| 1. |
- Archer, Trevor, 1949, et al.
(author)
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Influence of noradrenaline denervation on MPTP-induced deficits in mice
- 2006
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In: Journal of neural transmission. - : Springer Science and Business Media LLC. - 0300-9564 .- 1435-1463. ; 113:9, s. 1119-1129
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Journal article (peer-reviewed)abstract
- C57/BL6 mice were administered either DSP4 (50 mg/kg, s.c., 30 min after injection of zimeldine, 20 Cemg/kg, s.c.) or vehicle (saline) at 63 days of age. Three weeks later, one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered MPTP (2 x 40 mg/kg, s.c., 24 hours between injections; the High dose groups), one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered MPTP (2 x 20 mg/kg, s.c., 24 hours between injections; the Low dose groups), and one group (n = 10) of DSP4-treated and one group of vehicle-treated mice were administered vehicle. Three weeks later, all six groups were tested in motor activity test chambers, followed by injections of L-Dopa (20 mg/kg, s.c.), and then tested over a further 360 min in the activity test chambers. It was found that pretreatment with the selective NA neurotoxin, DSP4, deteriorated markedly the dose-dependent motor activity deficits observed in the vehicle pretreated MPTP treated mice. These 'ultra-deficits' in the spontaneous motor behaviour of MPTP-treated mice were observed over all three parameters: locomotion, rearing and total activity, and were restricted to the 1(st) and 2(nd) 20-min periods. Administration of L-Dopa (20 mg/kg) following the 60-min testing of spontaneous behaviour restored the motor activity of Vehicle + MPTP treated mice (neither the Vehicle + MPTP-Low nor the Vehicle + MPTP-High groups differed from the Vehicle-Vehicle group, here) but failed to do so in the DSP4 pretreated mice. Here, a dose-dependent deficit of L-Dopa-induced motor activity (over all three parameters) was obtained thereby offering further evidence of an 'ultra-deficit' of function due to previous denervation of the NA terminals. The present findings support the notion that severe damage to the locus coeruleus noradrenergic system, through systemic DSP4, disrupts the facilitatory influence on the nigrostriatal DA system, and interferes with the ability of the nigrostriatal pathway to compensate for or recover from marked injury, MPTP treatment.
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| 2. |
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| 3. |
- Archer, Trevor, 1949, et al.
(author)
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Behavioural supersensitivity following neonatal 6-hydroxydopamine : Attenuation by MK-801
- 2007
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In: Neurotoxicity research. - 1029-8428 .- 1476-3524. ; 12:2, s. 113-124
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Journal article (peer-reviewed)abstract
- Male rat pups were administered 6-hydroxydopamine (6-OHDA, 75 μg, intracisternally, 30 min after desipramine, 25 mg/kg, s.c.) on Days 1 or 2 after birth, or were sham-operated (receiving vehicle). In four experiments, the acute effects of apomorphine, with or without pretreatment with MK-801 (0.03 mg/kg), upon motor activity in test chambers was measured. Acute treatment with apomorphine (0.1 mg/kg) increased locomotor, rearing and total activity markedly compared to both the acute saline administered 6-OHDA rats and the sham-operated rats administered saline. Acute MK-801 (0.03 mg/kg) co-administered shortly before (5 min) apomorphine (0.3 or 1.0 mg/kg) reduced markedly locomotion and total activity in 6-OHDA-treated and sham-operated rats. Rearing behaviour was increased in both the 6-OHDA groups of rats. Acute MK-801 increased activity in the 6-OHDA-treated rats, which was not observed in sham-operated rats. At the 0.3 and 1.0 mg/kg doses of apomorphine, neonatal 6-OHDA treament increased all three parameters of motor activity. Acute treatment with apomorphine (0.1 mg/kg) induced different effects on the motor activity of 6-OHDA-treated and sham-operated mice. In sham-operated rats apomorphine reduced motor activity during the 1st 30-min period but increased locomotion and total activity, but not rearing, during the 2nd and 3rd periods, whereas in 6-OHDA-treated rats, apomorphine increased locomotor, rearing and total activity markedly. Dopamine loss and serotonin elevation in the striatum and olfactory tubercle were confirmed. The present findings confirm the influence of non-competitive glutamate antagonists in attenuating the behavioural supersensitivity to dopamine antagonists.
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| 4. |
- Archer, Trevor, 1949, et al.
(author)
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Delayed Exercise-Induced Functional and Neurochemical Partial Restoration Following MPTP
- 2012
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In: Neurotoxicity research. - : Springer Science and Business Media LLC. - 1029-8428 .- 1476-3524. ; 21:2, s. 210-221
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Journal article (peer-reviewed)abstract
- In two experiments, MPTP was administered to C57/BL6 mice according to a single-dose weekly regime (MPTP: 1 x 30 mg/kg on the fifth day of the week, Friday, over 4 weeks) with vehicle group (Vehicle: 1 x 5 ml/kg) treated concurrently. Exercise schedules (delayed) were introduced either at the beginning of the week after the second MPTP injection (MPTP + Exercise(2) group), or at the beginning of the week after the fourth MPTP injection (MPTP + Exercise(4) group). Wheel-running was provided on the first 4 days of each week (Monday-Thursday) more than 30-min periods. In Experiment I, wheel-running exercise was introduced either after 2 or 4 weeks after MPTP/Vehicle. MPTP and Vehicle groups not provided access to the running wheels were placed in single cages within the wheel-running room over 30-min concomitantly with the wheel-running groups. In Experiment II, wheel-running exercise was introduced 2 weeks after MPTP/Vehicle but a no-exercise control group with non-revolving wheel included (MPTP-Wheel). In both experiments, spontaneous motor activity tests during 60-min intervals were performed at the end (Fridays) of weeks 1, 2, 3, 4, 6, 8, and 10, where the week on which the first injection of MPTP was the first week; in the case of weeks 1-4, this was immediately before MPTP/Vehicle injections. It was observed that the introduction of the exercise schedule after the second MPTP injection, but not after the fourth injection, restored motor activity that had been markedly elevated by the end of the tenth week. Subthreshold administration of l-dopa tests was performed after the spontaneous motor activity tests 6, 8 and 10; these indicated significant effects of exercise, MPTP + Exercise(2) group, on Tests 6 and 8, but not Test 10. The physical exercise schedule in that group also showed markedly attenuated loss of dopamine (DA). Restoration of MPTP-induced motor activity deficits and DA loss was a function of the point at which exercise was introduced, in the present case after two administrations of the neurotoxin. In Experiment II, physical exercise markedly attenuated the hypokinesic effect of MPTP in the exercise condition, MPTP-exercise, but not in the non-exercise conditions, MPTP-Cage and MPTP-Wheel, for both spontaneous motor activity and l-dopa-induced activity. MPTP-induced loss of DA was also attenuated by exercise.
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| 5. |
- Archer, Trevor, 1949, et al.
(author)
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Functional consequences of iron overload in catecholaminergic interactions: the Youdim factor
- 2007
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In: Neurochemical Research. - : Springer Science and Business Media LLC. - 0364-3190 .- 1573-6903. ; 32:10, s. 1625-1639
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Research review (peer-reviewed)abstract
- The influence of postnatal iron overload upon implications of the functional and interactive role of dopaminergic and noradrenergic pathways that contribute to the expressions of movement disorder and psychotic behaviours in mice was studied in a series of experiments. (1) Postnatal iron overload at doses of 7.5 mg/kg (administered on Days 10–12 post partum) and above, invariably induced a behavioural syndrome consisting of an initial (1st 20–40 min of a 60-min test session) hypoactivity followed by a later (final 20 min of a 60-min test session) hyperactivity, when the mice were tested at adult ages (age 60 days or more). (2) Following postnatal iron overload, subchronic treatment with the neuroleptic compounds, clozapine and haloperidol, dose-dependently reversed the initial hypoactivity and later hyperactivity induced by the metal. Furthermore, DA D2 receptor supersensitivity (as assessed using the apomorphine-induced behaviour test) was directly and positively correlated with iron concentrations in the basal ganglia. (3) Brain noradrenaline (NA) denervation, using the selective NA neurotoxin, DSP4, prior to administration of the selective DA neurotoxin, MPTP, exacerbated both the functional (hypokinesia) and neurochemical (DA depletion) effects of the latter neurotoxin. Treatment with L-Dopa restored motor activity only in the animals that had not undergone NA denervation. These findings suggest an essential neonatal iron overload, termed “the Youdim factor”, directing a DA–NA interactive component in co-morbid disorders of nigrostriatal-limbic brain regions.
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| 6. |
- Archer, Trevor, 1949, et al.
(author)
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Influence of Physical Exercise on Neuroimmunological Functioning and Health : Aging and Stress
- 2011
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In: Neurotoxicity research. - : Springer Science and Business Media LLC. - 1029-8428 .- 1476-3524. ; 20:1, s. 69-83
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Journal article (peer-reviewed)abstract
- Chronic and acute stress, with associated pathophysiology, are implicated in a variety of disease states, with neuroimmunological dysregulation and inflammation as major hazards to health and functional sufficiency. Psychosocial stress and negative affect are linked to elevations in several inflammatory biomarkers. Immunosenescence, the deterioration of immune competence observed in the aged aspect of the life span, linked to a dramatic rise in morbidity and susceptibility to diseases with fatal outcomes, alters neuroimmunological function and is particularly marked in the neurodegenerative disorders, e.g., Parkinson's disease and diabetes. Physical exercise diminishes inflammation and elevates agents and factors involved in immunomodulatory function. Both the alleviatory effects of life-long physical activity upon multiple cancer forms and the palliative effects of physical activity for individuals afflicted by cancer offer advantages in health intervention. Chronic conditions of stress and affective dysregulation are associated with neuroimmunological insufficiency and inflammation, contributing to health risk and mortality. Physical exercise regimes have induced manifest anti-inflammatory benefits, mediated possibly by brain-derived neurotrophic factor. The epidemic proportions of metabolic disorders, obesity, and diabetes demand attention; several variants of exercise regimes have been found repeatedly to induce both prevention and improvement under both laboratory and clinical conditions. Physical exercise offers a unique non-pharmacologic intervention incorporating multiple activity regimes, e.g., endurance versus resistance exercise that may be adapted to conform to the particular demands of diagnosis, intervention and prognosis inherent to the staging of autoimmune disorders and related conditions.
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| 7. |
- Archer, Trevor, 1949, et al.
(author)
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Physical Exercise Attenuates MPTP-Induced Deficits in Mice
- 2010
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In: Neurotoxicity research. - : Springer Science and Business Media LLC. - 1029-8428 .- 1476-3524. ; 18:3-4, s. 313-327
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Journal article (peer-reviewed)abstract
- Two experiments were performed to investigate the effects of physical exercise upon the hypokinesia induced by two different types of MPTP administration to C57/BL6 mice. In the first, mice were administered either the standard MPTP dose (2 x 20 or 2 x 40 mg/kg, 24-h interval) or vehicle (saline, 5 ml/kg); and over the following 3 weeks were given daily 30-min period of wheel running exercise over five consecutive days/week or placed in a cage in close proximity to the running wheels. Spontaneous motor activity testing in motor activity test chambers indicated that exercise attenuated the hypokinesic effects of both doses of MPTP upon spontaneous activity or subthreshold l-Dopa-induced activity. In the second experiment, mice were either given wheel running activity on four consecutive days (30-min period) or placed in a cage nearby and on the fifth day, following motor activity testing over 60 min, injected with either MPTP (1 x 40 mg/kg) or vehicle. An identical procedure was maintained over the following 4 weeks with the exception that neither MPTP nor vehicle was injected after the fifth week. The animals were left alone (without either exercise or MPTP) and tested after 2- and 4-week intervals. Weekly exercise blocked, almost completely, the progressive development of severe hypokinesia in the MPTP mice and partially restored normal levels of activity after administration of subthreshold l-Dopa, despite the total absence of exercise following the fifth week. In both experiments, MPTP-induced loss of dopamine was attenuated by the respective regime of physical exercise with dopamine integrity more effectively preserved in the first experiment. The present findings are discussed in the context of physical exercise influences upon general plasticity and neuroreparative propensities as well as those specific for the nigrostriatal pathway.
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| 8. |
- Archer, Trevor, 1949, et al.
(author)
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Restoration of MPTP-induced deficits by Exercise and Milmed® Co-treatment
- 2014
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In: PeerJ. - : PeerJ. - 2167-8359. ; 2:e531
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Journal article (peer-reviewed)abstract
- 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces permanent neurochemical and functional deficits. Following the administration of either two or four injections of the dopamine neurotoxin, MPTP, at a dose of 40 mg/kg, C57/BL6 mice were given access to running-wheels (30-min sessions, four times/week, Monday–Thursday) and treatment with the treated yeast, Milmed® (four times/week, Monday–Thursday), or simply running-wheel exercise by itself, over ten weeks. It was observed that the combination of physical exercise and Milmed® treatment, the MPTP + Exercise + Yeast (MC) group [MPTP + Ex- ercise + Milmed® (MC)], restored spontaneous motor activity markedly by test day 10, restored completely subthreshold L-Dopa-induced activity, and dopamine concentration to 76% of control values, in the condition wherein two adminis- trations of MPTP (2 × 40 mg/kg) were given prior to initiation of exercise and/or Milmed® treatment. Physical exercise by itself, MPTP + Exercise (MC) group, attenuated these deficits only partially. Administration of MPTP four times (i.e., 40 mg/kg, s.c., once weekly over four weeks for a total of 160 mg/kg, MPTP + Exer- cise + Yeast (MC) group [MPTP + Exercise + Milmed® (SC)] and MPTP + Exercise (SC), induced a lesioning effect that was far too severe for either exercise alone or the exercise + Milmed® combination to ameliorate. Nevertheless, these findings indicate a powerful effect of physical exercise reinforced by Milmed® treatment in restoring MPTP-induced deficits of motor function and dopamine neurochemistry in mice.
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| 9. |
- Archer, Trevor, 1949, et al.
(author)
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The Yeast Product Milmed Enhances the Effect of Physical Exercise on Motor Performance and Dopamine Neurochemistry Recovery in MPTP-Lesioned Mice
- 2013
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In: Neurotoxicity Research. - : Springer Science and Business Media LLC. - 1029-8428 .- 1476-3524. ; 24:3, s. 393-406
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Journal article (peer-reviewed)abstract
- Both clinical and laboratory studies have demonstrated that different types of physical exercise may alleviate Parkinsonism yet evidence for complete restoration of motor function and biomarker integrity are difficult to identify. MPTP (1 x 30 mg/kg, s.c., 4 groups) or saline (vehicle 1 x 5 ml/kg, s.c., 1 group) were administered in a single dose regime over three consecutive weeks on Fridays. Three MPTP groups were given four 30-min periods/week (Mondays to Thursdays), of these two groups, MPTP + Exer + M(i) and MPTP + Exer + M(ii); the former were introduced to exercise and Milmed (oral injection) on the week following the 1st MPTP injection and the latter on the Monday prior to the 1st injection of MPTP onwards. One MPTP group, MPTP + Exer, was given access to exercise (running wheels) from the week following the 1st MPTP injection onwards. The fourth MPTP group, MPTP-NoEx, and the Vehicle group were only given access to exercise on a single day each week (Wednesdays, exercise test) from the week following the 1st MPTP injection onwards. The exercise/exercise + Milmed regime was maintained for a further 9 weeks. It was observed that exercise by itself ameliorated MPTP-induced deficits regarding motor function and dopamine loss only partially whereas in the groups combining exercise with twice weekly dosages of Milmed the MPTP-induced deficits were abolished by the 10th week of the intervention. The three main conclusions that were drawn from correlational analyses of individual mice were: (i) that DA integrity was observed to be a direct function of ability to express running exercise in a treadmill wheel-running arrangement, and (ii) that DA integrity was observed to be a direct function of the capacity for motor performance as measured by spontaneous motor activity and subthreshold l-Dopa (5 mg/kg) induced activity in the motor activity test chambers, and (iii) that the extent to which running exercise in a running wheel was predictive of later motor performance in the activity test chambers was highly convincing.
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