Cerebral embolization leads to memory impairment of several learning tasks in rats

Pharmacology Biochemistry & Behavior, Vol 24. pp 687-692, 1986 c Ankho International lnc Printed m the U S A 0091-3057/86 $3 00 + 00

Cerebral Embolization Leads to Memory Impairment of Several

Learning Tasks in Rats

Y O S H I H I R O K I Y O T A , M A S A O M I M I Y A M O T O , A K I N O B U N A G A O K A A N D Y U J I N A G A W A

Bio logy Labora tor i e s , Cen tra l R e s e a r c h Dtws lon . Takeda C h e m i c a l Indus t r ies , L td Yodogawa- l ,u , Osaka 532, J a p a n

R e c e i v e d 13 M a y 1985

K1YOTA, Y . M MIYAMOTO, A NAGAOKA AND Y NAGAWA Cerebral embohzatlon leads to memory trnpalrrnent oJ ~evelal lealmng ta~k~ m rats PHARMACOL BIOCHEM BEHAV 24(3) 687-692. 1986--The effects of cerebral embolizat~on, produced by m.lectlng mlcrospheres into the left internal carotid artery, on passive and active avoidance tasks and water filled multiple T-maze task, were stud~ed m male W~star rats The rats with cerebral embohzat~on were markedly ~mpa~red acquisition and retention of the one-trial passive avoidance response The impairment depended on the number of mlcrospheres rejected and continued for 2 weeks The cerebral embohzed rats were also impaired acqmsltlon of two-way active avoidance response m a shuttle box These ~mpalrments are not due to decrease m shock sensitivity, because there was no slgmficant change m the flinch-jump threshold The embohzed rats also exhibited a significant d~sturbance in performance of water filled multiple T-maze learning These results suggest that rats with cerebral embohzatlon are impaired m three different types of learning tasks, and may be useful as an animal model for the vascular type of dementm

Cerebral embohzatlon Passive and active avoidance tasks Ammal model for dementia

Water maze learning Memory impairment

A N I M A L S with ce rebra l e m b o h z a t l o n p roduced by dif ferent man ipu la t ions (mtra-ar te r la l Inject ion of a r a c h i d o n a t e [5, 8, 9, 22], adenos ine d l p h o s p h a t e [6], h o m o l o g o u s blood c lots [15,20] or air [7,10]) have been used as e x p e r i m e n t a l mode l s for b ra in l schemla Solid m l c r o s p h e r e s [4, 13, 21, 23] were also used to p roduce a p e r m a n e n t occ lus ion of m l c r oves se l s It has been d e m o n s t r a t e d by many inves t iga t ions tha t cerebral e m b o h z a t l o n great ly affects bra in energy m e t a b o h s m an increase in lacta te level , dec rease in A T P level and de- c rease in oxygen or g lucose u t ihza t lon [13, 14, 17, 18] How- ever . the effects of ce rebra l e m b o h z a t l o n on behav io r , espe- cially on learning b e h a v i o r [12,16], have not been s tudied ex t ens ive ly , a l though ce rebra l e m b o h z a t l o n is t hough t to dis- tu rb learn ing and m e m o r y

The p re sen t s tudy was c o n d u c t e d to inves t iga te the effects of ce rebra l e m b o h z a t l o n , p roduced by in jec t ing micro- sphe re s into the left in terna l carot id a r te ry , on pass ive or ac t ive avo idance task and wa te r filled mult iple T - m a z e task in rats

METHOD

Suble¢ t~

The sub jec t s were male J C L / W l s t a r ra ts tha t we ighed 250-300 g and were 8--10 weeks old at the beg inn ing of the e x p e r i m e n t s The an imals were housed in g roups of 8-10 in large wi re -mesh cages u n d e r con t ro l led cond i t i ons of tem- pe ra tu re (25+- I°C), humid i ty (55+5%) and light (7 00-19 00) Food and wa te r were f reely ava i lab le in the h o m e cage

Embohzatton

The ce rebra l e m b o h z a t l o n was pe r fo rmed accord ing to the m e t h o d desc r ibed by Kogure et al [13] wi th mino r mod- i f icat ions The rats were anes the t i zed wi th e thyl e the r and the left carot id b i fu rca t ion was e x p o s e d The left ex te rna l caro t id a r te ry and the p te rygo-pa la t lne a r te ry , a b r a n c h of the in ternal carot id a r te ry , were hga ted The origin of the ex te rna l caro t id a r te ry was occ luded wi th a vascu la r c l amp An incis ion was made in the a r te ry , and a PE-50 polyethyl - ene tub ing filled wi th sal ine was inse r ted th rough the incis ion into the c o m m o n carot id a r te ry C a r b o n m l c r o s p h e r e s (35+-5 /xm in d iamete r ) s u s p e n d e d in 50/~1 sahne con ta in ing 20% dex t r an were in jec ted Into the in terna l carot id a r t e ry t h rough the tubing, the origin of the ex te rna l caro t id a r te ry was then hga ted S h a m - o p e r a t e d ra ts were in jected wi th the same vol- ume of 20% dex t r an so lu t ion ins tead of the m l c r o s p h e r e sus- pens ion

Fhnt h-Jump Threshold

Each rat was p laced in a tes t c h a m b e r (30x 30x 30 cm) and was g iven a l -mln hab i tua t i on per iod before the measu re - m e n t E igh t d i f ferent AC cu r r en t s of shock (0 l - l 0 mA) were apphed in a scend ing o rde r for I 0 sec at 30 sec in te rva ls t h r o u g h the grid f loor A '~f lmch" was def ined as a s tar t le or c rouch ing r e sponse and " j u m p " as r emova l of two or more paws f rom the grid f loor The shock in tens i ty at wh ich ra ts exh ib i t ed each r e sponse was m e a s u r e d for the th resho ld

687

6~S KI 'YO] &, M I Y A M O F ( ) , N A G A O K A A N D N a , ( ; A W ~

S Star t

G Goal

FIG 1 Maze pattern of water filled multiple T-maze Six choice points are present in the correct pathway 'S and "'G' represent the start and goal points of the maze, respecuvel}

(A)

E ~

0

3 7 1/, 28

[ ~ Sham l E, mbol,zed

(B)

m ~ 1 0 -

¢e~

~ s -

0

3 7 1/, 28

Days After Operahor,

FIG 2 Ambulation (A) and rearing (B) behavior m the open-field test in rats with cerebral embohzaUon produced by reJecting 2000 microspheres into the left internal carotid artery Different groups of rats (9-12) were used for each test after the operation *p<0 05, ***p<0 001, compared with sham-operated rats

T A B L E 1

E F F E C T O F T H E C E R E B R A L E M B O L I Z A T I O N t ) N F L I N £ H - J U M P

THRESHOLD IN RATS

Flinch ( m A ) Jump ImA)

3 Days Sham 023 + 002 045 + 003 Embohzed 0 33 ± 0 04* 0 61 ± 0 13"

1 Week Sham 021 ± 001 038 ± 006 Embohzed 0 18 ± 0 04 0 44 ± 0 12

2 Weeks

Sham 020 ± 004 038 ± ()06 Embohzed 0 17 + 0 02 0 35 ± 0 09

Fhnch-jump threshold was measured at various times rafter the cerebral embohzation The embohzatmn was produced by rejecting 2000 microspheres into the left internal caroUd artery

Each value ls the mean ± S E (mA) o f l 0 o r II rats *p<0001 compared with sham-operated rats

(A) (8 /

300 • 300

200

g

100

v 200

c

m

c 1(30

o ~ - , ,

e** t

0 - - 0 1000 2000 1003 20CO

Sham Sham Embohzed Embohzed

FIG 3 Effects ol cerebral embohzat]on on passive avoldam.e response m rats The embohzahon was produced by rejecting 1000 or 2000 m]crospheres into the left internal carotid artery In the experiment A, the acqmslt,on trial was done 7 days after the operation and the retention test was carried out 24 hr later In the experiment B the acquisition trml was done 24 hr before the embohzatlon and the retention test was carried out 7 days after the operation Each point represents the 10dlvidual avoidance latency and each bar shows the mean latency m the retention test *p<0 05, **p<0 01, compared with sham-operated rats

O p e n - F w l d Behav toJ

The general behavior of the rats was obse rved in the open- field as desc r ibed by Hall [11] The tes t ing a p p a r a t u s cons i s t s of a c i rcular f loor 60 cm in d i a m e t e r enc losed by a 50 cm high wall Th e f loor is d iv ided into 19 sec to r s , each o f wh ich has approx ima te ly same area marked with a black line The open- field is i l lumina ted by 100 W bulb 80 c m above the cen t e r o f the f loor A rat was p laced in the cen t e r o f the floor, and two p a r a m e t e r s were m e a s u r e d for 3 m i n u t e s " a m b u l a t i o n , " e x p r e s s e d as the total n u m b e r o f s ec to r s c r o s s e d by the rat, and " r e a r i n g , " e x p r e s s e d as the f r e q u e n c y with wh ich it s tood on its hind l imbs The open-f ie ld b e h a v i o r was ob-

s e rved 3 to 28 days af ter the opera t ion Dif ferent g roups of rats were used in each tes t

Pa.~ st ve A vo tdanc e l a ~l,

Rats were tes ted in a s t e p - t h r o u g h type pas s ive avo idance t a sk [I] The e xpe r ime n t a l a p p a r a t u s cons i s t s of two com- p a r t m e n t s , i l luminated one (25× 10x25 cm) and dark one ( 3 0 × 3 0 × 3 0 cm) equ ipped with a grid floor, and two com- p a r t m e n t s are separa ted by a guil lot ine door (8× 8 cm) In the acquis i t ion trial, a rat was placed m the i l luminated ~.om- p a r t m e n t and al lowed to en te r the dark c o m p a r t m e n t , as soon as it did so. the door was c losed and u n e s c a p a b l e foot-

C E R E B R A L EMBOLIZATION AND MEMORY IMPAIRMENT 689

shock (2 5 mA, 3 sec) was delivered through the grid floor In 300- the retention test, the rat was again placed m the dlummated compartment and the latency to enter the dark compartment was measured If the rat avoided longer than 300 sec, a ceiling score of 300 sec was assigned In the experiment to study the effects of cerebral embollzatlon on the acquisition of the ~00 - passive avoidance response, the acquisition trial was carried , ~" out 7 days after the embohzatlon and the retention test was performed 24 hr after the acqmsltlon trial The effects of .= cerebral embohzatlon on the retention of passive avoidance

• s lOO- response acquired 24 hr before the embohzatlon, were eval- uated by a retention test performed 7 days after the opera- tlon

At twe AvoMan( e Tasl,

Rats were trained in a shuttle box type of active avoidance apparatus [3] The experimental apparatus equipped with a grid floor, consists of two compartments (20x23x20 cm) separated by a hurdle (6 cm high) A buzzer is put on a ceiling of a shuttle box for the source of the conditioned stimulus The conditioned stimulus (2 8 kHz, 70 dB) was presented for a maximum 5 sec, and if the rat did not cross to the opposite s~de of the shuttle box. an uncon- ditioned stimulus of footshock (1 0 mA) was dehvered through the grid floor for a maximum 5 sec Training was started 7 days after the operation Each rat was gwen 20 trials dally for 6 days, a variable interval ranging from 30 to 50 sec between the trials was used Two measures of behavior were recorded "avoidance response," crossing to the opposite side during the conditioned stimulus and "lntertrlal response," spontaneous crossing between the trials

Watel Fdled Multiple T-Maze Tasl,

Rats were trained in a water maze task [2] The experimental apparatus consists of a water tank (125 × 125 × 35 cm) comprising a multiple T-maze with 6 choice points and a straightaway (Fig 1) The maze pathway is 13 cm wide, and the tank was filled with water (21-+ I°C and 20 cm deep) A platform (22 cm high), with an inchned landing approach, is equipped at the goal where the rat IS able to escape from the water Training was started 7 days after the operation On the first day, the rat was put m the straightaway for three prehmmnary swimming training trials the rat was put In one end of the straightaway and latency to reach the other end. equipped with the platform, was recorded The next day, the rat was put at the start point (S) of the maze. and latency to reach the goal (G) and the number of errors in choice was recorded Each rat was given 3 trials a day for 3 days (Days 1-3)

Sttttt~ttt

Statistical comparison between different groups was made using Student 's t-test and Mann-Whitney U-test (two- taded), and analysis of variance (ANOVA) was used for data in active avoidance and the water maze tasks

R E S U L T S

Nelo ologtt al Symptom~

The embohzed rats exhibited ptosls and paralysis ofcon- tralateral paws Some occasionally showed circling or rolling behavior These neurological deficts were marked for three days after the embollzatlon, then gradually improved and

( 9 ) ( 9 )

I I f 10)

I

o /

7 14 28 56 Days After Opera t lon

Sham ~ Embohzed

FIG 4 Acqms~t]on of passive avoidance response at various times after cerebral embohzatlon m rats The embohzatlon was produced by injecting 2000 mJcrospheres into the left internal carotid artery Different groups of rats were used m each test The retention test was performed 24 hr after the acquisition trial Number of rats is shown m parentheses **p<0 01, compared with sham-operated rats

completely disappeared 7 days after the embohzatlon Neurological defiots increased in proportion to the number of mlcrospheres injected Incidence of death was 0, 8, 40 and 70% in the rats injected with 1000, 2000, 3000 and 4000 mtcrospheres, respectively Based on this finding, we chose 2000 microspheres for standard experiments, because this number produced prominent neurological deficits but the incidence of death was relatively low

No~ it epttve Thresholds m the Embohzed Rat~

The thresholds for the flmch and jump responses were significantly higher in the embohzed rats than m sham- operated rats 3 days after the operation However. both thresholds recovered to the control level 7 days after the embohzatlon (Table 1)

General Behavior

In all tests, ambulatory activities m embohzed rats did not differ significantly from those m sham-operated rats (Fig 2A) However, the embohzed rats showed less rearing behavior than the sham-operated rats. and the difference was significant 3 and 7 days after the operation (Fig 2B)

EJJec t ~ (ff Cel ebral Emboltzatton on A( qutJmon oJ Pa s3lI'e Avmdan t e Response (Pte-Tratnmg Embohzat ton)

To study the effect of cerebral embohzatlon on acquisition of passive avoidance response, the acquisition trial was carried out 7 days after embollzatlon produced by the injection of 1000 or 2000 mlcrospheres In the retention test done 24 hr after the acquisition trial, most of the sham-operated rats exhibited long response latencles to enter the dark compartment In contrast, the embohzed rats exhibited short response latencles and the change was more marked in rats rejected with 2000 mlcrospheres mean response latency was

~90 KIYOTA, MIYAMOTO, N A G A O K A AND N A G A W A

(A)

100

u c

5 0 o

k k

j -

! I I I I I

1 2 3 ~ 5 6

Tra~mng

(B)

6 0 in

i/1 t - o Q. =

40

1-

7

i i i I i l

1 2 3 4 5 6

Training

o o S h a m ( N = I 4 )

: = Eml~hzed (N=I4)

FIG 5 Effects of cerebral embohzatlon on active avoidance response in rats Training was started at 7 days after the operation The embohzatlon was produced by injecting 2000 rmcrospheres into the left internal carotid artery Each value represents the percentage of avoidance responses (A) or the number of mtertrml responses (B), which is shown as mean_+S E *p<0 05, **p<0 01, compared with sham-operated rats

(A)

BOO

600

Ill E

400

el

;~ 200

(B)

J3

i i i | i I

I 2 3 t 2 3

Day 1 Day 2

Training

i i i

I 2 3

Day 3

w

o

Q

E z

I [

6 o

0 i I i

l 2 3

Dayl

i i i

1 2 3 i i i

1 2 3

Day 2 D a y 3

T r a l n = n g

o - - o S h a m ( N=I 5 ) o - - o E m b o l , z e d ( N=15 )

FIG 6 Effects of cerebral embohzanon on water maze learmng in rats Training was started at 8 days after the cerebral embohzatlon The embohzahon was produced by rejecting 2000 mlcrospheres into the left internal carottd artery Time to reach the goal (A) and the number of errors (B) are expressed as mean_+S E "p<0 05, compared w~th sham-operated rats

136 7 sec (U=25 5 , p < 0 05) or 46 4 sec ( U = 7 5, p < 0 01) in rats injected with 1000 or 2000 m~erospheres , respec t tve ly (F~g 3A)

Nex t , we de te rmined w h e t h e r the tmpatred acqmsl t ton of p a s s w e avoidance r e sponse m the e m b o h z e d rats r ecove red t r ine-dependent ly The acquis i t ion trials were c a m e d out at var ious t tmes f rom 3 to 56 days after the e m b o h z a t | o n made by mjec tmg 2000 mlc rosphe re s , dtfferent groups of rats were used in each test Sham-ope ra t ed rats showed long avoidance la tencles m each test , pe r fo rmed 24 hr af ter the acqutsl t lon trml In cont ras t , the r e sponse la tencles in the e m b o h z e d rats were s~gmficantly shor t 3, 7 and 14 days

after the opera t ion H o w e v e r , the shor tened response latencles were gradually r ecovered to the level of the sham- opera ted rats, and normal 56 days after the embohza t lon (Fig 4)

Ejfe~ t s oJ Cerebral Embohza tum on Retent ton o/Pass t~ e A votdan~ e Re ~pon ~e (Po~t-Trammg Ernbohz.atton)

Rats given an acquisi t ion trial o f pass ive avoidance task m the intact state, were e m b o h z e d using 1000 or 2000 microspheres 24 hr after the acqulst t ton trial Eight o f 9 sham- opera ted rats showed a ceiling score of 300 sec in the reten-

C E R E B R A L EMBOLIZATION AND MEMORY IMPAIRMENT

t~on test, performed 7 days after the operation In contrast, the response iatenctes were very short m the embohzed rats AvoMance latenctes were inversely related to the number of mlcrospheres injected mean response latency was 145 2 sec (U=I6 , p < 0 05) or 21 3, sec ( U = I , p < 0 01) m the rats em- bolized by 1000 or 2000 mtcrospheres, respectively (Fig 3B)

Effec ts oj Cerebral Embohzation on Acquisition o f Actn'e A voMance Re ~pon s e (Pre-Trammg Ernbohzatlon)

The percentage of avoidance responses gradually increased wah training m both the embohzed and sham- operated rats However, the percentage of avoidance responses m the embohzed rats was lower than that m the sham-operated rats in every session, F(1,26)=6 2, p < 0 05 In the final session, the sham-operated rats showed an avoidance response m 8(1% of the trials whereas the embohzed rats exhibited a response in only 50% of the trials (Fig 5A) The number of lntertrlal responses in the embollzed rats was significantly less than that in sham-operated rats in the fourth and fifth session (Fig 5B) However , no significant difference was observed between the two groups in ANOVA, F(1,26)=3 0, p > 0 05

Water Maze Per h . m a n c e In the Cerebral Embohzed Rat~

The embohzed rats swam as well as the sham-operated rats the time taken to reach the goal was not different between the two groups in the straightaway (sham-operated rats 4 84_+0 93 sec, embohzed rats 5 13+--0 72 sec) In the water maze, the swimming time to reach the goal was gradually shortened by training in both groups of rats, and no significant difference was observed between the two groups in ANOVA, F(1,28)=2 0, p > 0 1 The embohzed rats could also learn to reach the goal with a few number of errors, however, the mean number of errors was more in the embohzed than m the sham-operated rats. F(I ,28)=173, p < 0 01, m all trials (Fig 6B) In the final trial, 10 out of 15 sham-operated but only 4 out of 15 embollzed rats reached the goal with no errors

DISCUSSION

Cerebral embohzed rats, produced by rejecting microspheres into the left internal carotid artery, had impaired acquisition ot the passive avoidance response Retention of the avoidance response, acquired in the intact state before the embollzatlon, was also disturbed by the embohzatlon The impairment was proportional to the number of mlcrospheres inJected In addmon, acquisition of the active avoidance response in a shuttle box was also disturbed in the embohzed rats

Emotional response to an electric shock is an important factor in learning tasks that use an aversive stimulus for conditioning The embohzed rats showed a temporary decrease in sensitivity to the electric shock, but the thresholds for the responses were normal 7 days after the embohzatlon, indicating that the tmpalrment in the passive or active

avoMance task IS not due to a decrease in sensitivity to the electric shock As shown by the normal ambulation in the open-field test, general activity m the rats was not disturbed 7 days after the embohzatlon This result also mdlcates that a secondary factor (motor disturbance) did not cause the impairment in the passive and active avoidance tasks There- fore, the disturbances in learning tasks in these rats seem to be due to dysfunction of the memory process mduced by the cerebral embohzatlon

Learning behavior in the embohzed rats was also studied in another learnmg task without electric shock Although their ability to swim was not lmpmred, the rats' performance in the water maze was significantly disturbed they had an increased number of errors This result suggests that the disturbance in water maze performance Is not due to a deficit in swimming ability This assumption is also supported by the fact that there was no difference betwen two groups m performance time in the maze learning Sham-operated rats stopped at the choice points and then chose the correct pathway, whereas the embohzed rats swam toward the goal quickly, often entering into dead ends without hesitating at the choice points Thus, sham-operated rats took as long as the embohzed rats to reach the goal but they made fewer errors

The hypothesis that the unilateral injection of microspheres leads to bilateral damage is supported by reports that unilateral embohzatlon ot the cerebral hemisphere produces dysfunction of the opposite hemisphere (dlaschlsls [19]), and that some mlcrospheres injected unilaterally move to the opposite side [4] We also found that a shght edema occurred not only in the lpsllateral but also in the contralaterai cerebral hemisphere after unilateral injection (unpublished data)

To assess recovery from the disturbances of learning behavior in the embohzed rats, we studied the effects of cerebral embolizatlon on acqmsltlOn of passive avoidance response at various times after the operation The impaired acquisition of passive avoidance response gradually improved and disappeared 8 weeks after the embohzatlon However, the effects of cerebral embohzatlon on the function of the central nervous system have not completely disappeared 8 weeks later, because cerebral edema was still observed in the left cerebral hemisphere at this time As the one-trial passive avoidance task is a simple one for learning, recovery from impairment in the passive avoidance task may be observed m the present experiment If we had used a more complex task, a longer-term disturbance might have been revealed in the embohzed rats

In conclusion, the results of the present experiment demonstrate that rats with the cerebral embohzatlon showed impairment in three different types of learning tests, and suggest that the embohzed rat may be useful as an animal model for the vascular type of dementia

ACKNOWLEDGEMENTS

We thank Dr J R Mdler for advice on the manuscript and Mr K Hamajo for valuable techmcal assistance

REFERENCES

I Ader, R , J A W M WeunenandP Moleman Retentlonofa passive avoidance response as a function of the intensity and duration of electric shock P~whon Sit 26 125-128, 1972

2 Blel, W C Early age differences m maze performance m the albino rat J Genet Psychol 56. 439-453, 1940

3 Blgnaml, G Effects of benactyzme and adlphemne on instru- mental avoidance condmonmg m a shuttle box Psy~ hophatma- c ology (Berhn) 5 262-279, 1984

61;2 K I ~ O T A M I Y A M O T O , NA, G A O K A :kND N A G A ~ A

4 Bralet, A -M , A Beley, P Bele), and J Bralet B~am edema and blood-brain b a m e r permeablhty following quan t | t ahve cerebral m~croembohsm 3t~ol, e 10 ~,4--38 1979

"~ Cahn J and M -G Borze~x The sodmm arach~donate-mduced cerebral mtarct m the rat A model for the ',tud,~ ol drugq 1 Ce~eh Blood FIo~ Metab 2 $74-77, 1982

6 F ~ e s c h ~ , C , N Batt~stml, F Volante, E Zanet te G Weber and S Passero Ammal model of TIA An exper imental stud~ w~th mtracarot~d ADP infusion m rabb~ts 5t~o~e 6 617-621 1975

7 Fritz, H and K -A Ho, ,smann Arterial a~r e m b o h s m m the cat brain 5t~o~e 10 581-589 1979

8 Furlow T W , J1 and N H Bass Stroke m rats produced by carotid mject~on of sodmm arach~donate 51 w m e 187 658--660, 197'~

9 Fmlow T W Jr a n d N H Bass Arach~donate-mducedcere- brovascular occlusion m the rat The role ofpla te le ts and aspirin in stroke Netoolot,,~ 26, 297-304, 1976

10 Garc~a J H , l Klatzo, T Archer and A S L os smsky Arterial a~r e m b o h s m Structural effects on the gerbd brain St~o/,e 12 414-421 1981

11 Hall, C S Emotional behawor m the rat 1 Defecation and u rmahon as measures of mdlwdual differences m emot~onahty I ( o m p P s ~ h o l 18 385-403, 1934

12 Klyota Y , K Hamajo , M M~yamoto and A Nagaoka Effect of ldebenone (CV-2619t on memory ~mpmrment observed m passive avoidance task m rats w~th cerebral embohzat~on Ipn I P h a t m a t ~ l 37 300--302 1985

13 Kogure , K R Busto O R e m m u t h a n d P Schemberg Energy metabohtes water content , and ca techo lamme changes m a model of cerebral embohc lnfarctmn Netooloex 23 438--439 1973

14 Kogure , K , R Busto and P Schemberg Energy metabohtes and water content in rat brain d u n n g the early stage of develop- ment of cerebral infarction B~am 97, 103-114, 1974

15 Kudo M , A Aoyama S h-hlmorl and N f u k u n a g a An aroma[ model of cerebral mla]~tJon Homologou,, blood ,.lo1 emboh in rats ~ttol, e 13 50'~-~08 1982

16 Le Poncm-Lafi t te , M C Orosdemouge (. Ro,,-Blllon D Duterte, P Potrat, P Lespma, ,se and J R Rapm Shol t - te lm memor,, and cerebral lschem~a Pharmacological apphcat~on f~to Neto~l 20 265-269, 1981

17 Le Poncm-Lafi t te M C Grosdemouge C Roy-Blllon D Duterte and J R Rapm Fffec.ts of naftldroturvl on ~.erebral hemodynam~c, me t abohsm and funchon afte~ a ~etra~.ted ~',- chaemla A t ( h lnt Phalma(~d~n 7her 260 218-229 1982

18 Le Poncm-Lafi t te , M , 1 Rapm and J R Rapm [ ' | iec ls ol ginkgo bdoba on changes reduced by quant l ta t l , e celebral ml- ~.roembohzahon m rats 41~ tt hit Phtttnta( ¢~11~ tl 7her 243 236- 244 1980

19 Me)e r J S xt Shmohara T Kanda ~ l~ukuuchl, A D EHcsson and N K Kok DlaschlsJs Jesultmg trom acute umlat- eral cerebral infarction At¢h N e m o l 23 241 19711

20 Passero S N BattlStm~ and C Fteschl Platelet embohsm m rabbit brain Stp~d,e 12 781-786, [981

21 Siegel B A , R Meldmgel A J Elhott, R btuder C Curus J Mmgan and J Potchen E×penmenta l cerebral m~croembohsm Multiple tracer a ssessment ot brain edema ,4#c It "~(,it#,;l 26 73-77 1972

22 Uzunova A D E R Ramey and P W Ramwell Ara~.h|donate-lndu~.ed thrombo~,lS m mice Elfe~.ts of gender or tes tos terone and estrad~ol adm|mstra tJon Pt¢~slt¢~l~lll~lttt~ 13 995-101)2 [977

23 Vise W M [ Schmer , K - A H o s s m a n n S T a k a g J a n d K J Zulch Cerebral m~croembohzat~on 1 Pathophys~olog~cal studle ~, Al(/ t Netool 34 660-665 1977

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