitive abnormalities (Ylikoski et al., 1995), but
rather represents chronically progressive neuropathology
(Hedden et al., 2012), much like amyloid plaques in
nondiseased elderly (Hedden et al., 2012). White matter
hyperintensities are more common and severe in late-
onset depression than in early-onset depression, as
reviewed by Disabato and Sheline (2012). The existence
of a causal relationship between depression and vascular
deficits has been hypothesized clinically but has not been
established, as the two diseases share a large number of
common risk factors, such as genetics, lifestyle, environ-
mental stress, diabetes, hypertension, and vascular
dysfunction. Chief among the challenges is the demon-
stration of a causal link between cerebrovascular disease
and depression (Culang et al., 2010). A second challenge is
finding effective therapeutics. The treatment outcome
DOI: 10.1097/FBP.0b013e3283618afe

with currently available antidepressants in the patients
with vascular impairment-associated depression is re-
ported to be much worse than that in those with
nonvascular depression (Fujikawa et al., 1996; Yanai et al.,
1998; Yamashita et al., 2001; Bella et al., 2010; Willey et al.,
2010; Naarding and Beekman, 2011). Patients with more
severe white matter hyperintensities have a several times
increased likelihood of poor treatment outcome (Sheline
et al., 2010; Sneed and Culang-Reinlieb, 2011). In the
present study, we have therefore evaluated whether
cerebral ischemia would directly shape the sensitivity of
rats to potentially depressogenic events.
We have observed that rats show an age-dependent and
intensity-dependent sensitivity to depressogenic events
in the open space swim test (OSST, Sun and Alkon,
2008). The impact of cerebral ischemia on depressive-
like behaviors was evaluated in the OSST in elderly/
8-month-old rats. We have previously reported that
depression-like immobility could be induced in rats of
all ages and both sexes, as long as the duration (or
intensity) of the OSST is above the ‘threshold’ (Sun and
Alkon, 2006, 2008). The present study reveals that a
below-threshold event can trigger an above-threshold
behavioral response because of the episode of cerebral
ischemia. In addition, we have recently found that
bryostatin-1, a relatively specific activator of protein
kinase CE (PKCE), could postischemically repair the
injured neural network (Sun et al., 2008, 2009), probably
through its PKC-mediated action on promoting new
protein synthesis, synaptic remodeling, and synaptogen-
esis (Alkon et al., 2005, 2007; Hongpaisan and Alkon,
2007; Nelson et al., 2008, 2009). We have therefore, in this
study, determined whether bryostatin-1 has an effective
antidepressant profile against the depression-like beha-
vior induced after cerebral ischemia, as compared with
alaproclate, a selective serotonin reuptake inhibitor
(SSRI) antidepressant.
Methods
Subjects
Adult male experimentally naive Wistar rats (175–200 g
when purchased; Charles River Lab., Massachusetts,
USA) were housed in a temperature-controlled
(20–241C; two per cage) room, allowed free access to
food and water, and kept on a 12-h light/dark cycle. They
were randomly assigned to different groups (n = 8–10
each.) All procedures were conducted according to
National Institutes of Health Animal Care and Use
Committee guidelines and approved by the Ethical
Committee of the Institute.
Cerebral ischemia/hypoxia, and drug treatments
Nine days before they reached 8 months of age, global
cerebral ischemia was induced in vivo by the two-artery
occlusion (2-VO) method, combined with a controlled
period of hypoxia. Combined cerebral ischemia–hypoxia
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Ischemic depression and therapeutics in rats Sun and Alkon 223
has been shown to lead to TUNEL-positive staining and
a dramatic loss of synapses in the hippocampal CA1 area
(Sun et al., 2009). Briefly, the bilateral common carotid
arteries (from the ventral side of the neck) were tied with
silk threads, under an appropriate level of pentobarbital
anesthesia (60 mg/kg, intraperitoneally, with additional
supplemental doses whenever necessary). The 2-VO
occlusion leads to a chronic reduction in cerebral blood
flow by about 40% of the original flow rate in rats at this
age. Rectal temperature was monitored throughout the
surgery and maintained at 37.51C using a heat lamp. At
the end of surgery and under appropriate anesthesia, rats
received ketoprofen (5 mg/kg, subcutaneously) for post-
surgical pain relief and 5 ml saline to compensate for any
loss of water and minerals. A 7-day recovery period from
surgery was allowed before the period of hypoxic
exposure (about 10 min in a jar with blowing in of air
with a low oxygen content of about 5%, moderate
ischemic hypoxia). Control rats were subjected to an
identical procedure, except that the arteries were not
occluded and the oxygen level was not reduced in the
same jar. We have observed that a short duration of OSST
sessions (i.e. below the ‘threshold’ for triggering the
depressive behavior) does not affect sucrose intake and
that neither the 2-VO nor the period of hypoxia alone
causes ischemic injury, synaptic and memory impair-
ments, sucrose intake, or changes in OSST behavior (Sun
and Alkon, 2004b; and Miao-Kun Sun and Daniel L.
Alkon, unpublished data).
Bryostatin-1 (20 mg/m2) was administered through a tail
vein (two doses in the acute study and 2 doses/week for
10 doses in the chronic study, detailed in the Results
section). Alaproclate, an SSRI antidepressant, was
administered at an effective dose of 10 mg/kg (intraper-
itoneally, daily; Sun and Alkon, 2003). Brain-derived
neurotrophic factor (BDNF) was administered bilaterally
(1 mg/ml/side, intracerebroventricularly) about 0.5 h after
each daily OSST session. It was solubilized immediately
before the administration in artificial cerebrospinal fluid
consisting of 125 mmol/l NaCl, 3 mmol/l KCl, 1.3 mmol/l
MgSO4, 2.4 mmol/l CaCl2, 26 mmol/l NaHCO3,
1.25 mmol/l NaH2PO4, and 10 mmol/l glucose.
Open space swim test
Rats (at 8 months of age when the first OSST induction
session started) were placed individually in a round pool,
which had a diameter of 152 cm and a height of 60 cm and
was filled with 40 cm H2O (24±11C). No escape was
provided in the OSST session trials. Rats were free to
swim (or not) for 15 min and were then returned to their
home cages after drying. The observers were obscured
from sight of the rats, but were able to observe the
animals’ behaviors online (Video Monitor BWM9; Javelin
Electronics Inc., Los Angeles, California, USA). The same
procedure with the same trial length was followed 24 h
later for two more days (one session per day). We have
224 Behavioural Pharmacology 2013, Vol 24 No 3
reported that the OSST induces a maximal level of
immobility during the third session (Sun and Alkon,
2003). The swimming/drifting path and distance were
recorded with a video tracking system (Poly-Track Video
Tracking System; San Diego Instruments Inc., San Diego,
California, USA). For evaluation of the long-term impact,
induction was followed by ‘monitoring’ sessions at a
frequency of one session per week (Sun and Alkon,
2004a).
Sucrose intake (anhedonia)
Hedonic state was measured as sucrose intake in tests in
which 1% sucrose solution and regular water were both
presented. Intakes during and after the OSST sessions
were compared with those before the OSST sessions in
each rat. Rats were first trained to consume a 1% sucrose
solution, a daily 1-h test in which a volume-marked
sucrose bottle was presented in the home cage for the
rats to select, for 1 week. On the OSST or ‘monitoring’
days, sucrose intake was measured at least 1 h after the
animal was returned to its home cage. Sucrose intake was
calculated as the amount of sucrose consumed during the
1-h period per 100 g body weight and was compared with
that on the day before the sessions in each rat (day
0 = 100%).
In-vivo cannulation
In some rats, direct effects of BDNF administration were
determined through intracerebroventricular administra-
tion. Cannulation took place on the surgery day (for
2-VO) in these rats, when they were anesthetized (see
above) and placed in a stereotactic apparatus (Kopf
Instruments, Tujunga, California, USA). Two stainless
steel guide cannulae were placed with their tips positioned
at the coordinates (anterior–posterior 0.5 mm; lateral
1.5 mm; horizontal, 3.2 mm), under aseptic conditions.
For intracerebroventricular injection, the injection cannula
was connected through PE20 tubing to a Hamilton
microsyringe. The injection was slow and in a small
volume (1 ml injected in 2 min), without anesthesia, using a
microinjection pump. The control rats received the same
volume of artificial cerebrospinal fluid solution (1 ml
injected in 2 min, intracerebroventricularly) at the same
frequency.
Statistical analysis
Statistical analysis was carried out using the two-way
analysis of variance test, followed by the Newman–Keuls
multiple comparisons test. A P-value less than 0.05 was
considered statistically significant.
Results
Cerebral ischemia increases the sensitivity of rats
to potentially depressogenic events (short distance
traveled and anhedonia)
When evaluated 2 days after the ischemic/hypoxic event,
ischemic rats showed a gradual reduction in the distance
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Fig. 1
120 Control/OSST CI/OSST
Distance moved (%)
100
80
60
40
3 10 17
Days
Cerebral ischemia increases the sensitivity of rats to OSST-induced
depressive immobility, which was measured in 15-min OSST sessions
(one session per day) for three consecutive days, followed by
‘monitoring’ sessions (one session per week). The swimming distance
in the first trial session [control/OSST: 19239.44±644.63
(B146±5 m) and CI/OSST: 19605.26±599.21] was calculated
as 100% in each rat. The actual distance of the first trial was not
significantly different between the groups and was thus not detailed
here. Data are represented as the mean±SEM. CI, cerebral ischemia;
OSST, open space swim test.
moved in the 15-min daily sessions (Fig. 1), whereas the
sham-operated controls did not. The trial duration
(15 min) was chosen because we have found that healthy
rats of this age group were not sensitive to the 15-min
OSST and required longer OSST trials to induce
depressive immobility (Sun and Alkon, 2008). Statistical
analysis revealed that there was a significant difference in
mobility during the three induction trials between the
ischemic and sham-operated control rats (Groups:
F1,47 = 29.42, P < 0.001; Groups  Trials: F2,47 = 3.52,
P < 0.05), indicating an induced depressive behavior in
the ischemic rats; the sham-operated control rats did not
exhibit a significant reduction in the distance traveled
during the first three trial sessions (P > 0.05). The
‘monitoring’ sessions (one session per week) after the
induction further revealed that the depressive behavior
was stable during the observed period (Fig. 1).
We further examined, in separate groups of rats, whether
the induced depressive behavior was associated with
anhedonia, a core symptom of depression. Hedonic state
was measured as sucrose intake (1% sucrose). The OSST
sessions (15 min/session) induced an anhedonic state in
the ischemic rats (Fig. 2), whereas the ischemic event
itself (without the OSST sessions) did not alter sucrose
intake (Fig. 2). There was a significant difference in the
sucrose intake between the ischemic depression and
ischemia-only rats after the first three induction sessions
(Groups: F1,47 = 35.30, P < 0.001; Groups  Trials:
F2,47 = 5.18, P < 0.01), indicating that ischemic depres-
sion significantly reduced the sucrose intake. Similarly,

Fig. 2
CI CI/OSST
20 Days
3 10 17
0
Sucrose intake (%)
−20
−40
−60
Effects of induced ischemic depression on sucrose intake in rats.
Rats were first trained to consume a 1% sucrose solution, in a 1-h test
conducted daily in which a volume-marked sucrose bottle was
presented in the home cage for the rats to select, for 1 week. The rats
were then subjected to 15-min OSST trial sessions for three
consecutive days (one session per day) from day 1. The sucrose intake
test was performed at least 1 h after the end of the OSST if on the
OSST days. Control rats were not subjected to the OSST sessions but
were subjected to the same ischemic events, which did not significantly
change sucrose intake over the period. Sucrose intake was calculated
as the amount of sucrose consumed per 100 g body weight during the
1-h period and compared with that on the day before the first OSST
session in each rat (taken as 100%, which did not differ between
the groups: CI-OSST: 6.9±0.7 ml/100 g body weight and CI:
6.6±0.6 ml/100 g body weight the day before the first OSST trial).
Each point represents the mean±SEM. CI, cerebral ischemia; OSST,
open space swim test.
the ‘monitoring’ sessions after the OSST induction period
(one session per week) further revealed that OSST
induction had a lasting impact on sucrose intake in the
ischemic group (Fig. 2).
The induced ischemic depression is sensitive to a direct
BDNF administration
We were interested in determining whether the induced
ischemic depression could be antagonized by enhanced
neurotrophic activity in the brain. Similar to the induced
depressive behavior in nonischemic rats (Sun and Alkon,
2006), induced ischemic depression was sensitive to
intracerebroventricular administration of BDNF during
the induction phase. Depressive behavior was not
induced when BDNF was administered 0.5 h after each
of the three OSST sessions (Fig. 3). A significant
difference was observed between the induced ischemic
depression groups with and without BDNF administra-
tion (Groups: F1,47 = 30.12, P < 0.001; Groups  Trials:
F2,47 = 3.23, P < 0.05). Thus, acute BDNF administration
prevented the induction of depressive behavior in the
ischemic rats. This was a lasting effect, as no change in
the distance traveled was also observed during the
‘monitoring’ sessions (one session per week; Fig. 3) after
BDNF administration.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Ischemic depression and therapeutics in rats Sun and Alkon 225
Fig. 3
CI/OSST CI/OSST/BDNF
120
BDNF
100
Distance moved (%)
80
60
40
3 10 17
Days
Acute intracerebroventricular BDNF administration eliminates the
cerebral ischemia-induced sensitivity to OSST. BDNF was
administered about 0.5 h after each of the 15-min OSST sessions
(1 mg/ml/side, bilaterally). The rats (ischemic with artificial cerebrospinal
fluid: CI/OSST) were sensitive to the OSST, but the sensitivity was
eliminated by acute BDNF (CI/OSST/BDNF) administration.
The different responses between the two groups persisted, as shown
by two ‘monitoring’ sessions (one session per week). Each point
represents the mean±SEM. BDNF, brain-derived neurotrophic factor;
CI, cerebral ischemia; OSST, open space swim test.
Bryostatin-1 acutely reverses the increased sensitivity
to OSST induction in ischemic rats
Bryostatin-1, a noncarcinogenic PKC activator with
relative selectivity for the PKCE isozyme, has been found
to produce antidementia therapeutic effects against
cerebral ischemia (Sun et al., 2008, 2009) and Alzheimer’s
disease pathology (Hongpaisan et al., 2011). Its therapeu-
tic mechanism probably includes enhancement of the
neurotrophic activity and synaptogenesis (Hongpaisan
and Alkon, 2007). When applied acutely, it has an acute
antidepressive action in nonischemic depression (Sun
and Alkon, 2005). In the acute setting, when bryostatin-1
was administered about 0.5 h after the first and the third
OSST trial, it effectively prevented the impact of OSST
(15-min sessions) on the distance traveled by the
ischemic rats (Fig. 4), whereas the distance traveled
was decreased in the ischemic OSST rats without
bryostatin-1 treatment. The difference between the
two groups was statistically significant (Groups: F1,47 =
31.33, P < 0.001; Groups  Trials: F2,47 = 3.42, P < 0.05),
indicating antidepressant-like activity. The two additional
‘monitoring’ sessions (one session per week) further
revealed a lasting impact of the bryostatin-1 treatment on
the distance traveled (Fig. 4).
Chronic bryostatin-1 administration reverses ischemic
depression
We further evaluated whether chronic bryostatin-1
administration, starting when depressive behavior became
226 Behavioural Pharmacology 2013, Vol 24 No 3

evident in order to mimic the clinical treatment of
depression in humans, would be effective against
ischemic depression. Figure 5 shows that the OSST
sessions induced lasting depressive behavior in the
ischemic rats without antidepressant treatments. The
distance traveled differed significantly among the groups
(Groups: F2,243 = 9.72, P < 0.001; Groups  Trials after
the induction: F14,176 = 1.83, P < 0.05; Fig. 5), whereas
the initial OSST sessions induced similar effects on the
distance traveled among the groups (effect on groups in
the first three sessions: F2,19 = 0.69, NS; Fig. 5). When
Fig. 4
120 CI/OSST
Bry
Distance moved (%)
bryostatin-1 or alaproclate (an SSRI antidepressant)
treatment was started 1 day after the end of the last
OSST induction session, no therapeutic effects were
observed in the first week with either drug, when
compared with the vehicle controls (Fig. 5). Improvement
in the distance traveled was observed after 2 weeks of
continued treatment with both bryostatin-1 and alapro-
clate, reaching a peak effect after another week of
continued treatment. Although both agents were effec-
tive against ischemic depression after chronic adminis-
tration, there were two differences in their therapeutic
profiles. First, bryostatin-1 produced a greater reduction
in depressive behavior than did alaproclate during weeks
3–5 (all at least P < 0.01). Second, when the chronic
CI/OSST/Bry
treatment was stopped, the effects of bryostatin-1 lasted
for the three additional weeks of the ‘monitoring’ period
(the longest time observed), suggesting a lasting ther-

100 apeutic effect. The antidepressant effects of alaproclate,

80
60
40
3 10
Days
Acute bryostatin-1 prevents the cerebral ischemia-induced higher
sensitivity to OSST. Bryostatin-1 was administered about 0.5 h after the
first and the third OSST session (20 mg/m2, intravenously). Without
bryostatin-1 (with vehicle: CI/OSST) treatment, the ischemic rats were
sensitive to the OSST sessions. Bryostatin-1 eliminated the sensitivity
when facing the same intensity of OSST events. The two ‘monitoring’
sessions (one session per week) further illustrate a lasting impact. Each
point represents the mean±SEM. Bry, bryostatin-1; CI, cerebral
ischemia; OSST, open space swim test.
however, began to decrease after its discontinuation, with
a significant decrease in the distance traveled observed a
week later. At the end of the third week after alaproclate
treatment, its antidepressant effect entirely disappeared
(Fig. 5). Therefore, alaproclate did not cause a long-
lasting reversal of ischemic depression at the doses used
and for the duration of treatment.
17
Discussion
It is well established that depression in elderly humans is
an important healthcare concern, attracting much re-
search attention (Frederick et al., 2007; Friedman et al.,
2007; Paranthaman et al., 2010; Andreescu and Reynolds,
2011; Naarding and Beekman, 2011; Sneed and Culang-
Reinlieb, 2011). Our results show that ischemic and
nonischemic rats exhibit a marked difference in beha-
vioral response to the same intensity of potentially

Fig. 5

110 CI/OSST CI/OSST/Alap CI/OSST/Bry

∗∗∗
Distance moved (%)

∗∗∗ ∗∗∗ ∗∗∗ ∗∗∗

∗∗∗
90 ∗∗∗ ∗∗∗ ∗∗∗
∗∗∗
∗∗∗
Agent ∗
70

50
10 21 32 43 54
Days

Chronic bryostatin-1 treatment produces a lasting therapeutic effect on the induced ischemic depression. Bryostatin-1 or alaproclate was
administered 1 day after the last OSST session for 5 weeks. Mobility of the rats was monitored weekly (one session per week). It took weeks of
treatments to observe the full therapeutic effects of either drug. The therapeutic impact of bryostatin-1 remained intact weeks after the end of the
treatment, whereas the effect of alaproclate quickly vanished. Data are presented as mean±SEM. * and *** indicate P < 0.05 and P < 0.001 vs. the
respective controls (two-way analysis of variance and post-hoc Newman–Keuls test), respectively. Alap, alaproclate; Bry, bryostatin-1; CI, cerebral
ischemia; OSST, open space swim test.

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

depressogenic events, when evaluated at intensities
below the threshold for inducing immobility under the
present conditions (Sun and Alkon, 2008). The three
15-min OSST sessions induced depressive immobility in
the ischemic rats but not in age-matched sham-operated
controls. Our results have therefore clearly demonstrated
that a single event of cerebral ischemia is sufficient to
increase the sensitivity of rats to potentially depressogenic
events. Depressive behavior was measured on the basis of
differences in mobility during the OSST, in which rats
might perform active searching swimming for a potential
‘escape’ or may remain inactively ‘floating’ at any moment,
and was confirmed on the basis of an anhedonia test. We
have determined that the swim distance in the test reliably
reflects the active swimming status of the animals during
the trial period (Sun and Alkon, 2003) and shown that the
ischemic hypoxic procedure, OSST sessions, and treat-
ments do not significantly alter the sensorimotor activity in
rats, as compared with the controls (Sun and Alkon,
2004a; Sun et al., 2008).
The term ‘ischemic depression’ is used here to describe the
increased sensitivity to depressogenic events after cerebral
ischemia as it more precisely defines the model in our
study and because whether ‘vascular depression’ indeed
constitutes a distinct entity from other cases of depression
is still under debate (McDougall and Brayne, 2007;
Naarding and Beekman, 2011; Sneed and Culang-Reinlieb
2011). The term, however, does not mean that cerebral
ischemia is sufficiently depressogenic by itself, as depresso-
genic events are required to trigger anhedonia and
depression-like behavior. Nevertheless, the induced is-
chemic depression should be considered within the broad
category of ‘vascular depression’, which should encompass
depression with small vessel disease of the brain (including
so-called silent strokes, which are five times more common
than symptomatic strokes; Vermeer et al., 2002), poststroke
depression, and depression related to myocardial infarction
or respiratory disease (Greenstein et al., 2010; Naarding and
Beekman, 2011). Although our results provide direct and
strong evidence that cerebral ischemia could indeed play a
causal role in sensitivity to depression, the precise
pathogenic mechanisms remain to be defined. Never-
theless, injury/damage (Thomas et al., 2003) evoked by
ischemia/hypoxia and cerebrovascular disease are mostly
likely to play the core role in the sensitivity of ischemic
depression. It might be important to indicate here that the
increased sensitivity associated with aging might not be
because of age itself, but more likely because of vascular and
brain injuries (including silent strokes; Vermeer et al., 2002).
In an earlier study, older healthy rats were found to actually
show lower sensitivity than the younger animals to the same
potentially depressogenic events (Sun and Alkon, 2008).
One consistent finding in clinical therapies of depression
is that ischemic depression, or ‘vascular depression’ at
large, is a more difficult disease to treat with the available
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Ischemic depression and therapeutics in rats Sun and Alkon 227
antidepressants than nonvascular depression (Fujikawa
et al., 1996; Yanai et al., 1998; Yamashita et al., 2001; Bella
et al., 2010; Willey et al., 2010; Naarding and Beekman,
2011). It is not surprising that alaproclate, an SSRI agent,
at an effective dose produced only temporary symptom
relief when administered chronically for 5 weeks.
However, on the basis of our therapeutic studies,
bryostatin-1-like agents, when applied for the same
duration, are more likely to provide a lasting therapeutic
effect through clinical administration. It has been
reported that a single dose of BDNF administered
intracerebroventricularly leads to long-lasting antidepres-
sant-like effects in the modified forced swim test in rats
(Hoshaw et al., 2005). We have shown in our previous
studies that the same doses of bryostatin-1 enhance
BDNF expression and reverse ischemic cell death and
synaptic damage in the hippocampal CA1 area (Sun et al.,
2008, 2009), consistent with the present finding on the
effectiveness of BDNF against induced ischemic depres-
sion. However, it is questionable whether BDNF alone
would be sufficient to mediate the bryostatin-1-induced
therapeutic effect, as most antidepressants, including
electroconvulsive shock, increase BDNF. It remains to be
studied whether bryostatin-1-induced synaptogenesis,
synaptic repair, protein synthesis, and other molecular
cascades may also play an essential role in therapy.
The strengths of our study include a direct evaluation of
the sensitivity of rats to potentially depressogenic events
after cerebral ischemia. In other words, cerebral ischemia/
hypoxia puts individuals at higher risk of developing
depression. The induced ischemic depression, however,
shares some common underlying mechanisms with
nonvascular depression, such as sensitivity to neuro-
trophic activity. Ischemic depression might be less
sensitive to clinical antidepressants, including SSRIs.
Our results suggest that chronic treatment with bryosta-
tin-1-like agents might provide a lasting therapeutic
effect on the disease.
Acknowledgements
Conflicts of interest
A US patent 7,977,377, entitled ‘Treatment of Depres-
sive Disorders’, was issued in 2011 to the authors. This
patent, however, covers neither ischemic depression nor
vascular depression.
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