CNS-active Drugs · Hypnotics · Psychotropics · Sedatives

Effect of Ibudilast on Non-specific
Symptoms in Patients with Chronic
Cerebral Ischemia
Analysis of cerebral blood flow

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Nobuhiro Inoue, Mikio Harada
Department of Neurosurgery, Kumamoto Neurosurgical Hospital, Kumamoto (Japan)
Corresponding author: Nobuhiro Inoue, M.D. Ph.D., 6-1-21 Honjo Kumamoto, 860-0811 Kumamoto (Japan);
e-mail: kenshin-info@iris.ocn.ne.jp

Abstract
Background and purpose: Many patients
with chronic cerebrovascular disease
complain that dizziness and depression
negatively affect their daily lives. In these
patients, ibudilast (CAS 50847-11-5) reportedly ameliorated dizziness. The efficacy of ibudilast was investigated and its
effect on the cerebral blood flow (CBF)
was recorded.
Methods: The study population consisted of 11 patients (male and female)
with chronic cerebrovascular disease
complaining of dizziness or depression.
They received 30 mg of ibudilast orally
per day. The grade of vertigo and depression at entry into this study and 2 and 6
months after the start of therapy was recorded. Their depressive state was scored
with the Japan Stroke Scale-Depression
Scale (JSS-D) and their cerebral blood
flow (CBF) was measured before and approximately 3 months after the start of
ibudilast therapy.
Results: At 6 months after the start of
ibudilast therapy, all patients reported
the resolution of dizziness; of the 6 patients with depression at entry, all experienced significant improvement. At 3
months, the CBF was significantly increased in the right frontal (p = 0.019)
and occipital cortex (p = 0.004) with no
significant changes in the cerebellar folia,

subcortical gray matter (striatum and
thalamus), and other cerebral cortices in
the right cerebral hemisphere. There were
no significant CBF changes in any areas
of the left cerebral hemisphere.
Conclusion: In patients treated with
ibudilast, the amelioration of dizziness
and depression was accompanied by a
CBF increase in the right frontal and occipital cortices. These findings suggest
that the right frontal and occipital cortices may be related to their dizziness and
depression.

Arzneimittel-Forschung (Drug Research) 2008;58(6):277–282

Key words
j	CAS 50847-11-5
j

Depression, post-stroke

j	Ibudilast, cerebral ischemia,

clinical study
Ketas®
j Phosphodiesterase inhibitors
j Vertigo
j

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1. Introducton
Vertigo, dizziness and unsteadiness are symptoms frequently reported by patients in the chronic stage after
stroke. The term “dizziness” has been applied to vertigo,
lightheadedness, presyncope, anxiety, and general malaise [1–4]. Although the percentage of patients whose
dizziness symptoms are unequivocally attributable to
stroke is low, considering the large number of stroke patients who report dizziness symptoms at evaluation [5],
the true number of patients whose dizziness symptoms
are due to a stroke etiology may be high [6]. Dizziness as
a non-specific complaint may also be related to depression [7]. The association between cerebrovascular disease and depression has been recognized [8, 9] and a
20-40 % incidence of post-stroke depression (PSD) has
been reported [10].
Ibudilast (CAS 50847-11-5) acts as a phosphodiesterase
(PDE)-4 inhibitor via modulation of the cyclic adenosine
monophosphate (cAMP) second messenger system [11,
12]. It is widely used for the treatment of central nervous
system disorders (such as depression) and asthma.
It has been shown to elevate the cerebral blood flow
(CBF) in patients with chronic ischemic cerebrovascular lesions [13, 14] and to ameliorate dizziness in the
chronic stage of cerebral infarction [15]. However, the
pathophysiological mechanism(s) underlying its effects
remain to be elucidated.
In this study, we investigated whether the ibudilastinduced amelioration of non-specific clinical symptoms
in patients in the chronic stage of cerebral ischemia is
attributable to an increase in the CBF.

2. Patients and methods
2.1. Patients
This study was approved by the Ethics Committee of our institution; prior oral informed consent to participate in this study
was obtained from all patients. The study population consisted

of 11 patients, 7 men and 4 women (mean age 72 ± 7.9 years)
who complained of dizziness, vertigo, unsteadiness, or feeling
faint. Of these, 8 (mean age 71.4 ± 8.8 years) had suffered a cerebral infarct more than 1 month earlier. The other 3 (mean age
73.7 ± 6.1 years) had experienced no obvious ischemic episodes
although MRI (magnetic resonance imaging) demonstrated hyperintense ischemic areas in the deep white matter. All 11 patients were treated with ibudilast (30 mg daily) orally and followed up for 6 months.
Patient profiles are presented in Table 1. Case 1 was a
75-year-old woman with a 5-year history of vertigo who was being treated for hypertension. She reported for a check-up at our
hospital. Attacks of vertigo rendered her unable to walk. MRI
demonstrated hyperintense areas in the bilateral deep white
matter; there were no new lesions attributable to stroke. Case 2
was a 71-year-old man with dysarthria. His right hand was
clumsy and he noticed hypoesthesia of the right hand and foot.
One month after onset he also suffered episodes of dizziness
and he reported to our hospital for a check-up. MRI demonstrated a relatively fresh infarct (subacute to chronic stage) in
the left putamen; there were multiple old lacunar infarcts in the
deep white matter. Case 3 was a 77-year-old man who reported
forgetfulness, decreased motivation and concentration ability,
and episodes of dizziness that had started several months earlier. MRI demonstrated multiple lacunar infarcts in the deep
white matter; there were relatively fresh (subacute stage) lacunar infarcts in the right corona radiata. MRA (magnetic resonance angiography) demonstrated severe stenosis of the right
middle cerebral artery. Case 4 was a 78-year-old woman with a
long history of diabetes mellitus and hypertension. She suddenly experienced the onset of vertigo, lateral left gaze palsy,
and gait disturbance. Her episodes of vertigo continued for 2
months and she suffered persistent depression. MRI demonstrated a small lacunar infarct in the left pons. Case 5 was a
75-year-old man with a long history of hypertension who noticed unsteadiness and gait disturbance. He also complained of
right homonemous hemianopsia. MRI demonstrated a subcortical infarct in the left occipital lobe accompanied by multiple
old lacunar infarcts in the deep white matter. Case 6 was a
67-year-old man who experienced dizziness episodes for several months. At check-up at our hospital he reported forgetfulness and decreased motivation and concentration ability. MRI

Table 1: Case profile.
Case No.

Age/Sex

Type of infarction

Site of lesion

Case 1
Case 2
Case 3
Case 4
Case 5
Case 6

75/F
71/M
77/M
78/F
75/M
67/M

multiple lacunar
lacunar
ATBI
ATBI
ATBI
multiple lacunar

deep white matter
left putamen
right corona radiata
left pons
left occipital lobe
deep white matter

Case 7
Case 8

79/F
80/F

multiple lacunar
BAD

deep white matter
right pons

Case 9
Case 10
Case 11

74/M
55/M
61/M

ATBI
ATBI
ATBI

left occipital lobe
left corona radiata
left MCA watershed
zone

Past history

Dizziness

JSS-D score
at entry

Handedness

HT
rt MCA severe stenosis
DM, HT
HT
HT
severe stenosis of lt
ICA
HT, HL
HT, lt MCA severe
stenosis
HT
rt MCA severe stenosis
DM, HT

vertigo
dizziness
dizziness
vertigo
unsteadiness
dizziness

7.31
3.35
6.20
20.11
1.00
1.44

right
right
right
right
right
right

unfitness
unsteadiness

6.60
1.17

right
right

dizziness
faintness
faintness

0.73
1.43
9.49

right
right
right

ATBI: atherothrombotic brain infarction; HT: hypertension; MCA: middle cerebral artery; DM: diabetes mellitus; BAD: branch atheromatous
disease; ICA: internal carotid artery.

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CNS-active Drugs · Hypnotics · Psychotropics · Sedatives

2.2. Drugs
Ibudilast (CAS 50847-11-5, 3-isobutyryl-2-isopropylpyrazolo
[1,5-a] pyridine, KC-404, Ketas®) capsules was obtained from
Kyorin Pharmaceutical Co., Ltd., Tokyo (Japan).

2.3. Recording of dizziness grade and scoring
of depression
Dizziness grade of all 11 patients were recorded at 2 and 6
months after the start of ibudilast therapy. Using the Japan
Stroke Scale-Depression Scale (JSS-D), the changes in their depressive state and dizziness grade were recorded before and 2
and 6 months after the start of ibudilast therapy. In 2003, the
Japan Stroke Society established the JSS-D to evaluate mood
disorders after stroke, especially post-stroke depression (PSD)
[16]. There is a strong correlation between the JSS-D and the
Hamilton Depression Scale (HAM-D17) [17]; the threshold for
PSD on the JSS-D is more than 2.48 [18].

2.4. CBF measurement
The patients’ CBF was measured at the start of therapy and 3
months later. For the CBF study the standard Xe-CT CBF system adapted to the Siemens scanner (120 kV, 195 mA, Siemens
Somaton Plus4, München, Germany) was used [19, 20]. Prior to
scanning, the patient’s head was immobilized and secured with
a vacuum-activated cranial mold. The head was aligned along
the orbitomeatal plane with a laser light. A scout film was used
to select the CT slices; two 10 mm-thick slices, separated by
15 mm, were selected for the CBF study. After selection of the
scan levels, the patient was connected to the xenon gas inhalation system (AZ-726, Anzai Medical Corp., Tokyo Japan); the
inhaled xenon concentration was 30 %. The patients inhaled
stable xenon for 3 min (wash-in); this was followed by 4-min
desaturation (wash-out). An AZ-7000 instrument (Anzai Medical Corp.) was used to evaluate CBF values. The airway was
tightly sealed with a facemask that covered the mouth and
nose.

Slice-1

Slice-2

Slice-3

Slice-4

Fig. 1: Analyzed sections of CT images. Slices 1, 2, 3, and 4 are axial images that include the cerebellar hemisphere, frontal base,
basal ganglia, and temporo-parietal cortex, respectively. ROIs were placed on each image. In slice 1, 1 and 2 indicate the cerebellar folia. In slice 2, 1 and 2 indicate the frontal base. In slice 3, the level of the analyzed slice passed through the basal ganglia and
included the midsection of the anterior horns of the lateral ventricles, the caudate putamen, thalamus, and pineal body posteriorly. For cortical areas, three pairs of cortices were determined corresponding to the frontal cortex. 1, 2, Temporal cortex; 3, 4,
occipital cortex; 5, 6, indicate subcortical gray matter areas; two pairs of regions were determined corresponding to the striatum
(7, 8) and thalamus (9, 10). In slice 4, 1, 2 indicate the temporo-parietal cortex.
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demonstrated multiple lacunar infarcts in the deep white matter. Case 7 was a 79-year-old woman with general malaise. She
complained of vertigo and severe depression. MRI demonstrated multiple lacunar infarcts in the deep white matter. Case 8
was an 80-year-old woman with a long history of hypertension.
She reported the sudden onset of unsteadiness and gait disturbance. MRI demonstrated infarction in the right pons and a
diagnosis of branch-atheromatous disease was made. Case 9
was a 74-year-old man with sudden onset of amaurosis fugax in
the left visual field and weakness of the right hand accompanied by dizziness. MRI demonstrated cerebral embolism in the
left occipital subcortical area. Cervical echography disclosed
severe stenosis of the left internal carotid artery. Case 10 was a
55-year-old man with a long history of untreated hypertension
and hyperlipidemia. He suddenly experienced dysarthria, right
facial palsy, and faintness. MRI demonstrated a new stroke in
the left corona radiata; there were old lacunar infarcts in the
right corona radiata and right cerebellar folia. MRA revealed severe stenosis from the carotid artery to the middle cerebral artery bilaterally. Case 11 was a 61-year-old man with a 5-year
history of untreated hypertension who experienced recurrent
transient ischemic attacks during several months, right-arm
dysesthesia, and episodes of faintness. MRI demonstrated left
parietal cortical and subcortical hyperintense spots, including
the left corona radiata on diffusion-weighted images. There was
severe left middle cerebral artery stenosis.

CNS-active Drugs · Hypnotics · Psychotropics · Sedatives

2.5. Statistical analysis
Statistical analysis was carried out using the paired t-test. In
­addition, a paired t-test with a Bonferroni correction was also
carried out.

3. Results
In Fig. 1 the analyzed sections of CT images are shown.
Slices 1, 2, 3, and 4 are axial images that include the cerebellar hemisphere, frontal base, basal ganglia, and temporo-parietal cortex, respectively. ROIs were placed on
each image. In slice 1, 1 and 2 indicate the cerebellar folia. In slice 2, 1 and 2 indicate the frontal base. In slice 3,
the level of the analyzed slice passed through the basal
ganglia and included the midsection of the anterior
horns of the lateral ventricles, the caudate putamen,
thalamus, and pineal body posteriorly. For cortical areas,
3 pairs of cortices were determined corresponding to the
frontal cortex. 1, 2 indicate the temporal cortex; 3, 4 indicate the occipital cortex; 5, 6 indicate subcortical gray
matter areas; 2 pairs of regions were determined corresponding to the striatum (7, 8) and thalamus (9, 10). In
slice 4, 1, 2 indicate the temporo-parietal cortex.

Table 2: Improvement of dizziness.
Case No.
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
Case 9
Case 10
Case 11

Dizziness grade
At entry
severe
mild
moderate
moderate
moderate
moderate
moderate
mild
mild
mild
mild

After 2 months
moderate
none
mild
none
none
none
none
none
none
none
none

After 6 months
none
none
none
none
none
none
none
none
none
none
none

As shown in Table 2, at 6 months after the start of
ibudilast therapy, dizziness was resolved in all patients.
At the start of treatment, 6 patients (cases 1-3, 4, 7, 11)
manifested depression (Fig. 2A) according to JSS-D parameters. Their depression was significantly ameliorated at 6 months after the start of therapy (Fig. 2B).
Table 3 shows that 3-month treatment resulted in
CBF changes analyzed in each ROI demonstrated in Fig
1. In the right cerebral hemisphere there was a significant CBF increase in the frontal (p = 0.019) and occipital
(p=0.004) cortices. There was no significant change in
the subcortical gray matter, the striatum, thalamus, cerebellar folia, or other cerebral cortices. In the left cerebral hemisphere there was no significant CBF change.
Comparison of the CBF in the right and left hemisphere
disclosed no significant differences (data not shown).

A 25
entry
2 months

JSS-D score

20

6 months

15

10

5

0
Case-1 Case-2 Case-3 Case-4 Case-5 Case-6 Case-7 Case-8 Case-9 Case-10 Case-11
Case No.

JSS-D score

B 15

10

5
*

0

entry

2 months

6 months

Fig. 2: Change in the JSS-D scores after administration of ibudilast in the patients with chronic cerebral ischemia. (A) Bar graph
showing changes in the depression score (JSS-D) of all 11 patients at study inception (open columns) and 2 (gray columns), and
6 months (solid columns) after the start of ibudilast treatment. (B) Line graph of the mean JSS-D score and standard deviation
of six patients (score at entry > 2.48, Case 1, 2, 3, 4, 7, 11). *Significant change in value obtained at 6 months after the start of
ibudilast treatment. Paired t-test with a Bonn-Ferroni correction, p < 0.025.

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Regions of interest (ROIs) were placed on cortical and subcortical areas on 4 slices. The analyzed sections on the CT slices
are shown in Fig. 1. The CBF (ml/100 g/min) was calculated in
the corresponding ROI on the CT slices using Kety’s autoradiographic equation [20, 21].

CNS-active Drugs · Hypnotics · Psychotropics · Sedatives

Table 3: Change of CBF.
ROI
Cerebellar folia
Frontal base
Frontal cortex
Temporal cortex
Occipital cortex
Striatum
Thalamus
Temporo-parietal cortex

Right region

Left region

Baseline CBF

Loading CBF

p value

Baseline CBF

Loading CBF

p value

43.26 ± 11.63
31.60 ± 12.00
35.16 ± 9.10
37.64 ± 11.35
29.79 ± 9.64
42.17 ± 12.26
54.03 ± 23.94
40.65 ± 11.73

35.54 ± 13.10
38.62 ± 9.49
40.65 ± 7.99*
39.75 ± 10.49
36.78 ± 10.76*
42.01 ± 10.45
50.22 ± 15.35
42.72 ± 8.80

0.184
0.101
0.019
0.474
0.004
0.939
0.608
0.467

44.01 ± 14.31
36.64 ± 20.09
33.30 ± 12.45
35.76 ± 11.99
32.91 ± 7.45
39.60 ± 14.27
52.05 ± 23.36
37.44 ± 11.01

41.86 ± 15.19
42.90 ± 24.89
37.56 ± 10.09
36.22 ± 11.21
33.62 ± 9.72
40.17 ± 10.40
48.84 ± 15.92
39.44 ± 11.71

0.697
0.201
0.253
0.863
0.723
0.846
0.658
0.408

4. Discussion
In the present study, administration of 30 mg/day of ibudilast resulted in amelioration of non-specific clinical
symptoms such as dizziness and depression and produced a significant increase in the CBF of the right frontal and occipital cortices. If this phenomenon reflects
the natural course of PSD patients treated with ibudilast,
not only the right, but also the left cortical areas should
show an increase in CBF. However, there was no significant change in the CBF in any areas of the left cerebral
hemisphere. As shown in Table 1, none of the patients
presented with lesions in the right frontal or occipital
cortices. Therefore, we focused on the relationship between their clinical symptoms and the ibudilast-induced
CBF changes in the right frontal and occipital cortices.
All 11 patients complained of dizziness, vertigo, unsteadiness, or feeling faint, symptoms attributable to
secondary chronic cerebral circulation impairment as
sequelae of brain infarction. Others who studied the relationship between dizziness and the regional CBF
demonstrated hypoperfusion in both occipital lobes
and posited that insufficient flow in the territory of the
vertebrobasilar system is a factor resulting in hypoperfusion of both occipital lobes [22, 23]. At 2 and 6 months
after the start of ibudilast therapy, all of the 11 patients
reported resolution of their dizziness episodes. As infarcts were present in the brainstem and occipital lobes
of 2 patients and another patient manifested infarction
in the cerebellar folia, we posit that these patients suffered from vertebrobasilar insufficiency.
In 6 patients who reported depression at the inception of our study, this symptom was significantly ameliorated at 6 months. Studies on the relationship between depression and the CBF demonstrated a significant reduction in the CBF in the left frontal lobe among
patients with PSD [24–27]. The most consistent regional
deficits were a decrease in the CBF and the metabolism
affecting the left dorso-lateral prefrontal cortex; low
CBF and glucose hypometabolism in the left prefrontal
cortex have been reported to be inversely correlated
with depression severity [28, 29]. However, there is no

Arzneimittel-Forschung (Drug Research) 2008;58(6):277–282

consensus whether the right or left side is the dominant
one involved in depression. Based on our findings, we
posit that our patients’ dizziness and depression reflect
involvement of the right frontal and occipital cortices.
Ibudilast therapy produced no significant CBF
changes in subcortical structures such as the striatum
and thalamus. Interruption of the cortical blood flow by
subcortical lesions reportedly produced neuropsychiatric symptoms [26, 30, 31]. Major PSD may occur secondary to disruption of subcortico-cortical biogenic
amine pathways and patients with PSD manifested cortical serotonergic deficits [32, 33]. Our results demonstrate that damage to subcortical regions may affect the
right frontal and occipital cortices and result in dizziness and depression.
Ibudilast has received attention for its role as a PDE4
inhibitor via modulation of the cylic anenosine monophosphate (cAMP) second messenger system and has
been used to treat CNS disorders [11, 12]. The PDE4D
gene has been identified as a risk factor for ischemic
stroke through regulation of cAMP signal transduction
[34]. PDE4D enzyme activity may play an important
role in stroke through its effects on inflammation,
plaque stability, response to injury, angiogenesis, and
the susceptibility and response to low-grade infections
[35]. Ibudilast may exert beneficial effects on the brain,
especially in chronically hypoperfused right frontal and
occipital lobes, by increasing the CBF and via a prostaglandin I2-related mechanism and PDE4I-related modulation of the cAMP second messenger system.
In conclusion, our results demonstrated that in patients with cerebral ischemia, the administration of ibudilast produced a significant increase in the CBF to the
right frontal and occipital cortices and amelioration of
non-specific symptoms such as dizziness and depression. Our findings suggest that the right frontal and occipital cortices are related to the symptoms experienced
by these patients. Studies are underway in our laboratory to identify the relevant hypoperfused location(s),
and the neurotransmission underlying the non-specific
post-stroke clinical symptoms.

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CBF (mL/100 g/min): mean ± S.D.; p value: paired t-test, *p < 0.05.

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Arzneimittel-Forschung (Drug Research) 2008;58(6):277–282

Heruntergeladen von: Harvard University Library. Urheberrechtlich geschützt.

CNS-active Drugs · Hypnotics · Psychotropics · Sedatives