Neurotoxicity and substance abuse: further fuel for regulatory dilemma.
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Journal Article↗
Biomedical subjects
T Archer
Publications and source records attributed to T Archer.
Co-administration of memantine and amantadine with sub/suprathreshold doses of L-Dopa restores motor behaviour of MPTP-treated mice.
The antiparkinsonian effects of the uncompetitive NMDA antagonists, memantine, amantadine and MK-801, in combination with an acute subthreshold dose of L-Dopa (5 mg/kg) in drug-naive MPTP-treated mice or a suprathreshold dose (20 mg/kg) in L-Dopa tolerant MPTP-treated mice were investigated. In the former case, memantine (locomotion: 3 mg/kg; rearing: 1 mg/kg) and amantadine (locomotion and rearing: 10 mg/kg) injected 60 min before the subthreshold dose of L-Dopa (5 mg/kg), each induced an antiparkinsonian action in hypokinesic MPTP-treated mice that consisted of dose-specific, as opposed to dose-related, elevations of locomotion and rearing behaviour. At the same time, higher doses of memantine reduced further the rearing (10 and 30 mg/kg) and locomotor (30mg/kg) behaviour of the MPTP-treated mice. MK-801 plus L-Dopa elevated locomotion (0.1 mg/kg) but reduced rearing at the 0.3 mg/kg dose. In control, saline-treated mice, memantine (3, 10 and 30 mg/kg) and MK-801 (0.1 and 0.3 mg/kg) increased locomotor behaviour but decreased rearing behaviour, while amantadine produced no effects. Memantine increased locomotor (1 and 3 mg/kg, s.c.; 1 mg/kg dose restored activity) and rearing (0.3 and 3 mg/kg) activity in the L-Dopa tolerant MPTP-treated mice, whereas amantadine (3 and 10 mg/kg) restored both locomotor (30 mg/kg significantly increased locomotion but did not restore the activity level) and rearing (3 mg/kg only) activity. MK-801 (0.1 and 0.3 mg/kg, s.c.) also increased significantly locomotor activity of L-Dopa-tolerant MPTP mice although the antikinetic action was not reversed, thereby precluding a restorative effect of the compound. These results, demonstrating both a synergistic and a restorative effect of the NMDA antagonists in coadministration with L-Dopa, demonstrate a putative antiparkinson action by these compounds in a functional animal model that incorporates the "wearing-off" complications of L-Dopa administration in the disorder.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Neonatal iron potentiates adult MPTP-induced neurodegenerative and functional deficits.
The interactive effects of neonatal iron and adult MPTP treatment groups of C57 Bl/6 mice were studied through adminustration of iron (Fe(2+)) 7.5mg/kg b.w., p.o. or vehicle (saline) on days 10-12 post partum, followed at 3months of age by administration of either MPTP (2x20 or 2x40mg/kg, s.c.) or saline. Neonatal iron administration to mice-induced hypoactivity during the first 20-min period of testing and hyperactivity during the 3rd and final 20-min period for all three parameters of motor activity tested at 4months of age. MPTP treatment caused a dose-related hypokinesia throughout the 3x20-min test periods; in the mice that received both neonatal iron and MPTP severe deficits of motor activity (akinesia) were obtained. Iron treatment impaired the ability of mice to habituate to the novel testing environment and later administration of MPTP potentiated the impairment markedly. Neurochemical analyses of striatal and frontal cortical dopamine (DA) and DA metabolites demonstrated that the depletions were potentiated under conditions of combined neonatal iron and adult MPTP. The analysis of total iron content (µg/g) in brain regions indicated notably elevated levels in the basal ganglia, but not in the frontal cortex, of mice administered Fe(2+). Iron-overload combined with MPTP treatment induced functional and neurochemical deficits with interactive consequences beyond a mere additive effect that may have implications for the neurodegenerative process in parkinsonism.
Journal Article↗
Internet blues revisited: replication and extension of an Internet paradox study.
This study is a replication of the Kraut et al. Internet paradox study designed to set guidelines for harmless Internet usage, without any potential for personal damage. The present study produced two main results: The first is a partial confirmation of the general response pattern found by Kraut et al. (i.e., that younger individuals tend to use the Internet to a higher degree and that they experience a lesser degree of psychological well-being). The second main result, however, contradicts the interpretation by Kraut et al. of the causal relationship between Internet usage and psychological well-being.
Adolescent↗
Effects of flotation-REST on muscle tension pain.
The purpose of the present study was to investigate whether the floating form of the restricted environmental stimulation technique (REST) may be applied within the field of pain relief. Flotation-REST consists of a procedure whereby an individual is immersed in a tank filled with water of an extremely high salt concentration. Thirty-seven patients (14 men and 23 women) suffering from chronic pain consisting of aching muscles in the neck and back area participated in the study. They were randomly assigned to either a control group (17 participants) or an experimental group (20 participants). The experimental group received nine opportunities to use the flotation-REST technique in the water tank over a three-week period. The results indicated that the most severe perceived pain intensity was significantly reduced, whereas low perceived pain intensity was not influenced by the floating technique. Further, the results indicated that circulating levels of the noradrenaline metabolite 3-methoxy-4-hydroxyphenylethyleneglycol were reduced significantly in the experimental group but not in the control group following treatment, whereas endorphin levels were not affected by flotation. Flotation-REST treatment also elevated the participants' optimism and reduced the degree of anxiety or depression; at nighttime, patients who underwent flotation fell asleep more easily. The present findings describe possible changes, for the better, in patients presenting with chronic pain complaints.
Adult↗
Maze learning and motor activity deficits in adult mice induced by iron exposure during a critical postnatal period.
Newborn mice were administered Fe(2+) (iron succinate: 7.5 mg/kg, b. wt) on either Days 3-5, 10-12 or 19-21, or vehicle (saline) at the same times, postnatally. Spontaneous motor behaviour and radial arm maze learning were tested at the age of 3 months. It was found that mice treated with Fe(2+) during postnatal Days 10-12 were markedly hypokinetic during the 1st 20-min test period and hyperkinetic during the 3rd and final 20-min test period. These mice showed an almost complete lack of habituation of spontaneous motor activity parameters to the test chambers. In the radial arm maze, the Days 10-12 treatment group evidenced significantly both more errors in arm choices and longer latencies to acquire all eight pellets; these mice showed also a severe trial-to-trial retention deficit as indexed by retention quotients. These behavioural deficits were observed also in animals treated with Fe(2+) during postnatal Days 3-5, but the effects were less pronounced, indicating the higher susceptibility of the brain for Fe(2+)-induced damage during Days 10-12 postpartum. Treatment with Fe(2+) on Days 19-21 did not induce behavioural alterations in comparison with its respective control (vehicle) group. Analysis of total brain iron content indicated significantly more iron (microg/g) accumulation in the basal ganglia, but not frontal cortex, of mice from the Days 3-5 and 10-12 Fe(2+) (7.5 mg/kg) treatment groups. The contribution of iron overload during the immediate postnatal to later functional deficits seems to implicate symptoms of Parkinsonism but the kinetics of iron uptake to the brain and its regional distribution at this critical period of development awaits elucidation.
Animals↗
Effects of clonidine and alpha-adrenoceptor antagonists on motor activity in DSP4-treated mice I: dose-, time- and parameter-dependency.
In three experiments the acute effects of clonidine administration upon locomotor and rearing behaviour of mice pretreated with the selective noradrenaline (NA) neurotoxin, DSP4 (1 x 75 mg/kg, i.p.) 10-12 days previously, were studied. Clonidine (0.01, 0.05, 0.25, 1.25 and 3.0 mg/kg, i.p.) induced a dose-dependent reduction of motor activity during the initial 30 min of testing in both DSP4-treated and control mice; this effect was attenuated by DSP4 treatment in the 0.01, 0.05, 0.25 and 3.0 mg/kg dose groups. By the third 30-min period of testing (60-90 min), each clonidine dose group, except the highest (3.0 mg/kg) dose for locomotion and the two highest (1.25 and 3.0 mg/kg) doses for rearing, induced increases in motor activity in the control mice. In DSP4-treated mice, a large increase in locomotor counts was produced by the 0.05 mg/kg dose of clonidine with lesser increases induced by the 0.01 mg/kg dose group, whereas a lesser effect of the 0.05 mg/kg group (30-60 min) was obtained for rearing but a larger effect of the 0.25 mg/kg group (60-90 min). Yohimbine (0.5 mg/kg, i.p., 15 min before clonidine) attenuated the suppressive effects of clonidine (0.01 and 0.05 mg/kg) during the initial 30 min of testing and markedly increased locomotor and rearing counts, both by itself and in combination with each dose of clonidine, in both DSP4-treated and control mice over the following 90 min of testing. Yohimbine treatment attenuated the large increase in locomotor counts induced by the 0.05 mg/kg dose of clonidine in the NA-denervated mice. Dihydroergotamine (0.5 mg/kg, i.p., 15 min before clonidine) did not antagonise either the initial suppressive effect or the later supersensitivity effect of the 0.05 mg/kg dose of clonidine. DSP4 treatment by itself reduced motor activity. The effects of clonidine, dose- and time-dependently, by itself or in co-administration with alpha-adrenoceptor antagonists, in DSP4-treated or control mice displayed denervation-induced supersensitivity that appear to reflect mainly postsynaptic alpha2-adrenoceptor mediation.
Journal Article↗
Effects of clonidine and alpha-adrenoceptor antagonists on motor activity in DSP4-treated mice II: interactions with apomorphine.
Adult mice were administered either the noradrenaline (NA) neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or distilled water (control), 10-12 days before motor activity testing, and 6 h before testing all the mice were administered reserpine (10 mg/kg), the monoamine-depleting agent. The interactive effects of (I) clonidine, the alpha(2)-adrenoceptor agonist, with the dopamine (DA) agonist, apomorphine, and the alpha(2)-antagonist, yohimbine, and (II) with either yohimbine or the alpha(1)-antagonist, prazosin, upon motor behaviour in activity test chambers were studied in reserpinized DSP4-treated and control mice. It was shown that apomorphine (3 mg/kg) increased locomotor and total activity in both reserpinized DSP4-treated and control mice but the effect was attenuated in the DSP4 mice. Co-administration of clonidine (3 mg/kg) with apomorphine potentiated the effects of apomorphine on motor activity and this effect was enhanced markedly by DSP4 pretreatment. Yohimbine (10 mg/kg) antagonized the motor activity-stimulating effects of apomorphine in both DSP4-treated and control mice. Co-administration of clonidine with apomorphine, following yohimbine, restored motor activity levels to those obtained in the absence of yohimbine and this effect upon locomotor activity was enhanced by DSP4 pretreatment. The effects of clonidine on motor activity were enhanced by NA-denervation. Prazzosin (3 mg/kg) enhanced the locomotor activity of both reserpinized DSP4-treated and control mice after the initial 30-min period but was not affected by DSP4 treatment. Analysis of post-decapitation convulsions (PDCs) indicated loss of the reflex by DSP4 pretreatment. Reserpine pretreatment abolished the initial, exploratory phase (30 min) of motor activity. These results demonstrate interactions between NA and DA systems that may bear eventual relevance to neurologic disorders such as parkinsonism.
Journal Article↗
Neuroprotective and neurorestorative strategies for neuronal injury.
Mechanisms of neuronal cell death in apoptosis and necrosis are examined. Neurotoxic processes underlying cellular destruction may involve N-methyl-D-aspartate (NMDA) receptor activation and/or activation of neuronal nitric oxide synthase but the depletion of energy and generation of free radicals appears to be critical. In Alzheimer's disease the damaging effects of peroxynitrite and exposure to beta-amyloid peptide is evident. Mitochondrial dysfunction is involved in several neurodegenerative diseases including Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease as well as Alzheimer's disease and in these disorders the innovations offered by techniques ranging from transgenic mouse models of the disorder to cell culture preparations are remarkable. Agents of neuroprotection and neurorestoration possess either characteristics specific to particular disorders or have a general applicability or both. The vast array of agents available are for the most part the objectives of laboratory examinations but an increasing selection of compounds are reaching the clinical necessities thereby influencing current strategic notions to modify tactical contingencies. Among the agents listed are included: inhibitors of the enzyme poly-ADP-ribose polymerase, inhibition of apoptotic cell death, agents acting on mitochondrial permeability transition, excitatory amino acid antagonists, applications of neurotrophins, immunophilins, agents influencing heme oxygenase-1 expression and iron sequestration in aging astroglia, improvements in mitochondrial energy production or buffering, and finally dopaminemimetics with differential affinities for dopamine receptors.
Journal Article↗
Restoration and putative protection in Parkinsonism.
Synergistic antiparkinsonian actions of different classes of putative therapeutic agents co-administered with a subthreshold dose of L-3,4-dihydroxyphenylalanine (L-Dopa) (5 mg/kg) in drug-naive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice as well as the restorative actions of those compounds in suprathreshold L-Dopa-tolerant MPTP-treated mice subjected to "wearing-off" of L-Dopa efficacy were assessed in a series of experiments. The classes of compounds studied included the noncompetitive NMDA antagonists, memantine, amantadine and MK-801, the anticonvulsive and putative anticonvulsive agents, lamotrigine, FCE 26743, phenytoin, the monoamine oxidase inhibitors, L-Deprenyl, amiflamine, alpha-ethyltryptamine, clorgyline and guanfacine. In this final case, the restorative effects of clonidine and guanfacine were antagonized by the alpha(2)-adrenoceptor antagonist, yohimbine, but not the alpha(1)-adrenoceptor antagonist, prazosin. Within each class of potentially therapeutic agents a differential restorative efficacy was obtained, but the combination of different doses of apomorphine with clonidine failed to restore motor activity. Finally, the neuroprotective actions of acute and subchronic administration of the nitrone spin-trapping compound, alpha-phenyl-tert-butyl nitrone upon the spontaneous motor behaviour and striatal dopamine concentrations of MPTP-treated mice was examined.
Journal Article↗
Neonatal nicotine administration influences ethanol-induced behaviors.
Neonatal mice were administered nicotine (66 microg (-)-nicotine base/kg body weight (bw) s.c. twice daily at 0800 and 1700 h on postnatal days 10 and 14) and control mice received saline (10 ml 0. 9% NaCl/kg bw s.c.) on the same occasions. Behavioral testing was initiated 3 months after birth. In Experiment 1, neonatal nicotine administration did not affect spontaneous motor activity but altered the peak dose stimulatory effect of ethanol upon locomotion and rearing activity from 3.0 mg/kg, in the control mice, to 1.5 mg/kg. Administration of the nicotine antagonist, mecamylamine (MEC, 2.0 mg/kg), had no effect upon the peak dose stimulatory effect (i.e., 1. 5 mg/kg) evidenced in the nicotine-treated mice, but attenuated the stimulatory effect of the 3.0 mg/kg dose of ethanol in the control mice. In Experiment 2, the effects of neonatal nicotine administration upon ethanol intake and preference were assessed. In the single fluid access (one-bottle) test, nicotine-treated mice consumed both more ethanol (2%, 4%, or 6% concentrations) and more tap water than control mice. In the two-bottle ethanol preference test, nicotine-treated mice consumed more ethanol and tap water. Further analysis of the high-preferring (HP) ethanol mice indicated higher ethanol intake and preference in the nicotine-treated mice but no differences in tap water or total fluid intake. The present findings are considered together with prevailing notions of nicotine receptor alterations and possible cross-sensitization effects modulating substance abuse.
Animals↗
Effects of MAO inhibitors upon MPTP mice chronically treated with suprathreshold doses of L-dopa.
Groups of mice were administered either saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (2 X 40 mg / kg, s.c., separated by a 24-hour interval) 4-6 weeks prior to behavioural testing. At testing, all the MPTP-injected mice were repeatedly administered L-dopa (20 mg / kg, s.c., five times each week, Monday-Friday), by applying a procedure that induced a severe reduction of motor activity parameters from Day 1 to Day 25. Control (uninjected mice) received only saline and were retained only for neurochemical analysis. In each of three experiments, following the reduction of the activity-stimulating effects of L-dopa by repeated administration, a restorative effect of different monoamine oxidase (MAO) inhibitors was tested by co-administration of the test compounds (irreversible MAO-B inhibitor, reversible MAO-A inhibitors, or irreversible MAO-A / mixed MAO inhibitors) with L-dopa (20 mg / kg). In each case the MAO inhibitor was injected 60 min prior to L-dopa. L-Deprenyl (3 or 10 mg / kg, s.c.), in combination with L-dopa, reinstated locomotion and total activity, but not rearing, dose-dependently, in L-dopa-tolerant mice. The reversible MAO-A inhibitors, amiflamine and alpha-ethyltryptamine, in combination with L-dopa, reinstated locomotion and total activity, leaving rearing unaffected; Ro 41-1049 (3 mg / kg, s.c.) restored all three parameters of activity; locomotor activity was restored by all three doses (1, 3, and 10 mg / kg, s.c.). On the other hand, neither the irreversible MAO-A inhibitor, clorgyline, nor the mixed MAO inhibitor, phenelzine, produced any directly effective restorative increments. Neurochemical analysis confirmed the severe striatal dopamine depletion of MPTP-treated mice. These results demonstrate a synergistic and restorative action of combining certain MAO inhibitors, namely the reversible MAO-A inhibitors, with the suprathreshold dose of L-dopa in MPTP-treated, L-dopa-tolerant mice.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Health of women: associations among life events, social support, and personality for selected patient groups.
This study examined the effects of life events, social support, personality traits, and siblings' birth-order on the health of women. 199 middle-class participants were included. 95 women, randomly assigned from four different patient groups, were compared with a control group of 96 randomly selected women without any special health problems. They completed a questionnaire which included questions regarding family background, health, different life events, social support, and signs of disease and a projective test, the Sivik Psychosomatism Test. Analysis indicated that report of negative life events was associated with more physical symptoms than positive life events and that the patient groups reported more negative life events and less social support than the control group.
Adolescent↗
Neonatal iron exposure induces neurobehavioural dysfunctions in adult mice.
Excess iron in the brain has been implicated in the pathogenesis of several human neurodegenerative disorders, i.e., Parkinson's and Alzheimer's disease. The neonatal period is critical for the establishment of normal iron content in the adult brain. In the present study, the long-term neurobehavioral effects of iron exposure during this period were assessed by treating NMRI mice orally with 0.0, 3.7, or 37.0 mg Fe(2+)/kg body wt on postnatal days 10-12. Spontaneous motor behavior and radial arm maze learning were tested at the age of 3 months. It was found that the mice treated with the higher dose of Fe(2+), 37.0 mg/kg body wt, were hypoactive during the first 20 min of testing but hyperactive during the final 20 min, showing an almost complete lack of habituation of spontaneous activity in the test chambers. These changes were also seen in animals treated with the lower dose of Fe(2+), 3.7 mg/kg body wt, but the effects were less pronounced, indicating a dose-response relationship. In the radial arm maze, the Fe(2+) 37.0 mg/kg group evidenced significantly both more errors in arm choices and longer latencies to acquire all eight pellets. Both dose groups showed attenuated performance increments on successive trials. Analysis of brain iron content indicated significantly more total iron (microgram/g) in the basal ganglia, but not frontal cortex, of the higher, 37 mg/kg, dose group. The knowledge of the long-term effects of iron entering the brain during this critical period of rapid brain growth is limited. Increased amounts of iron in the brain, especially in the basal ganglia, may contribute to neurodegenerative processes.
Animals↗
Tolerance to a suprathreshold dose of L-Dopa in MPTP mice: effects of glutamate antagonists.
Three experiments were performed to study the development and manipulation of tolerance to a suprathreshold dose of L-Dopa (20 mg/kg, s.c.) in MPTP-treated and control (saline-injected) C57 Bl/6 mice. The motor activity reinstatement effect of this dose of L-Dopa upon MPTP-treated mouse behaviour deteriorated from the 13th injection (Test Day 8) of L-Dopa onwards and reached basal level (i.e. no stimulatory effects of the drug) by the 16th administration (Test Day 10). Administration of L-Dopa to control mice reduced locomotor and rearing activity throughout the tolerance development period (Test Days 1-12) during the first hour after injection, and then increased locomotor activity during the second hour. The effects of combining either a noncompetitive, MK-801, or a competitive, CGP 40116, glutamate antagonist with L-Dopa, following tolerance development, were assessed in MPTP mice on the 23rd day of L-Dopa administration (Test Day 13). MK-801 (0.1 mg/kg, s.c.) reinstated the locomotory and rearing behaviour induced by L-Dopa; CGP 40116 did so also to a greater extent in the dose range 0.01 to 0.03 mg/kg. These results indicate that MPTP-treated mice continue to offer a useful parkinsonian model also for the examination of different aspects of the "wearing-off" phenomenon of L-Dopa tolerance and in particular the putative glutamatergic involvement. The clinical consequences may be far-reaching for the utility of L-Dopa in Parkinson's disease, whether the effects demonstrated be of a reinstatement or synergistic nature, once therapeutically adequate glutamate antagonists are more readily available.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Effects of co-administration of anticonvulsant and putative anticonvulsive agents and sub/suprathreshold doses of L-dopa upon motor behaviour of MPTP-treated mice.
The effects of co-administration of the dopamine precursor, L-Dopa, with anticonvulsant and putative anticonvulsive agents upon the motor activity of hypoactive MPTP-treated C57 BL/6 mice were measured in six experiments. In each case, MPTP (2 x 40 mg/kg, s.c., separated by a 24-hr interval) was administered four to six weeks prior to behavioural testing. Thus, the effects of these agents combined with either a single acute, subthreshold dose (5 mg/kg, s.c.) of L-Dopa, or, with chronically-administered, suprathreshold doses (20 mg/kg, s.c.) of L-Dopa were studied. In the former, lamotrigine, FCE 26743 and L-Deprenyl, injected 60 min before subthreshold L-Dopa (5 mg/kg), each induced an antiparkinsonian action in MPTP-treated mice that consisted of dose-specific, as opposed to dose-related, elevations of locomotion and rearing behaviour. In the latter, lamotrigine (all three measures of activity at 3 mg/kg), FCE 26743 (locomotion and total activity at 3; rearing at 1 and 3 mg/kg) and L-Deprenyl (locomotion and total activity at 1 and 3mg/kg), but not phenytoin (neither at 1 nor 3 mg/kg), reinstated the motor activity-stimulating effects of the threshold dose of L-Dopa (20 mg/kg) in L-Dopa-tolerant, MPTP-treated mice. Neurochemical analyses confirmed severe DA depletions in MPTP-treated mice. Since neither lamotrigine, FCE 26743 nor L-Deprenyl, nor subthreshold L-Dopa, by themselves increased the motor behaviour of MPTP-treated mice, a synergistic effect of the co-administration is concluded. Further, since the suprathreshold dose of L-Dopa by itself failed to stimulate motor activity in the MPTP mice following chronic (25 daily injections) administrations of the compound, it is suggested that a restorative effect, in combination with lamotrigine, FCE 26743 or L-Deprenyl was evidenced. The potential therapeutic benefits of anticonvulsant or putative anticonvulsive compounds for parkinsonian symptoms are discussed.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Effects of alcohol and frustration on experimental graffiti.
This study aimed to examine effects between alcohol and frustration in regard to graffiti. Forty-two subjects, 21 men and 21 women were randomly assigned in equal numbers to each of the three experimental groups, namely a Control group, an Alcohol group, and an Alcohol + Frustration group (alcohol dose: 1 ml 100% alcohol/kg body weight). For the purposes of this experiment, a test (AET) was constructed that provided scores of "scrawling-graffiti" (i.e., the amount of scrawling on pictures), "destruction", "aggression", and "sexuality". An elaboration test and a test measuring the "dispositional optimism" were also applied. The primary results indicated that (a) the Alcohol + Frustration group scored significantly higher on scrawling-graffiti compared to the Control group, (b) female subjects performed graffiti-scrawling to a greater extent than male subjects in all three groups, (c) women scored significantly higher on elaboration as compared to men. These results were interpreted as supporting the hypothesis that alcohol intake by itself is unlikely to induce destructive behavior unless accompanied by a "provocative" factor (e.g. frustration) that precipitates the putative expressions of aggressiveness.
Acting Out↗
MPTP-induced deficits in motor activity: neuroprotective effects of the spintrapping agent, alpha-phenyl-tert-butyl-nitrone (PBN).
In Experiment 1, groups of mice were administered either saline or MPTP (2 x 30 mg/kg, s.c., separated by a 24-hr interval) 30 min after being injected either PBN (15, 50 or 150 mg/kg, s.c., low, medium and high doses, respectively) or L-Deprenyl (0.25 or 10.0 mg/kg, s.c., low and high doses, respectively), the reference compound used, or saline. Tests of spontaneous motor activity 14 days later indicated that the MPTP-induced hypokinesia for locomotion and rearing was alleviated by prior administration with PBN (50 or 150 mg/kg) or L-Deprenyl (10.0 mg/kg); lower doses of PBN (15 mg/kg) and L-Deprenyl (0.25 mg/kg) did not affect the MPTP-induced deficits. Dopamine (DA) concentrations in the striatum confirmed a more severe loss of DA in the MPTP, PBN (15) + MPTP and Deprenyl(0.25) + MPTP groups than in the control group. Significant protection of DA was observed in the PBN(50) + MPTP, PBN(150) + MPTP and Deprenyl(10) + MPTP groups that did not exhibit an hypokinetic behaviour. In Experiment 2, the effects of repeated treatment with PBN (50 mg/kg, s.c. over 12 days), post-MPTP, were studied in aged (15-month-old) and young (3-month-old) mice. Subchronic administration of PBN increased substantially the motor activity of old and young mice that had received MPTP. Aged control (saline) mice showed an activity deficit compared to young control mice; this deficit was abolished by repeated PBN treatment. The results suggest that moderate-to-high doses of PBN whether injected in a single dose prior to MPTP or subchronically following MPTP injections may afford protective effects against both the functional changes and DA-loss caused by MPTP treatment, possibly through an antioxidant mechanism.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗