Research in

Res Exp Med (1991) 191 : 371-378

ExperimentalMedicine @ Springer-Verlag 1991

Comparative protective effects of vinconate, baclofen, and pentobarbital against neuronal damage following repeated brief cerebral ischemia in the gerbil brain T. Araki, H. Kato, and K.Kogure Department of Neurology, Institute of Brain Diseases, Tohoku University, School of Medicine, Sendal, Japan Received February 8, 1991 / accepted July 8, 1991

Summary. We investigated the neuroprotective effects of vinconate (a vinca alkaloid derivative), baclofen (a GABAB receptor agonist), or pentobarbital (a GABAA receptor-effector) on neuronal damage following repeated brief cerebral ischemia in the gerbils. The animals were allowed to survive for 7 days after two or three 2-rain ischemic insults induced by bilateral occlusion of the common carotid arteries. Morphological changes were evaluated in hippocampal CA1 sector and selectively vulnerable areas after two or three 2-min ischemic insults at i-h intervals, respectively. Pretreatment with vinconate significantly reduced histopathological neuronal damage to the hippocampal CA1 sector following two 2-rain ischemic insults. However, pretreatment with baclofen and pentobarbital failed to prevent neuronal damage. Pretreatment with vinconate also prevented neuronal damage to the frontal cortex, parietal cortex, and striatum following three 2-rain ischemic insults. Nevertheless, this drug failed to prevent neuronal damage to the hippocampal CA1 sector and the thalamus. Results suggest that vinconate, a vica alkaloid derivative, can prevent neuronal damage after repeated brief cerebral ischemia, but not GABAergic agents, such as baclofen and pentobarbital. These findings are of interest in relation to the mechanisms of neuronal damage induced by repeated brief cerebral ischemia.

Key words: Cerebral ischemia - Repeated ischemia - Selective vulnerability Vinca alkaloid - GABAergic agent - Gerbil Introduction A recently developed model of repeated cerebral ischemia in gerbil has a unique feature [4, 12, 231. Brief but non-lethal cerebral ischemia produces severe neuronal injury in the selectively vulnerable regions if the insult is induced repeatedOffprint requests" to: T. Araki

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ly at c e r t a i n intervals. T w o - r a i n i s c h e m i a induces no m o r p h o l o g i c a l b r a i n d a m age, w h e r e a s 2, 3, or 5 r e p e a t e d 2-rain ischemic insults at 1-h i n t e r v a l s cause n e u r o n a l d a m a g e in the selectively v u l n e r a b l e r e g i o n s , the s e v e r i t y b e i n g d e p e n d e n t on the n u m b e r o f e p i s o d e s . H o w e v e r , the n e u r o n a l d a m a g e is m o s t s e v e r e w h e n n o n - l e t h a l i s c h e m i a (2-rain i s c h e m i a ) is r e p e a t e d at 1-h i n t e r v a l s a n d is relatively m i l d w h e n the ischemic insult is i n d u c e d r e p e a t e d l y at s h o r t e r o r l o n g e r i n t e r v a l s [12]. T h e s e o b s e r v a t i o n s suggest t h a t the i n t e r v a l s a n d e p i s o d e s o f ische m i c insult p l a y an i m p o r t a n t f a c t o r on ischemic b r a i n d a m a g e . W e r e c e n t l y f o u n d that b r i e f a n d n o n - l e t h a l t r a n s i e n t i s c h e m i a causes a sev e r e i m p a i r m e n t o f p r o t e i n synthesis in selective v u l n e r a b l e a r e a s [3]. I n h i b i t i o n is e s p e c i a l l y f o u n d at an e a r l y stage of r e c i r c u l a t i o n after ischemia. F u r t h e r m o r e , we also r e p o r t e d that c o n s p i c u o u s c e r e b r a l b l o o d flow c h a n g e s a n d h y p o p e r f u sion t a k e p l a c e e v e n after n o n - l e t h a l t r a n s i e n t i s c h e m i a [14]. T h e s e o b s e r v a t i o n s s e e m to suggest t h a t e v e n a b r i e f ischemic insult causes m e t a b o l i c a l t e r a t i o n after i s c h e m i a , a n d the s u c c e e d i n g insult m a y injure the brain. H o w e v e r , the m e c h a nisms o f the c u m m u l a t i v e effect o f r e p e a t e d i s c h e m i a a r e n o t fully u n d e r s t o o d . W e , t h e r e f o r e , e x a m i n e d the effect of 7 - a m i n o b u t y r i c acid ( G A B A ) - e r g i c agents, such as b a c l o f e n (a G A B A B r e c e p t o r a g o n i s t ) , p e n t o b a r b i t a l (a G A B A A r e c e p t o r - e f f e c t o r ) , a n d v i n c o n a t e (a vinca a l k a l o i d d e r i v a t i v e ) , which are k n o w n for p r e v e n t i n g h i p p o c a m p a l d a m a g e after t r a n s i e n t 5-rain i s c h e m i a [1, 17, 22], on the n e u r o n a l d a m a g e following r e p e a t e d c e r e b r a l ischemia.

Materials and methods Male adult Mongolian gerbils weighing 60-95 g were used. They were anesthetized with 2% halothane in a mixture of 30% 02 and 70% N20. Bilateral common carotid arteries were exposed and anesthesia was discontinued to minimize the effect of the anesthesia. About 3 min later, when the animals showed no spontaneous movement, but twitched if pain stimuli were given, the arteries were occluded with aneurysmal clips for 2 min. Two or three occlusions were repeated at 1-h intervals. After occlusion, the clips were removed and the ischemic animals were allowed to survive for 7 days. Sham-operated animals were treated in the same manner except for clipping the bilateral common carotid arteries. Animals were kept on a heating pad with thermostat and rectal temperature was monitored in all cases. As described below, animals that were treated with baclofen and pentobarbital were warmed using a heating pad and a lamp so that the rectal temperature was comparable to that in the vehicle-treated group.

Experiment 1 A total of 40 animals were divided into six groups containing six to eight gerbils for two 2-min ischemic-insult studies. Group 1: baclofen in a dose of 25mg/kg was administered intraperitoneally (i.p.) 5 rain before first ischemic insult. Group 2: pentobarbital in a dose of 40 mg/ kg was administered i.p. 30 min before first ischemic insult. Group 3: vehicle (distilled water) was administered i.p. 30 min before first ischemic insult. Group 4: vinconate in a dose of 50 mg/ kg was administered i.p. 10min before each ischemic insult. Group 5: vinconate in a dose of 100 mg/kg was administered i.p. 10 min before each ischemic insult. Group 6: vehicle (distilled water) was administered i.p. 10 rain before each ischemic insult.

Experiment 2 A total of 30 animals were divided into 4 groups containing six to eight animals for three 2-min ischemic-insults study. Group 1: vinconate in a dose of 50 mg/kg was administered i.p. 10 rain before each ischemic insult. Group 2: vinconate in a dose of 100 mg/kg i.p. was administered

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10min before each ischemic insult. Group 3: vehicle (distilled water) was administered i.p. 10 min before each ischemic insult. Group 4: the remaining 6 animals were used as a sham-operated group for repeated ischemic-insult studies.

Histopathology Animals were anesthetized with pentobarbital 50mg/kg i.p. at 7 days of survival. They were briefly perfused with heparinized saline by transcardiac perfusion followed by perfusion-fixation with FAM (37% formaldehyde, glacial acetic acid, methanol; 1:1:8) for 20min. The brains were removed and were immersed in the same fixative until they were embedded in paraffin. Paraffin sections 5-1amthick were stained with hematoxylin-eosin and cresyl violet. Stained sections were examined with a light microscope, and ischemic neuronal damage was graded on a semiquantitative scale; 0: normal, h a few neurons damaged (up to 10% damaged), 2: many neurons damaged (up to 50% damaged), and 3: majority of neurons damaged (more than 50% damaged) according to the method of Pulsinelli et al. [20]. Statistical comparisons of the histological data were made with the two-tailed Mann-Whitney U-test; rectal temperature data were compared with the Student's non-paired t-test. For statistical analysis, each brain was treated separately according to our reports [3, 4, 6, 7].

Results Behavioral status V e h i c l e - t r e a t e d gerbils subjected to two 2 - m i n a n d three 2 - m i n ischemic insults s q u a t t e d w i t h o u t m o v i n g their limbs for 5 m i n a n d 1 h, respectively. B e h a v i o r of v i n c o n a t e - t r e a t e d a n i m a l s a p p e a r e d the same as the v e h i c l e - t r e a t e d group. O n the o t h e r h a n d , b a c l o f e n - t r e a t e d a n d p e n t o b a r b i t a l - t r e a t e d a n i m a l s did n o t start m o v i n g u n t i l 2 - 4 h after ischemic insults. R e c t a l t e m p e r a t u r e of the a n i m a l s is s h o w n in T a b l e s 1 a n d 2. T h e rectal t e m p e r a t u r e i n c r e a s e d b y 0 . 8 - 1 . I ~ following the first ischemic insult in the vehiclet r e a t e d g r o u p for the two 2 - m i n ischemic-insults study. T e m p e r a t u r e of baclof e n - t r e a t e d a n d p e n t o b a r b i t a l - t r e a t e d a n i m a l s whose b e h a v i o r was d e p r e s s e d was, due to w a r m i n g , n o t statistically different from that of the v e h i c l e - l - t r e a t e d animals. F u r t h e r m o r e , the t e m p e r a t u r e of v i n c o n a t e - t r e a t e d a n i m a l s was also

Table 1. Rectal temperature (~

of the animals following two 2-min ischemic insults

Dose (mg/k g, i.p.)

n

Before first ischemia

Before second ischemia

Sham-operated

-

6

37.1 + 0.1

37.4 + 0.1"*

Vehicle (1) Baclofen Pentobarbital

25 40

8 7 7

37.3 + 0,1 37.2 + 0.2 37.2 + 0.2

38.1 + 0.3 38.8 + 0.2 38.6 + 0.3

50 100

6 6 6

37.6 + 0,2 37.5 + 0.3 37.7 _+0.3

38.7 + 0.3 38.5 _+0.1 38.2 + 0.2

Vehicle (2) Vinconate

Values are expressed as means + SEM n = nnmber of animals ** P < 0.01 as compared to vehicle-2-treated group (Student's non-paired t-test)

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T. Araki et al.

Table 2. Rectal temperature (~

of the gerbils following three 2-min ischemic insults

Dose n (mg/kg, i.p.) Sham-operated Vehicle Vinconate

Before first ischemia

Before second ischemia

Before third ischemia

-

6

37.1 +- 0.1

37.4 +- 0.1"*

37.4 +- 0.1"*

50 100

8 8 8

37.1 _+0.1 36.9 + 0.1 37.0+_0.1

38.3 + 0.2 38.0 + 0.1 37.9+_0.2

38.2 _+0.1 37.8 _+0.1 37.8+_0.1

Values are expressed as means _+ SEM n = number of animals ** P < 0.01 as compared to vehicle-treated group (Student's non-paired t-test)

Table 3. Neuronal damage to the hippocampal CA1 sector following two 2-min ischemic insults Dose (mg/kg, i.p.)

Neuronal damage

Sham-operated

-

0.0 _+0.0"*

Vehicle (1) Baclofen Pentobarbital

25 40

2.6 _+0.1 3.0 +_0.0 3.0 + 0.0

50 100

3.0 _+0.0 2.2 _+0.4 1.8 _+0.4*

Vehicle (2) Vinconate

Values are expressed as means + SEM n = 12-16 hemispheres * P < 0.05 as compared to vehicle-2-treated group; ** P < 0.01 as compared to vehicle-I- and vehicle-2-treated groups (Mann-Whitney U-test). Neuronal damage was graded 0-3

n o t statistically different f r o m that of the vehicle-2-treated animals. F o r the t h r e e 2 - m i n ischemic-insults study, the t e m p e r a t u r e increased by 1 . 1 - 1 . 2 ~ following the first ischemic insult in the v e h i c l e - t r e a t e d group. T h e t e m p e r a t u r e of v i n c o n a t e - t r e a t e d gerbils was n o t statistically different from that of the vehiclet r e a t e d animals. I n a d d i t i o n , the increase of rectal t e m p e r a t u r e was n o t observed in s h a m - o p e r a t e d a n i m a l s t h r o u g h o u t the e x p e r i m e n t .

Histopathology N e u r o n a l d a m a g e to the h i p p o c a m p a l C A 1 sector following two 2 - m i n ischemic insults is p r e s e n t e d in T a b l e 3. G e r b i l s s u b j e c t e d to two ischemic insults r e v e a l e d severe n e u r o n a l d a m a g e in the h i p p o c a m p a l CA1 sector. V i n c o n a t e showed protective effects against h i p p o c a m p a l d a m a g e in a d o s e - d e p e n d e n t m a n n e r . Especially, at a dose of 100 mg/kg of v i n c o n a t e , the n e u r o n a l d a m a g e was significantly less t h a n that in the vehicle-2-treated group. H o w e v e r , b a c l o f e n a n d p e n t o b a r b i t a l failed to p r e v e n t h i p p o c a m p a l d a m a g e . D i s t r i b u t i o n s of b r a i n d a m a g e following three 2-rain ischemic insults are pres e n t e d in T a b l e 4, G e r b i l s s u b j e c t e d to three ischemic insults r e v e a l e d severe

375

Repeated ischemia and drugs Table 4. Distributions of brain damage following three 2-min ischemic insults

Regions

Neuronal damage Sham-operated

Frontal cortex Striatum Hippocampal CA1 sector Thalamus Parietal cortex

0.0 + 0.0"* 0.0 _+0.0** 0.0 _+0.0** 0.0 _+0.0"* 0.0 _+0.0"*

Vehicle 1.6 _+0.2 2.0 _+0.1 3.0 + 0.0 2.1 + 0.1 1.4 _+0.2

Vinconate 50 mg/kg

100 mg/kg

1.0 _+0.2* 2.3 + 0.1 3.0 _+0.0 2.1 + 0.1 0.7 + 0.3*

0.3 -+ 0.2** 1.4 + 0.2* 2.9 _+0.3 2.0 + 0.1 0.3 _+0.1"*

Values are expressed as means + SEM n = 12-16 hemispheres * P < 0.05; ** P < 0.01 as compared to vehicle-treated group (Mann-Whitney U-test). Neuronal damage was graded 0-3

neuronal damage in the brain. The most frequently affected regions were the hippocampal CA1 sector, thalamus, and dorsolateral part of the striatum, followed by the frontal cortex and the parietal cortex. Administration of vinconate significantly reduced neuronal damage to the frontal and the parietal cortexes in a dose-related manner. In the striatum, the protective effect of vinconate was significant only at the higher dose. However, protection against the hippocampal CA1 sector and the thalamus was not observed in vinconate-treated animals (data not shown).

Discussion

The vulnerability of nerve cells in response to ischemia differs considerably among the different populations in the central nervous system. It is evident that neurons in certain regions, such as neocortex, striatum, hippocampus, and thalamus, are selectively vulnerable to transient cerebral ischemia [2, 10, 18, 20]. Interestingly, recent evidence suggests that repeated cerebral ischemia has a cumulative effect, because neuronal damage is greater following three episodes of 5-rain ischemia at 1-h intervals in the gerbil than 15-min ischemia produced as a single insult [23]. We recently found that non-lethal cerebral ischemia produces neuronal damage in the selectively vulnerable areas when the insult is induced repeatedly at a certain interval [4, 13]. The present study also suggests that repeated non-lethal ischemic insults can produce severe neuronal damage in selective vulnerable regions when it is induced repeatedly at 1-h intervals. These patterns of neuronal damage after two 2-min and three 2-min ischemic insults are essentially the same as those following single 5- and 10-min ischemia in the gerbil, respectively. However, little is known about the action of drugs against neuronal damage following non-lethal but repeated cerebral ischemia. Vinca alkaloids are known to prevent hippocampal damage after transient ischemia in the gerbil [1]. These drugs also have a mild calcium antagonistic action [16], and increase cerebral metabolism and circulation [15]. Furthermore, vinca alkaloids reportedly increase the intracerebral adenosine level after ischemia and prevents hippocampal damage in the rat model [21]. Moreover, these

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drugs increase the turnover of noradrenaline in the brain [19]. Thus, vinca alkaloids are expected to have beneficial effects in cerebrovascular insufficiency. Vinconate, a new vinca alkaloid derivative, easily penetrates the blood-blain barrier and distributes in the gerbil brain [6]. This drug is also known to partly prevent neuronal damage to selective vulnerable areas after transient ischemia in the gerbil [6]. Baclofen and pentobarbital are well known to protect against ischemic hippocampal damage after transient ischemia [17, 22]. Baclofen is a selective GABA~ receptor agonist, and the protective effect of this drug is thought to be mediated by modifing both calcium uptake and the release of an excitatory neurotransmitter, such as glutamate [22]. Pentobarbital is a GABAA receptor-effector. The beneficial effect of pentobarbital is thought to be mediated by a powerful sedative action on the central nervous system or by opening the chloride ionophore channel and enhancing GABAA- and benzodiazepine-receptot bindings [22]. We have recently demonstrated that pentobarbital can partly offer neuronal protection of selective vulnerable areas after transient ischemia [5]. From this observation, we have also reported that transient ischemia-induced neuronal damage of selective vulnerable areas, such as the neocortex, striatum, and hippocampus, may be partly caused by an imbalance between excitatory and inhibitory input. The present study demonstrated that vinconate can partly prevent hippocampal damage after two 2-min ischemic insults. However, baclofen and pentobarbital were not protective. This suggests that the protective effects of GABAergic agents, such as baclofen and pentobarbital, may be less than that of vinconate. Although the reason for this is presently unclear, the mechanism of the cumulative effect of non-lethal repeated ischemia may be at least in part different from that of transient ischemia. We recently found that a severe impairment of protein synthesis and hypoperfusion in selective vulnerable areas takes place at an early stage of recirculation after non-lethal ischemic insult [3, 14]. These observations seem to suggest that even a brief non-lethal ischemic insult may cause more severe metabolic alteration than that of transient ischemia when non-lethal ischemic insult is induced repeatedly at 1-h intervals. Therefore, the disturbance of cerebral metabolism may play an important role in the cumulative effect of repeated ischemia. The present study also demonstrated that vinconate can partly prevent mild neuronal damage of selective vulnerable regions, such as the neocortex and the striatum, after three 2-rain ischemic insults. However, this drug failed to prevent damage to the hippocampal CA1 sector and the thalamus. For this reason it is conceivable that the protective effect of vinconate was not observed in the hippocampal CA1 sector and the thalamus, which are most vulnerable to repeated ischemic insults under the present experimental conditions, probably because the ischemic insults in these regions were too severe. In fact, the thalamic neuronal damage following three ischemic insults seems to be more severe than that after transient 10-min ischemia in the present study. This phenomenon is consistent with a previous report [11]. It is well known that hypothermia can protect ischemic neuronal damage in the gerbil [8, 9, 24]. Therefore, thermal control becomes important for evaluating drugs effects on ischemic neuronal damage. In the present study, there was no statistical different between rectal temperature in the vehicle-treated group and that in the vinconate-treated group throughout the experiment. This suggests that the neuroprotective effect of vinconate does not occur through hypo-

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377

thermia. In addition, rectal t e m p e r a t u r e increased by approximately 1~ after the first ischemic insult in the vehicle-treated groups. Increase of rectal t e m p e r ature m a y be caused by the action of ischemia on the central nervous system, because such an increase was not f o u n d in the s h a m - o p e r a t e d animals u n d e r same experimental conditions [5]. In conclusion, the results indicate that vinconate can partly prevent hippocampal d a m a g e after two 2-min ischemic insults, but not G A B A e r g i c agents, such as baclofen and pentobarbital. F u r t h e r m o r e , results suggest that vinconate can partly offer n e u r o n a l protection of the n e o c o r t e x and striatum after three 2min ischemic insults, but that it c a n n o t prevent d a m a g e to the h i p p o c a m p a l C A 1 sector and the thalamus. A l t h o u g h the mechanisms of the vinconate neuroprotective effect against n e u r o n a l d a m a g e after r e p e a t e d non-lethal ischemia are presently unclear, our results suggest that the disturbance of cerebral m e t a b o lism m a y also play a role in developing neuronal d a m a g e following repeated ischemia. F u r t h e r drug studies should be p e r f o r m e d to investigate the detailed mechanisms of n e u r o n a l d a m a g e induced by r e p e a t e d non-lethal ischemic insults.

References 1. Araki T, Kogure K (1989) Prevention of delayed neuronal death in gerbil hippocampus by a novel vinca alkaloid derivative (vinconate). Mol Chem Neuropathol 11:33-43 2. Araki T, Kato H, Kogure K (1989) Selective neuronal vulnerability following transient cerebral ischemia in the gerbil: distribution and time course. Acta Neurol Scand 80:548-553 3. Araki T, Kato H, Inoue T, Kogure K (1990) Regional impairment of protein synthesis following brief cerebral ischemia in the gerbil. Acta Neuropathol 79 : 501-505 4. Araki T, Kato H, Kogure K (1990) Neuronal damage and calcium accumulation following repeated brief cerebral ischemia in the gerbil. Brain Res 528:114-122 5. Araki T, Kato H, Kogure K, Inoue T (1990) Regional neuroprotective effects of pentobarbital on ischemia-induced brain damage. Brain Res Bull 25 : 861-865 6. Araki T, Kogure K, Murakami M (1991) Prevention of abnormal calcium accumulation in postischemic gerbil brain by vinconate. Acta Neurol Scand 83 : 155-160 7. Araki T, Kato H, Hara H, Kogure K (1991) Postischemic alteration of [3H]forskolin binding sites in selectively vulnerable areas: an autoradiographic study of gerbil brain. Neurosci Lett 125 : 159-162 8. Buchan A, Pulsinelli WA (1990) Hypothermia but not the N-Methyl-D-aspartate antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J Neurosci 10 : 311-316 9. Corbett D, Evans S, Thomas C, Wang D, Jonas RA (1990) MK-801 reduced cerebral ischemic injury by inducing hypothermia. Brain Res 514 : 300-304 10. Crain B J, Westerkam WD, Harrison AH, Nadler JV (1988) Selective neuronal death after transient forebrain ischemia in the Mongolian gerbil: a silver impregnation study, Neuroscience 27 : 387-402 11. Ikeda J, Nagashima G, Nowak TS, Mies G, Joo F, Xu S, Lohr J, Ruetzler C, Wagner HG, Klatzo I (1989) Observations on accumulation of calcium in gerbils subjected to cerebral ischemia. In: Krieglstein J (ed) Pharmacology of cerebral ischemia 1988. Proceedings of the Second International Symposium on Pharmacology of Cerebral Ischemia, CRC Press, Florida, pp 37-44 12. Kato H, Kogure K (1990) Neuronal damage following non-lethal but repeated cerebral ischemia in the gerbil. Acta Neuropathol 79 : 494-500 13. Kato H, Kogure K, Nakano S (1989) Neuronal damage following repeated brief ischemia in the gerbil. Brain Res 479 : 366-370 14. Kato H, Araki T, Kogure K, Murakami M, Uemura K (1990) Sequential cerebral blood flow changes during and after nonlethal cerebral ischemia in gerbils. Stroke 21 : 1346-1349

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15. KSrp~ti E, Szporny L (1976) General and cerebral haemodynamic activity of ethy apovincaminate. Arzneimittelforschung 26:1908-1912 16. Katsuragi T, Ohba M, Mori R, Kushiku K, Furukawa T (1984) Calcium antagonistic action involved in vasodilation by brovincamine. Gen Pharmacol 15:43-45 17. Kirino T, Tamura A, Sano K (1986) A reversible type of neuronal injury follwing ischemia in the gerbil hippocampus. Stroke 17:455-459 18. Kitagawa K, Matsumoto M, Ninobe M, Mikoshiba K, Hata R, Ueda H, Handa N, Fukunaga R, Isaka Y, Kimura K, Kamada T (1989) Microtuble-associated protein 2 as a sensitive marker for cerebral ischemic damage-immunohistochemical investigation of dendritic damage. Neuroscience 31:401-411 19. Olpe HR, Steinmann MW (1982) The effects of vincamine, hydrgine and piracetam on firing rate of locus coeruleus neurons. J Neural Transm 55 : 101-109 20. Pulsinelli WA, Brierley JB, Plum F (1982) Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11:491-498 21. Sauer D, Rischke R, Beck T, Rogberg C, Mennel HD. Bielenberg GW, Krieglstein J (1988) Vinpocetine prevents ischemic cell damage in rat hippocampus. Life Sci 43 : 17331739 22. Sternau LL, Lust WD, Ricci AJ, Racheson R (1989) Role for 7-aminobutyric acid in selective vulnerability in gerbils. Stroke 20 : 281-287 23. Tomida S, Nowak TS, Vass K, Lohr JM, Klatzo I (1987) Experimental model for repetitive ischemic attacks in the gerbil: the cumulative effect of repeated ischemic insults. J Cereb Blood Flow Metab 7 : 773-782 24. Welsh FA, Sims RE, Harris VA (1990) Mild hypothermia prevents ischemic injury in gerbil hippocampus. J Cereb Blood Flow Metab 10:557-563

Comparative protective effects of vinconate, baclofen, and pentobarbital against neuronal damage following repeated brief cerebral ischemia in the gerbil brain.

We investigated the neuroprotective effects of vinconate (a vinca alkaloid derivative), baclofen (a GABAB receptor agonist), or pentobarbital (a GABAA...
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