Jourrial of Nrurochrmrrrry. 1979 Vol 32, pp. 2 2 9 ~231. Pergamon Press. Priritcd
in
Grcat Britain.
SHORT COMMUNICATION
Effects of clorgyline and pargyline on dearninated metabolites of norepinephrine, doparnine and serotonin in human cerebrospinal h i d
(Received 24 April 1978. Accepted 21 July 1978)
IN 1968, JOHNSTON described-two forms of monoamine oxidase (MAO) on the basis of a bimodal pattern of inhibition of tyramine deamination found with clorgyline (JOHNSTON, 1968). Later studies revealed that M A 0 type A preferentially deaminates 5-hydroxytryptamine (5-HT) and norepinephrine (NE) and is more susceptible to inhibition by clorgyline; in contrast M A 0 type B more readily deaminates ,!I-phenylethylamine and is preferentially inhibited by deprenyl (KNOLL & MAGYAR,1972) and pargyline (SQUIRES, 1972). Dopamine and tyramine are substrates for both forms of the enzyme (YANG& NEFF, 1974). Many mammalian tissues contain both these forms of the enzyme: but the apparent proportion of the two forms vary widely between various organs in an individual species as well as between different species, making extrapolation to man difficult (SQul~ts,1972; TIPTONef a!., 1976). The present study was undertaken to evaluate the it1 uiuo effect of selective M A 0 A and B inhibitors (clorgyline and pargyline, respectively) on the metabolism of biogenic amines in man. Cerebrospinal fluid samples were obtained from seven hospitalized depressed patients at the end of a 3-week period off all drugs. Six patients were subsequently treated with clorgyline (May & Baker, Ltd., Essex, England), 2@30mg/day, and were resampled in the fourth week of treatment. Five were treated with pargyline (Abbott Pharmaceutical Division, Chicago, IL) (75-100 mglday) and also were resampled in the fourth treatment week. The four patients in this group who received both clorgyline and pargyline (as part of a randomized, cross-over trial et a/., in press) had described in detail elsewhere) (MURPHY a 3-week placebo period between the trials with the two drugs. The cerebrospinal fluid samples werc obtaincd at 8 a.m. after 8 h of bed rest for the determination of homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxyphenylglycol (MHPG), TABLE 1. EFFECTSOF
CLORGYLINE AND PARGYLIPI’E Oh AMINE ME1ABOI.IIES I N H U M A N CEREBROSPINAL FLU111
HVA Baseline (N = 7) Clorgyline (N = 6) Pargyline (N = 5)
*P
=
0.05,
(ns/mJ)
MHPG (ng/ml)
26.9 f 2.6
7.41 k 0.40
2.61 & 0.95
1.89
17.7 & 1.9**?
0.67 i 0.42***
2.72 k 0.66
1.84 f. 0.45
+ 2.9***
0.93 2 0.20***
1.92 f 0.48
0.96
9.8
** P
3-methoxy-4-hydroxy-~-mandelicacid (VMA), and 5-hydroxyindoleacetic acid (5-HIAA) following collection and assay procedures which have been previously described (ASHCROFT e t a / . , 1966; GORDON et a/., 1974, 1976; WATSON et a/., 1974). The monoamine metabolites measured before and after clorgyline and pargyline treatment are presented in Table 1. HVA, the major acidic metabolite of dopamine, was significantly decreased during clorgyline (P < 0.02, paired t-test). as well as pargyline ( P i0.01) treatment, although pargyline caused a significantly greater reduction than clorgyline ( P < 0.05) (Fig. I). MHPG, the main metabolite of norepinephrine was markedly reduced ( P < 0.01) to an equal extent by both drugs. Neither VMA, a minor metabolite of norepinephrine, nor DOPAC, a minor metabolite of dopamine, was significantly affected by either drug. 5-HIAA, the main metabolite of serotonin was significantly reduced by both clorgyline ( P < 0.02) and pargyline ( P i 0.05) as measured by the gas chromatography-mass spectroscopy (gc-ms) method. The fluorimetricallymeasured values for 5-HIAA were not comparable. They were significantly higher than the gc-ms values for patients receiving clorgyline (P < 0.02) as well as pargyline ( P < 0.05). and no significant reductions from baseline were observed during treatment with either drug using thc values from the fluoronietric assay. There are numerous reports in the literature showing both A and B forms of M A 0 in brain of various species including man (JOHNSTOX, 1968; HALLet a!., 1969). Human brain has been shown t o contain predominantly MAO-B activity (GLOVERet a/., 1977), and preliminary data from our laboratory indicates that human cortex contains approx 80% B type enzyme and 20% A type. Since dopamine is a substrate for both forms of the enzyme, the greater reduction in HVA, the major metabolite of dopamine, by the MAO-B inhibitor pargyline, was expected.
=
VMA (ngiml)
0.02, *** P < 0.01 compared to baseline;
229
DOPAC (ngiml)
k 0.54
+- 0.63
t P < 0.05 compared
5-HIAA 5-HIAA (ngiml) (ng/ml) (Fluorotnetric (gc-ms method) method) 18.8
2.2
22.6 i 3.0
10.4 k 1.8**
24.6 k 3.8
12.4
19.8 _+ 3.8
3.1*
to pargyline; means
s.F,.M.
Short communication
230
THE EFFECTS OF CLORGYLINE AND PARGYLINE ON HVA LEVELS IN CSF Clorgyline
40
35
*--a
\
Pargyline
P
in
Grcat Britain.
SHORT COMMUNICATION
Effects of clorgyline and pargyline on dearninated metabolites of norepinephrine, doparnine and serotonin in human cerebrospinal h i d
(Received 24 April 1978. Accepted 21 July 1978)
IN 1968, JOHNSTON described-two forms of monoamine oxidase (MAO) on the basis of a bimodal pattern of inhibition of tyramine deamination found with clorgyline (JOHNSTON, 1968). Later studies revealed that M A 0 type A preferentially deaminates 5-hydroxytryptamine (5-HT) and norepinephrine (NE) and is more susceptible to inhibition by clorgyline; in contrast M A 0 type B more readily deaminates ,!I-phenylethylamine and is preferentially inhibited by deprenyl (KNOLL & MAGYAR,1972) and pargyline (SQUIRES, 1972). Dopamine and tyramine are substrates for both forms of the enzyme (YANG& NEFF, 1974). Many mammalian tissues contain both these forms of the enzyme: but the apparent proportion of the two forms vary widely between various organs in an individual species as well as between different species, making extrapolation to man difficult (SQul~ts,1972; TIPTONef a!., 1976). The present study was undertaken to evaluate the it1 uiuo effect of selective M A 0 A and B inhibitors (clorgyline and pargyline, respectively) on the metabolism of biogenic amines in man. Cerebrospinal fluid samples were obtained from seven hospitalized depressed patients at the end of a 3-week period off all drugs. Six patients were subsequently treated with clorgyline (May & Baker, Ltd., Essex, England), 2@30mg/day, and were resampled in the fourth week of treatment. Five were treated with pargyline (Abbott Pharmaceutical Division, Chicago, IL) (75-100 mglday) and also were resampled in the fourth treatment week. The four patients in this group who received both clorgyline and pargyline (as part of a randomized, cross-over trial et a/., in press) had described in detail elsewhere) (MURPHY a 3-week placebo period between the trials with the two drugs. The cerebrospinal fluid samples werc obtaincd at 8 a.m. after 8 h of bed rest for the determination of homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxy-4-hydroxyphenylglycol (MHPG), TABLE 1. EFFECTSOF
CLORGYLINE AND PARGYLIPI’E Oh AMINE ME1ABOI.IIES I N H U M A N CEREBROSPINAL FLU111
HVA Baseline (N = 7) Clorgyline (N = 6) Pargyline (N = 5)
*P
=
0.05,
(ns/mJ)
MHPG (ng/ml)
26.9 f 2.6
7.41 k 0.40
2.61 & 0.95
1.89
17.7 & 1.9**?
0.67 i 0.42***
2.72 k 0.66
1.84 f. 0.45
+ 2.9***
0.93 2 0.20***
1.92 f 0.48
0.96
9.8
** P
3-methoxy-4-hydroxy-~-mandelicacid (VMA), and 5-hydroxyindoleacetic acid (5-HIAA) following collection and assay procedures which have been previously described (ASHCROFT e t a / . , 1966; GORDON et a/., 1974, 1976; WATSON et a/., 1974). The monoamine metabolites measured before and after clorgyline and pargyline treatment are presented in Table 1. HVA, the major acidic metabolite of dopamine, was significantly decreased during clorgyline (P < 0.02, paired t-test). as well as pargyline ( P i0.01) treatment, although pargyline caused a significantly greater reduction than clorgyline ( P < 0.05) (Fig. I). MHPG, the main metabolite of norepinephrine was markedly reduced ( P < 0.01) to an equal extent by both drugs. Neither VMA, a minor metabolite of norepinephrine, nor DOPAC, a minor metabolite of dopamine, was significantly affected by either drug. 5-HIAA, the main metabolite of serotonin was significantly reduced by both clorgyline ( P < 0.02) and pargyline ( P i 0.05) as measured by the gas chromatography-mass spectroscopy (gc-ms) method. The fluorimetricallymeasured values for 5-HIAA were not comparable. They were significantly higher than the gc-ms values for patients receiving clorgyline (P < 0.02) as well as pargyline ( P < 0.05). and no significant reductions from baseline were observed during treatment with either drug using thc values from the fluoronietric assay. There are numerous reports in the literature showing both A and B forms of M A 0 in brain of various species including man (JOHNSTOX, 1968; HALLet a!., 1969). Human brain has been shown t o contain predominantly MAO-B activity (GLOVERet a/., 1977), and preliminary data from our laboratory indicates that human cortex contains approx 80% B type enzyme and 20% A type. Since dopamine is a substrate for both forms of the enzyme, the greater reduction in HVA, the major metabolite of dopamine, by the MAO-B inhibitor pargyline, was expected.
=
VMA (ngiml)
0.02, *** P < 0.01 compared to baseline;
229
DOPAC (ngiml)
k 0.54
+- 0.63
t P < 0.05 compared
5-HIAA 5-HIAA (ngiml) (ng/ml) (Fluorotnetric (gc-ms method) method) 18.8
2.2
22.6 i 3.0
10.4 k 1.8**
24.6 k 3.8
12.4
19.8 _+ 3.8
3.1*
to pargyline; means
s.F,.M.
Short communication
230
THE EFFECTS OF CLORGYLINE AND PARGYLINE ON HVA LEVELS IN CSF Clorgyline
40
35
*--a
\
Pargyline
P
