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Effects of tobacco smoke constituents on MPTP-induced toxicity and monoamine oxidase activity in the mouse brain
Life Sciences, Vol. 48, pp. 1173-1177 Printed in the U.S.A.
Pergamon Press
EFFECTS OF TOBACCO SMOKE CONSTITUENTS ON MPTP4NDUCED TOXICITY AND MONOAMINE OXIDASE ACTIVITY IN THE MOUSE BRAIN Laurence A Carr and J Khrmten Basham Department of Pharmacology and Toxicology Unwerslty of Lomswlle Loumvflle, KY 40292 (Received -In f i n a l
form J a n u a r y 16, 1991) Summary
Exposure to c~garette smoke has been found to attenuate the reductton m strmtal dopamlne levels caused by 1-methyl-4-phenyl-l,2,3,6tetrahydropyndlne (MPTP) m mine and to inhibit monoamme oxldase (MAO) actwtty in brain tmsue To confirm whether specific smoke consntuents whmh have been reported to protect against MPTP toxm~ty were responsible for these effects, mine were treated chromcally w~th mcotme, 4phenylpyndme and hydrazme Although all three compounds prevented the decrease in dopamme metabohte levels reduced by MFI'P, there was no ssgmficant effect on dopamme levels None of the three compounds inhibited MAO actwlty m cerebral tmsue following treatment m vwo However, an extract of tobacco smoke partmulate matter caused a marked lnhlbmon of MAO A and MAO B actwlty when added m vitro The results suggest that one or more unidentified substances m tobacco smoke are capable of mhlbmng brain MAO and perhaps altering the formation of the actwe metabohte of MPTP The results of numerous epldemmlogmal studms whmh suggested an reverse relatmnshlp between smoking and the incidence of Parklnson's dmease (1) have led to a hypothesm that an mteracuon may exist between c~garette smoke and potenual etmlogmal factors m the enwronment (2) The mechamsms for such an lnteractton may involve an interference by specific smoke components w~th the toxin effects of enwronmental neurotoxms thought to be mvolved m the etmlogy of Parkmson's disease Although recent studms have cast doubt on thin hypothesm (3), the basra for the inverse relationship remains unknown The ldentlficatmn of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyndme(MPTP) as a neurotoxln whmh can reproduce many of the neurochemlcal and chnmal symptoms of ldmpathm Parkmson's dmease (4) has prowded a useful model for studying thin potential mteractmn It has been shown that chrome exposure to tobacco smoke or mcotme can attenuate various neurochemmal effects of MPTP (5,6) The mechanmm for these effects remains unclear, however Although exposure to tobacco smoke has been shown to inhibit MAO-B activity m vartous nssues including brain, homogenates of cerebral tmsue from animals chromcally exposed to tobacco smoke were found to metabohze MPTP to its actwe metabohte, MPP +, at a normal rate (5) The rams of the present study were to determine whether specsfic chemmal constituents of tobacco smoke whmh have been reported to attenuate the neurochemmal effects of MPTP alter MAO actwlty m vw0 or m vitro To further elucidate a role for mhthmon of MAO-B actwlty as a mechanmm m thin mteraetmn, the effects of an extract of filtered smoke partmulate matter on MAO aetwlty were also stud~ed Methods Animals Male C57B1 mine weighing 20-25 grams were obtained from Charles Rwer Laboratorms (Portage MI) and housed mdwldually They recewed food and water ad hb 0024-3205/91 $3.00 +.00 Copyrlght (c) 1991 Pergamon Press plc
1174
Tobacco Smoke Constztuents and MPTP
Vol. 48, No. 12, 1991
Drug Treatments For m wvo studies, individual drugs were administered chromcally by mfumon for two weeks w,th osmouc mlmpumps (Alzet model 2002) implanted subcutaneously The pumps contained 200 #1 either 0 7% mcoane, 20 8 mg/ml hydrazme or 52 mg/ml 4-phenylpyndme HCI m 10 mM sodmm phosphate buffer, pH 7 The mfumon rate was 0 5 #l/hr, resulting m approximate dally doses of 3 3 mg/kg, 10 mg/kg and 25 mg/kg, respectively MPTP was administered by subcutaneous rejection, 10 mg/kg, after one week of mfumon with the test drug After the two week infusion period, the ammals were sacrificed by decapitation, the brain was removed and stnatal and cortical tissues were prepared (5) Chemical Assays Strlatal concentrations of dopamme, homovanllhc acid (HVA) and 3,4dLhydroxyphenylaceuc acid (DOPAC) were determined by HPLC-EC as previously described (5) MAO actwity m frontal corUcal tissue homogenates was assayed according to a modification (5) of the method of Morlnan and Garratt (7) Preparation of c~garette smoke extract Nonfiltered 2RI reference c~garettes were obtained from the Tobacco and Health Research Institute (Lexmgton, KY) and smoked m a smoking machine developed at the Institute (8) Puffs were generated at the rate of I per minute for 12 minutes The smoke was passed through a Cambridge glass fiber filter After weighing, filters containing particulate matter from two ogarettes were extracted with dlmethylsulfox~de (DMSO) to give a stock soluUon of 8 mg/ml (9) The extract was stored at -20°C untd uuhzed Statistical Analy~ls The data were subjected to analyms of variance (one-way) and differences between individual means were tested by Neuman Keul's test The enzyme kinetic data were analyzed with Student's t test Results Effect of tobacco ¢omoonents on MPTP-mduced neurotoxicity The effects of chronic infusion of speofic tobacco constituents on the reduction m the levels of strlatal dopamme, DOPAC and HVA caused by MPTP are shown m Table I Administration of MPTP alone caused a statistically significant reduction in the concentraUon of dopamlne and metabolltes Although the pretreatments had no effect on the depletion of strmtal dopamme levels caused by MPTP, each compound did prevent the decrease m DOPAC and HVA levels None of the constituents altered dopamme levels when given alone Only nicotine and hydrazme slgmficantly increased levels of DOPAC or HVA when given alone TABLE I Effect of Some Tobacco Smoke Constituents on MPTP-mduced Depletion of Strlatal Dopamlne and MetabollteS Treatment
N
Dopamine
DOPAC
HVA
Control
20
15.06±0.75
1.01~0.08
1.40±0.10
MPTP
14
7.78±0.48*
0.59±0.07*
0.87±0.08*
Nlcotlne MPTP + N~cot~ne
12 7
14.97±0.62 7.50±0.43*
1.13±0.07 0.84~0.i0
1.83Z0.05" 1.28±0.12
4-PP MPTP + 4-PP
10 4
15.19±0.89 8.26±0.99*
0.93±0.12 0.84±0.15
1.57±0.10 1.31±0.02
Hydraz~ne MPTP + Hydrazine
6 6
17.72±1.07 10.56±0.75"
1.48±0.07. 0.92±0.06
2.13~0.13. 1.59±0.07
Animals were pretreated with vehicle or smoke components for one week before administration of MPTP as described m Methods Each value represents the mean + 1 S E expressed as #gig tissue * Significantly different from control (p < 05)
Vol. 48, No.
12, 1991
Tobacco Smoke Constituents and MPTP
1175
Effects of tobacco smoke comvonents on cerebral MAQ actwltv Neither mcotme nor hydrazme had any effect on cerebral MAO actw~ty after two weeks of infumon (Table II) However, MAO-A actwlty was slgmficantly increased following treatment with 4-phenylpyndme Stmdarly, nmther mcotme nor hydrazme had any effects on MAO actwlty when added to bram homogenate m vitro (Table HI) 4Phenylpyndme, on the other hand, mgmficantly mh~bited enzyme actwlty, subsequent analysis showed that this effect was observed only with MAO-B In an effort to determine whether other components of tobacco smoke are capable of inhibiting MAO, various concentrattons of smoke particulate matter extracted with DMSO were added to cerebral homogenates The extract was found to cause a concentration-dependent lnhibmon of MAO-A and MAO-B (Fig 1) A mmdar extract prepared from smoke-free filters had no effect on MAO actwity Analysis of the kmeUe properties of the enzyme mdteated that the K . for kynuramme oxtdauon was smgmficantly increased and the V x was slgmficantly decreased by a-ddmon of the smoke extract (Table IV) TABLE H Effect of m vw0 Treatment with Some Smoke Constituents on Cerebral MAO Actlwty
Treatment
N
MAO-A
Control
14
7.4±0.4
22.2±1.4
N~cotine
12
8.0±0.4
23.9±2.2
4-phenylpyrxd~ne
10
11.1±1.0"
28.5±1.1
7.1±0.7
25.5±1.6
Hydraz~ne
5
MAO-B
Drugs were infused for 14 days MAO activity expressed as nmoles/mg ~rotem/hr Slgmficantly different from control (p < 0 05)
TABLE III Effect of Some Smoke Constituents m vitro on Cerebral MAO Activity Treatment (10 ~M)
N
Total MAO Activity (percent of control)
Nicotxne
3
96.1±1.5
4-Phenylpyrld~ne
3
80.6±1.7"
Hydrazlne
3
103.6±7.1
Tissue preparation was premcubated with each drug for 10 minutes before addmon of kynuramme substrate * S l g m f i e a n t l y different from control (9 < 0 05)
1176
Tobacco Smoke Constztuents
and MPTP
Vol. 48, No.
12, 1991
40
30
o
20 )-
> 0
( O(
10
i
i
i
i
i
r
0
20
40
60
80
1 O0
SMOKE EXTRACT (pg/ml)
FIG 1
Effect of smoke extract on MAO-A (O) and MAO-B ( 0 ) actwlty m cerebral t*ssue The tissue preparatmon was premcubated w~th various concentraUons of DMSO extract for 10 minutes before addmon of substrate TABLE IV
Effect of Smoke Extract on Kinetic Properties of MAO Control
Km (@M)
Vma x (nmoles/mg
Smoke
Extract
27.6±1.2
91.0±8.5"
31.9±4.8
15.9±2.8"
prot/hr)
Tissue homogenate was incubated w~th various concentrations of kynuramme (10-100 #M) the presence of smoke extract (75 #g/ml) Value represents the mean + S E of 4 samples * Slgmficantly different from control (p < 05)
Dlscussl0n
Although each of the speofic tobacco smoke components uUhzed m this study has been reported by others to attenuate MPTP-mduced neurotoxlclty m the strlatum, none was found to rephcate all of the effects of smoke exposure in the current study Chrome treatment w~th mcotme m doses mmdar to those used m this study prevented the disappearance of stnatal tyrosme hydroxylase caused by MPTP (6), but apparently does not alter the effects of MPTP on dopamme levels (10-12) It seems unhkely, therefore, that mcotme has an Important role m the protectwe effects of smoke exposure 4Phenylpyndme has been shown to prevent the decrease m stnatal dopamme levels caused by MPTP (13), but the dose was significantly higher than that used m the present study (4 x 50 mg/kg over three hours vs 25 mg/kg/24 hours) and is probably much less relevant to concentraUons found m tobacco smoke Although hydrazmo has been reported to attenuate MPTP-mduced toxicity (10), the effects were marginal m the current study The d,screpancy between these two studies may be due to
Vol. 48, No.
12, 1991
Tobacco Smoke Constituents
and MPTP
1177
differences m the route of adnumstratlon or, more likely, to the stattstscal analyms, since Yong and Perry (10) found mgmficanee only when the combined treatment was compared to MPTP, not to controls, as m the current study The effects of hydrazme on dopamme metabohtes when gwen alone suggest that It may dsrectly sumulate dopamme turnover m the strmtum None of the specific compounds studied m thts mvest~gatlon mgmficantly inhibited MAO-B acUwty followmg chrome treatment m vw0, 4-phenylpyndme had only a moderate effect m vitro Thss suggests that the attenuatmn of MPTP-lndueed depletton of dopamlne metabohtes by the three compounds is probably not due to inhibition of oxidation MPTP of to MPP ÷ The smoke extract, however, possessed mgmficant inhibitory actwlty on both MAO-A and MAO-B m corttcal tissue This ~s m agreement with prewous reports that cigarette smokers have lower platelet MAO actwlty (14,15) and that an aqueous smoke extract inhibits MAO actw~ty m lung t~ssue m v~trQ (16) It appears that the inhibitory effect m vitro has characteristics of both competltwe and noncompetmve mh~bmon which ~s consistent with a prewous study (16) These results indicate that one or more umdentlfied components of tobacco smoke may be of mgmficant importance m terms of mh~b~tmg the formation of an acttve neurotoxm by oxidative mechamsms Acknowledgements This study was supported by a grant from the Tobacco and Health Research Institute, Lexington, KY References
10 11 12 13 14 15 16
J A BARON, Neurology 36 1490-1496 (1986) S H SNYDER and R J D'AMATO, Neurology 36 250-258 (1986) S -M AQUILONIUS, Nlcotmlc Receptors m the CNS (Eds, A Nordberg, K Fuxe, B Holmstedt and A Sundwall) pp 329-333, Elsevier, Amsterdam (1989) D B CALNE and J W LANGSTON, Lancet 2 1457-1459 (1983) L A CARR and P P ROWELL, Neuropharmacology 311-314 (1990) A M JANSON, K FUXE, E SUNDSTROM, L F AGNATI and M GOLDSTEIN, Acta Phymol Scand 132 589-591 (1988) A MORINAN and H M GARRATr, J Pharmac Method 13 213-223 (1985) R B GRIFF1TH and S STANDAFER, Toxicology 35 13-24 (1985) J H REINDERS, H -J M BRINKMAN, J A van MOURIK and P G deGROOT, Arteriosclerosis 6 15-23 (1986) V W YONG and T L PERRY, J Neurol Scl 72 265-272 (1986) H SERSHEN, M F MASON, M E A REITH, A HASHIM and A LAJTHA, Neuropharmacology 25 1231-1234 (1986) H SERSHEN, A HASHIM, H L WIENER and A LAJTHA, Neuroscl Lett 93 270-274 (1988). I IRWIN, J W LANGSTON and L E DeLANNEY, Life Sol 40 731-740 (1987) T R NORMAN, K (3 CHAMBERLAIN and M A FRENCH, Psych Res 20 199-206 (1987) L ORELAND, C J FOWLER and D SCHALLING, Life Sol 29 2511-2518 (1981) P H YU and A A BOULTON, Life Scl 41 675-682 (1987)
Pergamon Press
EFFECTS OF TOBACCO SMOKE CONSTITUENTS ON MPTP4NDUCED TOXICITY AND MONOAMINE OXIDASE ACTIVITY IN THE MOUSE BRAIN Laurence A Carr and J Khrmten Basham Department of Pharmacology and Toxicology Unwerslty of Lomswlle Loumvflle, KY 40292 (Received -In f i n a l
form J a n u a r y 16, 1991) Summary
Exposure to c~garette smoke has been found to attenuate the reductton m strmtal dopamlne levels caused by 1-methyl-4-phenyl-l,2,3,6tetrahydropyndlne (MPTP) m mine and to inhibit monoamme oxldase (MAO) actwtty in brain tmsue To confirm whether specific smoke consntuents whmh have been reported to protect against MPTP toxm~ty were responsible for these effects, mine were treated chromcally w~th mcotme, 4phenylpyndme and hydrazme Although all three compounds prevented the decrease in dopamme metabohte levels reduced by MFI'P, there was no ssgmficant effect on dopamme levels None of the three compounds inhibited MAO actwlty m cerebral tmsue following treatment m vwo However, an extract of tobacco smoke partmulate matter caused a marked lnhlbmon of MAO A and MAO B actwlty when added m vitro The results suggest that one or more unidentified substances m tobacco smoke are capable of mhlbmng brain MAO and perhaps altering the formation of the actwe metabohte of MPTP The results of numerous epldemmlogmal studms whmh suggested an reverse relatmnshlp between smoking and the incidence of Parklnson's dmease (1) have led to a hypothesm that an mteracuon may exist between c~garette smoke and potenual etmlogmal factors m the enwronment (2) The mechamsms for such an lnteractton may involve an interference by specific smoke components w~th the toxin effects of enwronmental neurotoxms thought to be mvolved m the etmlogy of Parkmson's disease Although recent studms have cast doubt on thin hypothesm (3), the basra for the inverse relationship remains unknown The ldentlficatmn of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyndme(MPTP) as a neurotoxln whmh can reproduce many of the neurochemlcal and chnmal symptoms of ldmpathm Parkmson's dmease (4) has prowded a useful model for studying thin potential mteractmn It has been shown that chrome exposure to tobacco smoke or mcotme can attenuate various neurochemmal effects of MPTP (5,6) The mechanmm for these effects remains unclear, however Although exposure to tobacco smoke has been shown to inhibit MAO-B activity m vartous nssues including brain, homogenates of cerebral tmsue from animals chromcally exposed to tobacco smoke were found to metabohze MPTP to its actwe metabohte, MPP +, at a normal rate (5) The rams of the present study were to determine whether specsfic chemmal constituents of tobacco smoke whmh have been reported to attenuate the neurochemmal effects of MPTP alter MAO actwlty m vw0 or m vitro To further elucidate a role for mhthmon of MAO-B actwlty as a mechanmm m thin mteraetmn, the effects of an extract of filtered smoke partmulate matter on MAO aetwlty were also stud~ed Methods Animals Male C57B1 mine weighing 20-25 grams were obtained from Charles Rwer Laboratorms (Portage MI) and housed mdwldually They recewed food and water ad hb 0024-3205/91 $3.00 +.00 Copyrlght (c) 1991 Pergamon Press plc
1174
Tobacco Smoke Constztuents and MPTP
Vol. 48, No. 12, 1991
Drug Treatments For m wvo studies, individual drugs were administered chromcally by mfumon for two weeks w,th osmouc mlmpumps (Alzet model 2002) implanted subcutaneously The pumps contained 200 #1 either 0 7% mcoane, 20 8 mg/ml hydrazme or 52 mg/ml 4-phenylpyndme HCI m 10 mM sodmm phosphate buffer, pH 7 The mfumon rate was 0 5 #l/hr, resulting m approximate dally doses of 3 3 mg/kg, 10 mg/kg and 25 mg/kg, respectively MPTP was administered by subcutaneous rejection, 10 mg/kg, after one week of mfumon with the test drug After the two week infusion period, the ammals were sacrificed by decapitation, the brain was removed and stnatal and cortical tissues were prepared (5) Chemical Assays Strlatal concentrations of dopamme, homovanllhc acid (HVA) and 3,4dLhydroxyphenylaceuc acid (DOPAC) were determined by HPLC-EC as previously described (5) MAO actwity m frontal corUcal tissue homogenates was assayed according to a modification (5) of the method of Morlnan and Garratt (7) Preparation of c~garette smoke extract Nonfiltered 2RI reference c~garettes were obtained from the Tobacco and Health Research Institute (Lexmgton, KY) and smoked m a smoking machine developed at the Institute (8) Puffs were generated at the rate of I per minute for 12 minutes The smoke was passed through a Cambridge glass fiber filter After weighing, filters containing particulate matter from two ogarettes were extracted with dlmethylsulfox~de (DMSO) to give a stock soluUon of 8 mg/ml (9) The extract was stored at -20°C untd uuhzed Statistical Analy~ls The data were subjected to analyms of variance (one-way) and differences between individual means were tested by Neuman Keul's test The enzyme kinetic data were analyzed with Student's t test Results Effect of tobacco ¢omoonents on MPTP-mduced neurotoxicity The effects of chronic infusion of speofic tobacco constituents on the reduction m the levels of strlatal dopamme, DOPAC and HVA caused by MPTP are shown m Table I Administration of MPTP alone caused a statistically significant reduction in the concentraUon of dopamlne and metabolltes Although the pretreatments had no effect on the depletion of strmtal dopamme levels caused by MPTP, each compound did prevent the decrease m DOPAC and HVA levels None of the constituents altered dopamme levels when given alone Only nicotine and hydrazme slgmficantly increased levels of DOPAC or HVA when given alone TABLE I Effect of Some Tobacco Smoke Constituents on MPTP-mduced Depletion of Strlatal Dopamlne and MetabollteS Treatment
N
Dopamine
DOPAC
HVA
Control
20
15.06±0.75
1.01~0.08
1.40±0.10
MPTP
14
7.78±0.48*
0.59±0.07*
0.87±0.08*
Nlcotlne MPTP + N~cot~ne
12 7
14.97±0.62 7.50±0.43*
1.13±0.07 0.84~0.i0
1.83Z0.05" 1.28±0.12
4-PP MPTP + 4-PP
10 4
15.19±0.89 8.26±0.99*
0.93±0.12 0.84±0.15
1.57±0.10 1.31±0.02
Hydraz~ne MPTP + Hydrazine
6 6
17.72±1.07 10.56±0.75"
1.48±0.07. 0.92±0.06
2.13~0.13. 1.59±0.07
Animals were pretreated with vehicle or smoke components for one week before administration of MPTP as described m Methods Each value represents the mean + 1 S E expressed as #gig tissue * Significantly different from control (p < 05)
Vol. 48, No.
12, 1991
Tobacco Smoke Constituents and MPTP
1175
Effects of tobacco smoke comvonents on cerebral MAQ actwltv Neither mcotme nor hydrazme had any effect on cerebral MAO actw~ty after two weeks of infumon (Table II) However, MAO-A actwlty was slgmficantly increased following treatment with 4-phenylpyndme Stmdarly, nmther mcotme nor hydrazme had any effects on MAO actwlty when added to bram homogenate m vitro (Table HI) 4Phenylpyndme, on the other hand, mgmficantly mh~bited enzyme actwlty, subsequent analysis showed that this effect was observed only with MAO-B In an effort to determine whether other components of tobacco smoke are capable of inhibiting MAO, various concentrattons of smoke particulate matter extracted with DMSO were added to cerebral homogenates The extract was found to cause a concentration-dependent lnhibmon of MAO-A and MAO-B (Fig 1) A mmdar extract prepared from smoke-free filters had no effect on MAO actwity Analysis of the kmeUe properties of the enzyme mdteated that the K . for kynuramme oxtdauon was smgmficantly increased and the V x was slgmficantly decreased by a-ddmon of the smoke extract (Table IV) TABLE H Effect of m vw0 Treatment with Some Smoke Constituents on Cerebral MAO Actlwty
Treatment
N
MAO-A
Control
14
7.4±0.4
22.2±1.4
N~cotine
12
8.0±0.4
23.9±2.2
4-phenylpyrxd~ne
10
11.1±1.0"
28.5±1.1
7.1±0.7
25.5±1.6
Hydraz~ne
5
MAO-B
Drugs were infused for 14 days MAO activity expressed as nmoles/mg ~rotem/hr Slgmficantly different from control (p < 0 05)
TABLE III Effect of Some Smoke Constituents m vitro on Cerebral MAO Activity Treatment (10 ~M)
N
Total MAO Activity (percent of control)
Nicotxne
3
96.1±1.5
4-Phenylpyrld~ne
3
80.6±1.7"
Hydrazlne
3
103.6±7.1
Tissue preparation was premcubated with each drug for 10 minutes before addmon of kynuramme substrate * S l g m f i e a n t l y different from control (9 < 0 05)
1176
Tobacco Smoke Constztuents
and MPTP
Vol. 48, No.
12, 1991
40
30
o
20 )-
> 0
( O(
10
i
i
i
i
i
r
0
20
40
60
80
1 O0
SMOKE EXTRACT (pg/ml)
FIG 1
Effect of smoke extract on MAO-A (O) and MAO-B ( 0 ) actwlty m cerebral t*ssue The tissue preparatmon was premcubated w~th various concentraUons of DMSO extract for 10 minutes before addmon of substrate TABLE IV
Effect of Smoke Extract on Kinetic Properties of MAO Control
Km (@M)
Vma x (nmoles/mg
Smoke
Extract
27.6±1.2
91.0±8.5"
31.9±4.8
15.9±2.8"
prot/hr)
Tissue homogenate was incubated w~th various concentrations of kynuramme (10-100 #M) the presence of smoke extract (75 #g/ml) Value represents the mean + S E of 4 samples * Slgmficantly different from control (p < 05)
Dlscussl0n
Although each of the speofic tobacco smoke components uUhzed m this study has been reported by others to attenuate MPTP-mduced neurotoxlclty m the strlatum, none was found to rephcate all of the effects of smoke exposure in the current study Chrome treatment w~th mcotme m doses mmdar to those used m this study prevented the disappearance of stnatal tyrosme hydroxylase caused by MPTP (6), but apparently does not alter the effects of MPTP on dopamme levels (10-12) It seems unhkely, therefore, that mcotme has an Important role m the protectwe effects of smoke exposure 4Phenylpyndme has been shown to prevent the decrease m stnatal dopamme levels caused by MPTP (13), but the dose was significantly higher than that used m the present study (4 x 50 mg/kg over three hours vs 25 mg/kg/24 hours) and is probably much less relevant to concentraUons found m tobacco smoke Although hydrazmo has been reported to attenuate MPTP-mduced toxicity (10), the effects were marginal m the current study The d,screpancy between these two studies may be due to
Vol. 48, No.
12, 1991
Tobacco Smoke Constituents
and MPTP
1177
differences m the route of adnumstratlon or, more likely, to the stattstscal analyms, since Yong and Perry (10) found mgmficanee only when the combined treatment was compared to MPTP, not to controls, as m the current study The effects of hydrazme on dopamme metabohtes when gwen alone suggest that It may dsrectly sumulate dopamme turnover m the strmtum None of the specific compounds studied m thts mvest~gatlon mgmficantly inhibited MAO-B acUwty followmg chrome treatment m vw0, 4-phenylpyndme had only a moderate effect m vitro Thss suggests that the attenuatmn of MPTP-lndueed depletton of dopamlne metabohtes by the three compounds is probably not due to inhibition of oxidation MPTP of to MPP ÷ The smoke extract, however, possessed mgmficant inhibitory actwlty on both MAO-A and MAO-B m corttcal tissue This ~s m agreement with prewous reports that cigarette smokers have lower platelet MAO actwlty (14,15) and that an aqueous smoke extract inhibits MAO actw~ty m lung t~ssue m v~trQ (16) It appears that the inhibitory effect m vitro has characteristics of both competltwe and noncompetmve mh~bmon which ~s consistent with a prewous study (16) These results indicate that one or more umdentlfied components of tobacco smoke may be of mgmficant importance m terms of mh~b~tmg the formation of an acttve neurotoxm by oxidative mechamsms Acknowledgements This study was supported by a grant from the Tobacco and Health Research Institute, Lexington, KY References
10 11 12 13 14 15 16
J A BARON, Neurology 36 1490-1496 (1986) S H SNYDER and R J D'AMATO, Neurology 36 250-258 (1986) S -M AQUILONIUS, Nlcotmlc Receptors m the CNS (Eds, A Nordberg, K Fuxe, B Holmstedt and A Sundwall) pp 329-333, Elsevier, Amsterdam (1989) D B CALNE and J W LANGSTON, Lancet 2 1457-1459 (1983) L A CARR and P P ROWELL, Neuropharmacology 311-314 (1990) A M JANSON, K FUXE, E SUNDSTROM, L F AGNATI and M GOLDSTEIN, Acta Phymol Scand 132 589-591 (1988) A MORINAN and H M GARRATr, J Pharmac Method 13 213-223 (1985) R B GRIFF1TH and S STANDAFER, Toxicology 35 13-24 (1985) J H REINDERS, H -J M BRINKMAN, J A van MOURIK and P G deGROOT, Arteriosclerosis 6 15-23 (1986) V W YONG and T L PERRY, J Neurol Scl 72 265-272 (1986) H SERSHEN, M F MASON, M E A REITH, A HASHIM and A LAJTHA, Neuropharmacology 25 1231-1234 (1986) H SERSHEN, A HASHIM, H L WIENER and A LAJTHA, Neuroscl Lett 93 270-274 (1988). I IRWIN, J W LANGSTON and L E DeLANNEY, Life Sol 40 731-740 (1987) T R NORMAN, K (3 CHAMBERLAIN and M A FRENCH, Psych Res 20 199-206 (1987) L ORELAND, C J FOWLER and D SCHALLING, Life Sol 29 2511-2518 (1981) P H YU and A A BOULTON, Life Scl 41 675-682 (1987)