- Email: [email protected]
A novel action of antidepressants: Effects on the regeneration of central catecholaminergic axons
$38
H O M O T O P I C A L GRAFTING OF E M B R Y O N I C H E M I C E R E B E L L U M IN C E R E B E L L E C T O M I Z E D N E O N A T A L RATS. SABURO KAWAGUCHI, M I Y A H I K O MURATA*, AND Y A S U O KURIMOTO*, D e p a r t m e n t of Integrative Brain Science, Faculty of Medicine, Kyoto University, Kyoto 606, Japan. In neonatal rats, under ether anesthesia, the h e m i c e r e b e l l u m or w h o l e cerebellum was r e m o v e d by suction and the e m b r y o n i c h e m i c e r e b e l l u m or h e m i c e r e b e l l a w e r e grafted into the vacant place homotopically. The graft was prepared in a conventional m a n n e r from fetuses taken from pregnant rats under deep p e n t o b a r b i t a l anesthesia. The m a j o r i t y of the grafts w e r e absorbed completely, but some survived and g r e w h o m o t o p i c a l l y or heterotopically. The h e t e r o t o p i c a l l y g r o w n grafts w e r e small, d i s o r g a n i z e d in cytoarchitecture, and d e m a r c a t e d f r o m the host b r a i n s t e m in w h i c h neurons of the p r e c e r e b e l l a r nuclei w e r e a l m o s t c o m p l e t e l y lost. By contrast, the h o m o t o p i c a l l y g r o w n grafts, m a r k e d l y larger than the h e t e r o t o p i c a l l y g r o w n ones, s h o w e d normal c y t o a r c h i t e c t u r e in the cortex and deep nuclei, and f o r m e d the c e r e b e l l a r peduncle united w i t h the host b r a i n s t e m in w h i c h neurons of the precerebellar nuclei w e r e well preserved. In cases g r a f t e d w i t h the h e m i c e r e b e l l u m after h e m i c e r e b e l l e c t o m y , the graft w a s also united w i t h the host h e m i c e r e b e l l u m w i t h o u t any boundary. In contrast to years of p e s s i m i s m about the failure of m a m m a l i a n central neurons to regenerate, the present results indicate the p r e s e n c e of their e n o r m o u s p o t e n t i a l i t y of r e g r o w t h and self-organization, and the p o s s i b i l i t y of r e c o n s t r u c t i o n of central neural connections on a large scale.
E F F E C T OF IL-6 ON D E V E L O P M E N T OF GRAFTED D O P A M I N E R G I C CELLS AND R E C O V E R Y OF FIOTOR DISTURBANCES. HITO0 NISttINO, TAKESHI HASttITANI, MICttlKO KUMAZAKI, FUJIYA FURUYAb~, Q I A N M I N G LI, Y U K I 0 A K I Y A ~ " AND KUNIO TORII', D e p a r t m e n t o f P h y s i o l o g y , N a g o y a City U n l v e r s l t x M e d i c a l School, Mlzuho-cho, Mlzuho-ku, Nagoya 467 and Central Research Laboratories, A J l n o m o t o Co. Inc., Suzukl-cho, Kawasaki-ku, Kawasakl 210, Japan. To c l a r l f y the effect of IL-6 on neuronal system in vlvo, we a p p l i e d IL-6 into the suspensions of g r a f t i n g dopamlnerglc cells and examined their d e v e l o p m e n t and functional recovery. Midbraln d o p a m l n e r g l c cells from fetal rats (E14-16) were made into cell suspensions (cell density, 107 cells/ml) enzymatlcally. They (i0 ~ i ) were grafted into u n i l a t e r a l l y d o p a m l n e - d e n e r v a t e d s t r l a t u m In h e m l - P a r k l n s o n l a n model rats. Development of the grafted cells was examined b y tyroslne hydroxylase (TII) I m m u n o h l s t o l 0 g y and motor recovery by the decrease of m e t h a m p h e t a m l n e rotations. IL-6 was added into the suspensions (3-60 ng/ml) In IL-6 treated rats. IL-6 treated rats showed much less rotations than control rats in the 2nd week after grafting. In IL-6 treated rats, n e u r l t e s of Tll-posltlve cells In the grafted area had more extensive a r b o l l z a t l o n s and denser v a r l c o s l t l e s than those of controls. These effects were blocked by s i m u l t a n e o u s treatment with anti- IL-6 antibody. The results suggest that IL-6 has a stlmulatory e f f e c t on d e v e l o p m e n t and d i f f e r e n t i a t i o n of grafted dopamlnergic cells. This might be a basis of facilitation in motor recovery. "
A NOVEL ACTION OF ANTIDEPRESSANTS: EFFECTS ON THE REGENERATION OF CENTRAL CATECHOLAMINERGIC AXONS. SHOJI NAKAMURA, Department of Physiology, Faculty of Medicine, Kanazawa University, Takara-machi 13-I, Kanazawa 920, Japan. The mechanism of the clinical efficacy of antidepressant drugs is unknown.
We found that
antidepressants such as maprotiline, desipramine and mianserin induce axonal regeneration of central catecholaminergic neurons.
Female Sprague-Dawley rats, 8-16 weeks of age, were used.
hydrate anesthesia (350-400
mg/kg), symmetrical conical sites of two hemispheres were pretreated with
6-hydroxydopamine (6-OHDA).
Under chloral
One to 2 weeks after the 6-OHDA pretreatment, the same cortical site of one
hemisphere was continuously infused with the antidepressants (1 mM) with an osmotic minipump, and the corresponding site of the other side with saline. infusion,
a
number
of
glyoxylic
acid-induced
After more than 2 weeks from the start of drug
fluorescent
catecholamine
fibers
appeared
antidepressant-infused cortex, whereas the cortex infused with saline remained denervated. indicate that brain.
antidepressants induce axonal
regeneration of catecholaminergic neurons in
in
the
The findings the
mature
H O M O T O P I C A L GRAFTING OF E M B R Y O N I C H E M I C E R E B E L L U M IN C E R E B E L L E C T O M I Z E D N E O N A T A L RATS. SABURO KAWAGUCHI, M I Y A H I K O MURATA*, AND Y A S U O KURIMOTO*, D e p a r t m e n t of Integrative Brain Science, Faculty of Medicine, Kyoto University, Kyoto 606, Japan. In neonatal rats, under ether anesthesia, the h e m i c e r e b e l l u m or w h o l e cerebellum was r e m o v e d by suction and the e m b r y o n i c h e m i c e r e b e l l u m or h e m i c e r e b e l l a w e r e grafted into the vacant place homotopically. The graft was prepared in a conventional m a n n e r from fetuses taken from pregnant rats under deep p e n t o b a r b i t a l anesthesia. The m a j o r i t y of the grafts w e r e absorbed completely, but some survived and g r e w h o m o t o p i c a l l y or heterotopically. The h e t e r o t o p i c a l l y g r o w n grafts w e r e small, d i s o r g a n i z e d in cytoarchitecture, and d e m a r c a t e d f r o m the host b r a i n s t e m in w h i c h neurons of the p r e c e r e b e l l a r nuclei w e r e a l m o s t c o m p l e t e l y lost. By contrast, the h o m o t o p i c a l l y g r o w n grafts, m a r k e d l y larger than the h e t e r o t o p i c a l l y g r o w n ones, s h o w e d normal c y t o a r c h i t e c t u r e in the cortex and deep nuclei, and f o r m e d the c e r e b e l l a r peduncle united w i t h the host b r a i n s t e m in w h i c h neurons of the precerebellar nuclei w e r e well preserved. In cases g r a f t e d w i t h the h e m i c e r e b e l l u m after h e m i c e r e b e l l e c t o m y , the graft w a s also united w i t h the host h e m i c e r e b e l l u m w i t h o u t any boundary. In contrast to years of p e s s i m i s m about the failure of m a m m a l i a n central neurons to regenerate, the present results indicate the p r e s e n c e of their e n o r m o u s p o t e n t i a l i t y of r e g r o w t h and self-organization, and the p o s s i b i l i t y of r e c o n s t r u c t i o n of central neural connections on a large scale.
E F F E C T OF IL-6 ON D E V E L O P M E N T OF GRAFTED D O P A M I N E R G I C CELLS AND R E C O V E R Y OF FIOTOR DISTURBANCES. HITO0 NISttINO, TAKESHI HASttITANI, MICttlKO KUMAZAKI, FUJIYA FURUYAb~, Q I A N M I N G LI, Y U K I 0 A K I Y A ~ " AND KUNIO TORII', D e p a r t m e n t o f P h y s i o l o g y , N a g o y a City U n l v e r s l t x M e d i c a l School, Mlzuho-cho, Mlzuho-ku, Nagoya 467 and Central Research Laboratories, A J l n o m o t o Co. Inc., Suzukl-cho, Kawasaki-ku, Kawasakl 210, Japan. To c l a r l f y the effect of IL-6 on neuronal system in vlvo, we a p p l i e d IL-6 into the suspensions of g r a f t i n g dopamlnerglc cells and examined their d e v e l o p m e n t and functional recovery. Midbraln d o p a m l n e r g l c cells from fetal rats (E14-16) were made into cell suspensions (cell density, 107 cells/ml) enzymatlcally. They (i0 ~ i ) were grafted into u n i l a t e r a l l y d o p a m l n e - d e n e r v a t e d s t r l a t u m In h e m l - P a r k l n s o n l a n model rats. Development of the grafted cells was examined b y tyroslne hydroxylase (TII) I m m u n o h l s t o l 0 g y and motor recovery by the decrease of m e t h a m p h e t a m l n e rotations. IL-6 was added into the suspensions (3-60 ng/ml) In IL-6 treated rats. IL-6 treated rats showed much less rotations than control rats in the 2nd week after grafting. In IL-6 treated rats, n e u r l t e s of Tll-posltlve cells In the grafted area had more extensive a r b o l l z a t l o n s and denser v a r l c o s l t l e s than those of controls. These effects were blocked by s i m u l t a n e o u s treatment with anti- IL-6 antibody. The results suggest that IL-6 has a stlmulatory e f f e c t on d e v e l o p m e n t and d i f f e r e n t i a t i o n of grafted dopamlnergic cells. This might be a basis of facilitation in motor recovery. "
A NOVEL ACTION OF ANTIDEPRESSANTS: EFFECTS ON THE REGENERATION OF CENTRAL CATECHOLAMINERGIC AXONS. SHOJI NAKAMURA, Department of Physiology, Faculty of Medicine, Kanazawa University, Takara-machi 13-I, Kanazawa 920, Japan. The mechanism of the clinical efficacy of antidepressant drugs is unknown.
We found that
antidepressants such as maprotiline, desipramine and mianserin induce axonal regeneration of central catecholaminergic neurons.
Female Sprague-Dawley rats, 8-16 weeks of age, were used.
hydrate anesthesia (350-400
mg/kg), symmetrical conical sites of two hemispheres were pretreated with
6-hydroxydopamine (6-OHDA).
Under chloral
One to 2 weeks after the 6-OHDA pretreatment, the same cortical site of one
hemisphere was continuously infused with the antidepressants (1 mM) with an osmotic minipump, and the corresponding site of the other side with saline. infusion,
a
number
of
glyoxylic
acid-induced
After more than 2 weeks from the start of drug
fluorescent
catecholamine
fibers
appeared
antidepressant-infused cortex, whereas the cortex infused with saline remained denervated. indicate that brain.
antidepressants induce axonal
regeneration of catecholaminergic neurons in
in
the
The findings the
mature