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The antiparkinsonian drug memantine interacts with NMDA-receptor channels
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66 NMDA RECEPTORS REGULATE BRAIN POLYAMINES DURING ISCHEMIA/RECIRCULATION Harold Koenig, Alfred D. Goldstone, Chung Y. Lu, Jerome J. Trout, VA Lakeside Medical Center & Northwestern University Medical School, Chicago, IL 60611 U.S.A. We found that NMDA receptors are coupled to ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine (PA) synthesis which converts ornithine to putrescine (PUT); PA in turn mediate NMDA-stimulated Ca 2+ fluxes & neurotransmitter release in synaptosomes, & excitotoxicity in chick embryo retina (Koenig et al., J. Neurochem. 52(Suppl.): $42, 1989; lqbal et al., ibid.). We studied the gerbil 2-vessel occlusion model of reversible forebrain ischemia. ODC activity & PUT increased 2-fold after 2-5 min of bilateral carotid occlusion, & returned to basal after 15 min of ischemia. Recirculation induced an immediate (
67 F O C A L C E R E B R A L I S C H E M I A IN A D U L T R A T S : E F F E C T S O F M O N O S I A L O G A N G L I O S I D E T. K o g a , M. S. S e r e n , A. L a z z a r o , N. S c h i a v o , R. Z a n o n i , S. M a z z a r i , G. T o f f a n o a n d A. L e o n , F i d i a R e s e a r c h L a b o r a t o r i e s , C N S D e p t . , 3 5 0 3 1 A b a n o T e r m e , Italy. In t h e e x p e r i m e n t a l m o d e l of rat m i d d l e c e r e b r a l a r t e r y o c c l u s i o n (MCAo) a c c o r d ing to T a m u r a , b o t h c o r t e x ( m a i n l y t h e p a r i e t a l p o r t i o n ) a n d s t r i a t u m a r e s e v e r e l y a f f e c t e d . U t i l i z i n g t h i s s a m e m o d e l , w e e v a l u a t e d t h e t e m p o r a l p r o f i l e of cortical and striatal infarction by monitoring edema, sodium and calcium accumul a t i o n as w e l l as loss of c h a r a c t e r i s t i c neurotransmitter-related parameters. E d e m a is e v i d e n t a l r e a d y at 3 h r s a f t e r i s c h e m i a w h i l s t c a l c i u m a n d s o d i u m a c c u mulation r e a c h e s m a x i m a l v a l u e s w i t h i n 24 hrs. T h e s e c h a n g e s a r e in t u r n a s s o c i a t e d w i t h loss of c h o l i n e a c e t y l t r a n s f e r a s e activity, thereby indicating occ u r r e n c e of n e u r o n a l c e l l d a m a g e . T h e l a t t e r is h i s t o l o g i c a l l y e v i d e n t a l r e a d y a f t e r 2 hrs. A l l t o g e t h e r t h e s e d a t a i n d i c a t e t h a t m e t a b o l i c a l t e r a t i o n s o c c u r at v e r y a c u t e s t a g e s a f t e r a f o c a l i s c h e m i c e p i s o d e . In t h i s s a m e m o d e l s y s t e m i c ganglioside administration, e.g. G M 1 (30 m g / k g p o s t - o p e r a t i v e l y ) , was efficac i o u s in r e d u c i n g b r a i n e d e m a as w e l l as c a l c i u m a c c u m u l a t i o n . T h e s e f i n d i n g s a r e c o m p a t i b l e w i t h the o b s e r v e d p r o t e c t i v e a c t i o n of g a n g l i o s i d e s following ischemic brain injury.
68 THE ANTIPARKINSONIAN DRUG MEMANTINE INTERACTS WITH NMDA-RECEPTOR CHANNELS Johannes Kornhuber, Joachim Bormann * and Peter Riederer: Department of Psychiatry, Unieersity of W~rzburg, 8700
W~rzbv.rg, F.R.G.; * Merz + Co. GmbH 8; Co, 6000 Frankfurt, F.R.G. Recently it has been suggested that NMDA antagonists might be useful in the treatment of Parkinson's disease (1). The present investigation demonstrates that the long known antiparkinson and antispastic substance memantine inhibits binding of [SH]MK-801 to postmortem human brain homogenates at therapeutic concentrations (2). Tissue from the frontal cortex was taken at autopsy from 3 subjects. Both. MK-801 and memantine completely inhibited [SH]MK-801 binding at 100/~M. In agreement with our eadier investigation (3). the displacement curves with MK-801 had Hill coefficients less than unity (0.424 + 0.033: mean ± SEM: n = 3) and were best fitted by assuming an interaction with two binding sites (K~x = 1.20 • 0.15 nM. K~2 = 10.10 ± 0.81 pM). On the other hand, the displacement curves produced by memantine had Hill coefficients near unity (0.911 + 0.059) and were best fitted using a one-site model. The Ki value of memantine was 0.536 :1:0.035 pM. which is below the brain concentration in the treatment of Parkinson's disease (about 2/~M)(4). This is in line with electrophysiological findings showing that memantine reduces NMDA-induced currents (5). Since the dopamioe-mimetic effects of memantine are weak. the present results provide an alternative explanation for the mechanism of action of memantine in the therapy of Parkinson's disease. 1. Olney et al, Eur J Pharmacol 142 (1987) 319; 2. Kornhuber et al, £ur J Pharmacol 166 (1989) 589; 3. Kornhuber et al. Eur J Pharmacol 162 (1989) 483: 4. Wesemann et al, J Neural Transm Suppl.16 (1980) 143: 5. Bormann, Eur J Pharmacol 166 (1989) 591
66 NMDA RECEPTORS REGULATE BRAIN POLYAMINES DURING ISCHEMIA/RECIRCULATION Harold Koenig, Alfred D. Goldstone, Chung Y. Lu, Jerome J. Trout, VA Lakeside Medical Center & Northwestern University Medical School, Chicago, IL 60611 U.S.A. We found that NMDA receptors are coupled to ornithine decarboxylase (ODC), the rate-limiting enzyme of polyamine (PA) synthesis which converts ornithine to putrescine (PUT); PA in turn mediate NMDA-stimulated Ca 2+ fluxes & neurotransmitter release in synaptosomes, & excitotoxicity in chick embryo retina (Koenig et al., J. Neurochem. 52(Suppl.): $42, 1989; lqbal et al., ibid.). We studied the gerbil 2-vessel occlusion model of reversible forebrain ischemia. ODC activity & PUT increased 2-fold after 2-5 min of bilateral carotid occlusion, & returned to basal after 15 min of ischemia. Recirculation induced an immediate (
67 F O C A L C E R E B R A L I S C H E M I A IN A D U L T R A T S : E F F E C T S O F M O N O S I A L O G A N G L I O S I D E T. K o g a , M. S. S e r e n , A. L a z z a r o , N. S c h i a v o , R. Z a n o n i , S. M a z z a r i , G. T o f f a n o a n d A. L e o n , F i d i a R e s e a r c h L a b o r a t o r i e s , C N S D e p t . , 3 5 0 3 1 A b a n o T e r m e , Italy. In t h e e x p e r i m e n t a l m o d e l of rat m i d d l e c e r e b r a l a r t e r y o c c l u s i o n (MCAo) a c c o r d ing to T a m u r a , b o t h c o r t e x ( m a i n l y t h e p a r i e t a l p o r t i o n ) a n d s t r i a t u m a r e s e v e r e l y a f f e c t e d . U t i l i z i n g t h i s s a m e m o d e l , w e e v a l u a t e d t h e t e m p o r a l p r o f i l e of cortical and striatal infarction by monitoring edema, sodium and calcium accumul a t i o n as w e l l as loss of c h a r a c t e r i s t i c neurotransmitter-related parameters. E d e m a is e v i d e n t a l r e a d y at 3 h r s a f t e r i s c h e m i a w h i l s t c a l c i u m a n d s o d i u m a c c u mulation r e a c h e s m a x i m a l v a l u e s w i t h i n 24 hrs. T h e s e c h a n g e s a r e in t u r n a s s o c i a t e d w i t h loss of c h o l i n e a c e t y l t r a n s f e r a s e activity, thereby indicating occ u r r e n c e of n e u r o n a l c e l l d a m a g e . T h e l a t t e r is h i s t o l o g i c a l l y e v i d e n t a l r e a d y a f t e r 2 hrs. A l l t o g e t h e r t h e s e d a t a i n d i c a t e t h a t m e t a b o l i c a l t e r a t i o n s o c c u r at v e r y a c u t e s t a g e s a f t e r a f o c a l i s c h e m i c e p i s o d e . In t h i s s a m e m o d e l s y s t e m i c ganglioside administration, e.g. G M 1 (30 m g / k g p o s t - o p e r a t i v e l y ) , was efficac i o u s in r e d u c i n g b r a i n e d e m a as w e l l as c a l c i u m a c c u m u l a t i o n . T h e s e f i n d i n g s a r e c o m p a t i b l e w i t h the o b s e r v e d p r o t e c t i v e a c t i o n of g a n g l i o s i d e s following ischemic brain injury.
68 THE ANTIPARKINSONIAN DRUG MEMANTINE INTERACTS WITH NMDA-RECEPTOR CHANNELS Johannes Kornhuber, Joachim Bormann * and Peter Riederer: Department of Psychiatry, Unieersity of W~rzburg, 8700
W~rzbv.rg, F.R.G.; * Merz + Co. GmbH 8; Co, 6000 Frankfurt, F.R.G. Recently it has been suggested that NMDA antagonists might be useful in the treatment of Parkinson's disease (1). The present investigation demonstrates that the long known antiparkinson and antispastic substance memantine inhibits binding of [SH]MK-801 to postmortem human brain homogenates at therapeutic concentrations (2). Tissue from the frontal cortex was taken at autopsy from 3 subjects. Both. MK-801 and memantine completely inhibited [SH]MK-801 binding at 100/~M. In agreement with our eadier investigation (3). the displacement curves with MK-801 had Hill coefficients less than unity (0.424 + 0.033: mean ± SEM: n = 3) and were best fitted by assuming an interaction with two binding sites (K~x = 1.20 • 0.15 nM. K~2 = 10.10 ± 0.81 pM). On the other hand, the displacement curves produced by memantine had Hill coefficients near unity (0.911 + 0.059) and were best fitted using a one-site model. The Ki value of memantine was 0.536 :1:0.035 pM. which is below the brain concentration in the treatment of Parkinson's disease (about 2/~M)(4). This is in line with electrophysiological findings showing that memantine reduces NMDA-induced currents (5). Since the dopamioe-mimetic effects of memantine are weak. the present results provide an alternative explanation for the mechanism of action of memantine in the therapy of Parkinson's disease. 1. Olney et al, Eur J Pharmacol 142 (1987) 319; 2. Kornhuber et al, £ur J Pharmacol 166 (1989) 589; 3. Kornhuber et al. Eur J Pharmacol 162 (1989) 483: 4. Wesemann et al, J Neural Transm Suppl.16 (1980) 143: 5. Bormann, Eur J Pharmacol 166 (1989) 591