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Influence of niacinamide administration on brain 5-HT and a possible mode of action
Life Sciences Vol . 11, Part I, pp . 189-195, 1972 . Printed to Great Britain
Pergamon Press
INFLIIENCE OF NIACINÀMIDE ADMINISTRATIOA OH BRAIN 5-HT AH,D. A POSSIBLE MODE OF ACTION Burkhard Scherer ~) and Yolf grämet Maz-Planck-Institut für Psychiatrie, gräpelinstrasee 2 München, Germany (Received 27 Septemtler 1971 ; in final form 7 January 1972) SZJIß'iARY The ability of some niacin compounds to inhibit the tryptophan-pyrrolase or to repress the de novo synthesis of this enzyme is ossibly responsible ~rt~ increase of brain 5-HT (1796 after aiacinamide administration . Sedation observed at the same time may be due to this 5-HT increase . Recently many investigations have been carried out to see xhether peripheral metabolism of tryptophan and tyrosine can influence the concentration of 5-hydroxytryptamine (5-HT) and catecholamines in brain.
To answer this question tryptophan-
pyrrolase(TP) has repeatedly been examined in the last years(4,5,8) .
Compounds like hydrocortisone and betamethasone
for instance induce TP(8,11,12,17), while other compounds are known to inhibit TP activity .
Allopurinol as well as some
niacin compounds belong to this inhibiting group(2,8) .
Madras
and Sovrkes(13) examined the effect of tryptophan analogues and a larger number of TP inhibitors on TP . A decrease of 5-HT levels in rat brain has been demonstrated after corticosteroid administration or stress-induced corticosteroid increase(4,8,12,17) .
However, Benkert and Matussek(1)
did not observe a decrease in 5-HT .
The corticosteroid induced
decrease of . 5-HT levels in brain could be prevented by allopurinol administration, while allopurinol alone did not 189
190
Effect od Niacinamide on Brain 5HT
Vol . il, No . 4
bring about any significant changes in 5-HT content(8) .
A aeries
of niacin compounds known to inhibit TP have been analysed and considerable quantitative differences were found(2) .
All
analyseà niacin compovnds,however, were capable of inhibiting TP ; the inhibition by NADH was over 80916 in vitro .
Investigations
regarding the influence of niacinamide compounds on 5-HT brain levels have not been carried out prior to these experiments.The question of interest is whether administration of niacin or niacin derivatives will result in an increased content of 5-HT in rat brain. Materials and Methods Male rats(Sprague-Dawley), weighing 140 - 20o g were housed iII
COm~+~T~A l
5-HT levels (14) .
cages for at least one week before experimentation.
in
brain were estimated according to Maickel et al .
TP activity was determined spectrophotometrically following
the procedure of Snox and Auerbach(11) .
All drugs were adminis-
tered i .p ., the given doses a.re indicated in the tables . animals were injected with saline of the same volume .
Control
F~periments
on the motilitymeter "Animex" were done according to Svensson and Thieme(18) . Results and Discussion No significant change in 5-HT content of rat brain could be found by examining a group of animals which had received NADH (78omg/kg) compared to animals which had only received saline (Table 1) .
This might be due to a higher activity of one or
more aldehyde dehydrogenasea in rat brain of which NADH is a coenzyme(6) .
This higher aldel~yde dehydrogenase activity could
lead to an increased 5-HT metabolism to 5-hydroayindoleacetaldehyde .We, therefore, analysed the effect of niacinamide administration alone .
We chose a dose(1g/kg) known to have
Effsct ad Niacinamide on Hraia 5HT
Yol . il, No. 4
191
TABLE 1 Influence of NADH on 5-HT in rat brain.Decapitatioa 6o min after i .p . injection. Treatment
5-HT in brain(ng/g tissue)
78o mg xADH/kg (n-5)
790 ± 70
saline
740 ± 70
(n-5)
a sedative effect on rata(1o,19) . A significant increase of 1796 in 5-HT level of the brain of niacinamide treated animals was found as compared to controls (Table 2) .
Sedation previously observed after niacinamide, was
TABLE 2 Influence of niacinamide on 5-HT in rat braia.Decapitation 6o min after i .p . injection. 5-HT in brain(ng/g tissue)
Treatment 1 g aiac ; nam; de/kg (n-10) saline ')
894 ± 80 `) 764 ± So
(n-8)
p < o .o1(statistics applied :U-test by Mann and Whitney)
confirmed by an Animex trial(18)(Fig.1) .
Animex trials were
carried out at night because of the higher motility of rats at this time .All other experiments took place between 9 and 11 a.m . . Animex trials during daytime looked similar to Fig . 1 but the difference between the niacinamide group and the control group was smaller . As Cho-Chung and Pitot(2,3) have shown, TP can be inhibited by niacin compounds .
A feed-back control of the TP pathway by
the physiological end-product niacin or niacinmononucleotide was
192
Effect od Niacinamide on Hrain 5HT
Vol . 11, No . 4
Impulses 1500
1000 -
500 -
r
1 .0~ Niacinamide/kg
i .p . injections 21
23
1
3
5
7
hrs
FIG . Sedation after i .p . injection of niacinamide compared with controls .
The ordinate shows the impulses/5 min as counted
by the motilitymeter Animex(18) .
proposed to be the cause .
Cho-Chung and Pitot postulated in
1967 that niacin binding to the regulatory site of the enzyme molecule leads to formation of a relative inactive enzyme . inhibition therefore would not be competitive .
The
Having shown
repressed de novo synthesis of TP in vivo after administration of niacinamide, Cho-Chung and Pitot postulated in 1968(3) that niacinamide may exert its inhibitory effect on tryptophan induced synthesis of TP at the level of genetic translation. A utilization of the accumulated tryptophan by other metabolic pathways
seems possible .
Recently the influence of niacinamide administration on
Vol. 11, No . 4
l~ect a~ Niacinamide on Hrain 5HT
193
urinary excretion of tryptophan metabolites in Hodgkin's disease of man was eaamined(16) . nine excretion.
Niacin leads to s decrease of i~ynure-
This result points to as in vivo inhibition
of TP or repressed de novo synthesis of TP by niacin . used were leas than those administered by us .
The doses
We chose a dose
which corresponded to the dose Cho-Chung and Pitot used in vitro . The dose applied by Cho-Chung and Pitot for thei.~ in vivo trials was much lower . There was no significant change in liver TP activity that could account for the increase in brain 5-HT(Table 3) "
On the
TABLE 3 Niacinamide administration and tryptophan pyrrolase activity . Treatment
Nmô~ë ~yn~ën3néTg ~issûé Decapitation 3o min , 6o min after ink .
1 g niacinamide/kg saline
3 .6±o .2(n-4)
3 .1±o .5(n~4)
3 .5±o .2(n=4)
3.7-o .5(n=4)
other hand it is possible that the injection stress induced corticosteroid secretion leading to TP induction.
Experiments with
adrenalectomized rats are planned to answer this question .
The
observed sedation(Fig .~) could be correlated with the observed 5-HT increase in brain.
A larger difference in animal motility,
however, could only be shown during the night, while the increase observed in 5-HT levels of rat brain took place during the day . Tryptophan-5-hydroxylase is usually assumed to be the rate limiting step of the over all metabolism of 5-HT(~) .
Nevertheless
Moir and Eccleston(~5) did point out that an elevation of approx imately 50 % in brain 5-HT could be observed after i .p . administration of 5o mg 1-tryptophaa/kg.
This would imply that an
increased hydrozylation by additional substrate supply is
ESect ad Niacinamide on Hrain 5HT
194 possible .
Vol . 11, No . 4
Aa increase of brain 5-HT by an additional tryptophan
supply appears therefore conceivable .
We believe that an inhibi-
tion of TP in vivo and (or) repressed de novo synthesis of TP (2,3) is the cause of the increase in 5-HT content of rat brain after niacinamide administration . How far the sedative effect and the repeatedly published therapeutic effect on psychosis(9,1o) can be based on an increased 5-HT formation should be studied by further analysis of the 5-HT turnover .
The doses applied by us to rats, in any
case are far above the doses given to man for therapeutical reasons. References 1.
SEN~RT,O .,N.MATUSSES, Nature 228 ,73(1970)
2.
CHO-CHIING,Y .S .,H .C .PITOT, J .biol .Chem 242 ,1192(1967)
3.
CHO-CIiUNG,Y .S .,H .C .PITOT, Europ.J .Biochem . ~ ,401(1968)
4.
CURZON,G .,A .R .GREEN, Br .J .Pharmac . ~ ,689(1969)
5.
CURZON,G .,P .K .BRIDGES, J.Neurol.Neurosur~ .Psychiat . ~ ,698 (19']0) -
6.
FELDSTEIN ,A .,O.WILLIAMSON, Br .J .Pharmac . ~4 ,38(1968)
7.
GARATTINI,S .,L.VALZELLI, Serotonin,Elsevier Publ .Comp. Amsterdam 1965
8.
GREEN,A.R .,G.CURZON, Nature 220 ,1095(1968)
9.
HOFFER ;A .,H .OSMOND,M.J .CALLBECH,J .KAHAN, J.clin .exp . Psychopathol . 18 ,131(1957)
10 .
SANIG,g., Wiesenach . Berichte 4 ,E .Merck,Darmstadt 1968
11 .
gPTO%,W .E .,J .AUERBACH, J .biol .Chem. 214, 307(1955)
12 .
BONONENKO,V.,O.M .ZRIAKOW,T .K .AONONENKO, Fiziol .Zh.(Kiev) 16~ 600(1970)
13 .
MADRAS,B .K .,Th .L .SOURKES, Biochem.Pharmacol . ~
14 .
MAICSELL,R .P .,R.H .CO%,J .SAILLANT,B .P .MILLER, -_ Int .J_,.Neurogharmacol . 7,275(1968)
103~(1968)
Vol . 11, No . 4
Effect cd Niacinamide on Brain 5HT
195
15 .
MOIR,A .T .B .,D.ECCLESTON, J.Neurochem . ~ ,1093(1968)
16 .
MUGGEO,M .,A.de ANTCNI,G .ALLEGRI,C .COSTA,G .CREPALDI Clia .chim~$~a ~o, 779(1970)
17 . '
SCAPAGNII~I U.,P.PREZIOSI,A .de 6CHAEPDRYER, Pharmac .Res .Comm. ~~ 63(1969j
18 .
SYENSSON,T .H .,G.THIEME, Psychopharm .(Berlin) 14, 157(1969)
19 .
woohESr,D.w ., science 12s, 1277(1958)
') Burkhard Scherer's present address : Institut für physiologische Chemie und physikalische Biochemie der Universität 8 München 2,Pettenkoferstrasse 14 a ,Germany
Pergamon Press
INFLIIENCE OF NIACINÀMIDE ADMINISTRATIOA OH BRAIN 5-HT AH,D. A POSSIBLE MODE OF ACTION Burkhard Scherer ~) and Yolf grämet Maz-Planck-Institut für Psychiatrie, gräpelinstrasee 2 München, Germany (Received 27 Septemtler 1971 ; in final form 7 January 1972) SZJIß'iARY The ability of some niacin compounds to inhibit the tryptophan-pyrrolase or to repress the de novo synthesis of this enzyme is ossibly responsible ~rt~ increase of brain 5-HT (1796 after aiacinamide administration . Sedation observed at the same time may be due to this 5-HT increase . Recently many investigations have been carried out to see xhether peripheral metabolism of tryptophan and tyrosine can influence the concentration of 5-hydroxytryptamine (5-HT) and catecholamines in brain.
To answer this question tryptophan-
pyrrolase(TP) has repeatedly been examined in the last years(4,5,8) .
Compounds like hydrocortisone and betamethasone
for instance induce TP(8,11,12,17), while other compounds are known to inhibit TP activity .
Allopurinol as well as some
niacin compounds belong to this inhibiting group(2,8) .
Madras
and Sovrkes(13) examined the effect of tryptophan analogues and a larger number of TP inhibitors on TP . A decrease of 5-HT levels in rat brain has been demonstrated after corticosteroid administration or stress-induced corticosteroid increase(4,8,12,17) .
However, Benkert and Matussek(1)
did not observe a decrease in 5-HT .
The corticosteroid induced
decrease of . 5-HT levels in brain could be prevented by allopurinol administration, while allopurinol alone did not 189
190
Effect od Niacinamide on Brain 5HT
Vol . il, No . 4
bring about any significant changes in 5-HT content(8) .
A aeries
of niacin compounds known to inhibit TP have been analysed and considerable quantitative differences were found(2) .
All
analyseà niacin compovnds,however, were capable of inhibiting TP ; the inhibition by NADH was over 80916 in vitro .
Investigations
regarding the influence of niacinamide compounds on 5-HT brain levels have not been carried out prior to these experiments.The question of interest is whether administration of niacin or niacin derivatives will result in an increased content of 5-HT in rat brain. Materials and Methods Male rats(Sprague-Dawley), weighing 140 - 20o g were housed iII
COm~+~T~A l
5-HT levels (14) .
cages for at least one week before experimentation.
in
brain were estimated according to Maickel et al .
TP activity was determined spectrophotometrically following
the procedure of Snox and Auerbach(11) .
All drugs were adminis-
tered i .p ., the given doses a.re indicated in the tables . animals were injected with saline of the same volume .
Control
F~periments
on the motilitymeter "Animex" were done according to Svensson and Thieme(18) . Results and Discussion No significant change in 5-HT content of rat brain could be found by examining a group of animals which had received NADH (78omg/kg) compared to animals which had only received saline (Table 1) .
This might be due to a higher activity of one or
more aldehyde dehydrogenasea in rat brain of which NADH is a coenzyme(6) .
This higher aldel~yde dehydrogenase activity could
lead to an increased 5-HT metabolism to 5-hydroayindoleacetaldehyde .We, therefore, analysed the effect of niacinamide administration alone .
We chose a dose(1g/kg) known to have
Effsct ad Niacinamide on Hraia 5HT
Yol . il, No. 4
191
TABLE 1 Influence of NADH on 5-HT in rat brain.Decapitatioa 6o min after i .p . injection. Treatment
5-HT in brain(ng/g tissue)
78o mg xADH/kg (n-5)
790 ± 70
saline
740 ± 70
(n-5)
a sedative effect on rata(1o,19) . A significant increase of 1796 in 5-HT level of the brain of niacinamide treated animals was found as compared to controls (Table 2) .
Sedation previously observed after niacinamide, was
TABLE 2 Influence of niacinamide on 5-HT in rat braia.Decapitation 6o min after i .p . injection. 5-HT in brain(ng/g tissue)
Treatment 1 g aiac ; nam; de/kg (n-10) saline ')
894 ± 80 `) 764 ± So
(n-8)
p < o .o1(statistics applied :U-test by Mann and Whitney)
confirmed by an Animex trial(18)(Fig.1) .
Animex trials were
carried out at night because of the higher motility of rats at this time .All other experiments took place between 9 and 11 a.m . . Animex trials during daytime looked similar to Fig . 1 but the difference between the niacinamide group and the control group was smaller . As Cho-Chung and Pitot(2,3) have shown, TP can be inhibited by niacin compounds .
A feed-back control of the TP pathway by
the physiological end-product niacin or niacinmononucleotide was
192
Effect od Niacinamide on Hrain 5HT
Vol . 11, No . 4
Impulses 1500
1000 -
500 -
r
1 .0~ Niacinamide/kg
i .p . injections 21
23
1
3
5
7
hrs
FIG . Sedation after i .p . injection of niacinamide compared with controls .
The ordinate shows the impulses/5 min as counted
by the motilitymeter Animex(18) .
proposed to be the cause .
Cho-Chung and Pitot postulated in
1967 that niacin binding to the regulatory site of the enzyme molecule leads to formation of a relative inactive enzyme . inhibition therefore would not be competitive .
The
Having shown
repressed de novo synthesis of TP in vivo after administration of niacinamide, Cho-Chung and Pitot postulated in 1968(3) that niacinamide may exert its inhibitory effect on tryptophan induced synthesis of TP at the level of genetic translation. A utilization of the accumulated tryptophan by other metabolic pathways
seems possible .
Recently the influence of niacinamide administration on
Vol. 11, No . 4
l~ect a~ Niacinamide on Hrain 5HT
193
urinary excretion of tryptophan metabolites in Hodgkin's disease of man was eaamined(16) . nine excretion.
Niacin leads to s decrease of i~ynure-
This result points to as in vivo inhibition
of TP or repressed de novo synthesis of TP by niacin . used were leas than those administered by us .
The doses
We chose a dose
which corresponded to the dose Cho-Chung and Pitot used in vitro . The dose applied by Cho-Chung and Pitot for thei.~ in vivo trials was much lower . There was no significant change in liver TP activity that could account for the increase in brain 5-HT(Table 3) "
On the
TABLE 3 Niacinamide administration and tryptophan pyrrolase activity . Treatment
Nmô~ë ~yn~ën3néTg ~issûé Decapitation 3o min , 6o min after ink .
1 g niacinamide/kg saline
3 .6±o .2(n-4)
3 .1±o .5(n~4)
3 .5±o .2(n=4)
3.7-o .5(n=4)
other hand it is possible that the injection stress induced corticosteroid secretion leading to TP induction.
Experiments with
adrenalectomized rats are planned to answer this question .
The
observed sedation(Fig .~) could be correlated with the observed 5-HT increase in brain.
A larger difference in animal motility,
however, could only be shown during the night, while the increase observed in 5-HT levels of rat brain took place during the day . Tryptophan-5-hydroxylase is usually assumed to be the rate limiting step of the over all metabolism of 5-HT(~) .
Nevertheless
Moir and Eccleston(~5) did point out that an elevation of approx imately 50 % in brain 5-HT could be observed after i .p . administration of 5o mg 1-tryptophaa/kg.
This would imply that an
increased hydrozylation by additional substrate supply is
ESect ad Niacinamide on Hrain 5HT
194 possible .
Vol . 11, No . 4
Aa increase of brain 5-HT by an additional tryptophan
supply appears therefore conceivable .
We believe that an inhibi-
tion of TP in vivo and (or) repressed de novo synthesis of TP (2,3) is the cause of the increase in 5-HT content of rat brain after niacinamide administration . How far the sedative effect and the repeatedly published therapeutic effect on psychosis(9,1o) can be based on an increased 5-HT formation should be studied by further analysis of the 5-HT turnover .
The doses applied by us to rats, in any
case are far above the doses given to man for therapeutical reasons. References 1.
SEN~RT,O .,N.MATUSSES, Nature 228 ,73(1970)
2.
CHO-CHIING,Y .S .,H .C .PITOT, J .biol .Chem 242 ,1192(1967)
3.
CHO-CIiUNG,Y .S .,H .C .PITOT, Europ.J .Biochem . ~ ,401(1968)
4.
CURZON,G .,A .R .GREEN, Br .J .Pharmac . ~ ,689(1969)
5.
CURZON,G .,P .K .BRIDGES, J.Neurol.Neurosur~ .Psychiat . ~ ,698 (19']0) -
6.
FELDSTEIN ,A .,O.WILLIAMSON, Br .J .Pharmac . ~4 ,38(1968)
7.
GARATTINI,S .,L.VALZELLI, Serotonin,Elsevier Publ .Comp. Amsterdam 1965
8.
GREEN,A.R .,G.CURZON, Nature 220 ,1095(1968)
9.
HOFFER ;A .,H .OSMOND,M.J .CALLBECH,J .KAHAN, J.clin .exp . Psychopathol . 18 ,131(1957)
10 .
SANIG,g., Wiesenach . Berichte 4 ,E .Merck,Darmstadt 1968
11 .
gPTO%,W .E .,J .AUERBACH, J .biol .Chem. 214, 307(1955)
12 .
BONONENKO,V.,O.M .ZRIAKOW,T .K .AONONENKO, Fiziol .Zh.(Kiev) 16~ 600(1970)
13 .
MADRAS,B .K .,Th .L .SOURKES, Biochem.Pharmacol . ~
14 .
MAICSELL,R .P .,R.H .CO%,J .SAILLANT,B .P .MILLER, -_ Int .J_,.Neurogharmacol . 7,275(1968)
103~(1968)
Vol . 11, No . 4
Effect cd Niacinamide on Brain 5HT
195
15 .
MOIR,A .T .B .,D.ECCLESTON, J.Neurochem . ~ ,1093(1968)
16 .
MUGGEO,M .,A.de ANTCNI,G .ALLEGRI,C .COSTA,G .CREPALDI Clia .chim~$~a ~o, 779(1970)
17 . '
SCAPAGNII~I U.,P.PREZIOSI,A .de 6CHAEPDRYER, Pharmac .Res .Comm. ~~ 63(1969j
18 .
SYENSSON,T .H .,G.THIEME, Psychopharm .(Berlin) 14, 157(1969)
19 .
woohESr,D.w ., science 12s, 1277(1958)
') Burkhard Scherer's present address : Institut für physiologische Chemie und physikalische Biochemie der Universität 8 München 2,Pettenkoferstrasse 14 a ,Germany