Nigrostriatal Dopaminergic Neurotoxicity Research Articles

Age-related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype.

While advancing age is the only unequivocally accepted risk factor for idiopathic Parkinson's disease, it has been postulated that exposure to environmental neurotoxicants combined with ageing could increase the risk for developing Parkinson's disease. The current study tested this hypothesis by exposing C57BL/6 mice that were 6 weeks, 5 months or 18 months old to the herbicide paraquat, the fungicide maneb or paraquat + maneb, a combination that produces a Parkinson's disease phenotype in young adult mice. Paraquat + maneb-induced reductions in locomotor activity and motor coordination were age dependent, with 18-month-old mice most affected and exhibiting failure to recover 24 h post-treatment. Three months post-treatment, reductions in locomotor activity and deficits in motor coordination were sustained in 5-month-old and further reduced in 18-month-old paraquat + maneb groups. Progressive reductions in dopamine metabolites and dopamine turnover were greatest in 18-month-old paraquat + maneb and paraquat groups 3 months post-treatment. Increased tyrosine hydroxylase enzyme activity compensated for striatal tyrosine hydroxylase protein and/or dopamine loss following treatment in 6-week-old and 5-month-old, but not 18-month-old paraquat and paraquat + maneb mice. Numbers of nigrostriatal dopaminergic neurons were reduced in all age groups following paraquat alone and paraquat + maneb exposure, but these losses, along with decreases in striatal tyrosine hydroxylase protein levels, were progressive in 18-month-old paraquat and paraquat + maneb groups between 2 weeks and 3 months post-exposure. Collectively, these data demonstrate enhanced sensitivity of the ageing nigrostriatal dopamine pathway to these pesticides, particularly paraquat + maneb, resulting in irreversible and progressive neurotoxicity.

Methamphetamine–gonadal steroid hormonal interactions:: Effects upon acute toxicity and striatal dopamine concentrations

Methamphetamine (MA)-related deaths and nigrostriatal dopaminergic (NSDA) neurotoxicity are greater in males. The exact basis for this gender difference is not known, but data, which show that estrogen (E) can function as a protectant of both the cardiovascular and NSDA systems, suggest an important role for gonadal steroids in modulating toxicity to this psychostimulant. In the present report, we examined the effects of treatment with the gonadal steroid hormones E and testosterone (T) upon MA-induced toxicity within intact and castrated female and male CD-1 mice. Treatment of intact males with E produced a severe acute toxicity to MA, with only 41% (7/17) males surviving at 24-h post-MA. This incidence of mortality was significantly different from that of nonhormonally treated mice receiving an identical regimen of MA [94% survival (16/17)]. None of the other treatment groups showed mortality rates, which differed significantly from the nonhormonally treated mice. Striatal dopamine (DA) concentrations of E-treated female mice (intact or castrated) were significantly greater than that of the nonhormonally treated mice, which failed to differ statistically among each other. In an attempt to understand some of the bases for the mortality rates in E-treated intact males, body temperatures, heart rates and heart catecholamine concentrations were measured from an additional group of intact male mice treated or not treated with E. Heart rates of E-treated intact males were significantly decreased compared with non-E-treated males. No statistically significant differences were obtained for body temperatures or heart catecholamine concentrations. These data demonstrate that MA induces an exacting, acute toxicity, which is specific for E-treated intact male mice and is associated with a reduction in heart rate. In addition, E can function as a neuroprotectant of NSDA system within female, but not male, mice. These data suggest that acute MA toxicity observed with E in intact male mice may result from a change in cardiac function. Accordingly, gonadal steroid hormones can function as critical modulators of both central and peripheral toxicological effects of MA.

Tamoxifen abolishes estrogen's neuroprotective effect upon methamphetamine neurotoxicity of the nigrostriatal dopaminergic system.

The effects of 17beta-estradiol and the anti-estrogen, tamoxifen, on methamphetamine-induced neurotoxicity of the nigrostriatal dopaminergic system were examined in ovariectomized CD-1 mice. In Experiment 1, striatal dopamine concentrations from estrogen treated mice were significantly greater than that from non-estrogen treated mice following methamphetamine. Dopamine concentrations from estrogen+tamoxifen+methamphetamine treated mice were decreased compared to estrogen+methamphetamine treated mice and not significantly different from those of tamoxifen+methamphetamine treated mice or mice receiving methamphetamine alone. These results suggest that estrogen is functioning as a neuroprotectant of methamphetamine-induced nigrostriatal dopaminergic neurotoxicity and that this neuroprotective effect of estrogen is abolished in the presence of tamoxifen. In Experiment 2, estrogen administration after methamphetamine treatment did not produce any significant changes in dopamine concentrations compared with methamphetamine treatment alone. The data from Experiment 2 show that estrogen cannot reverse the methamphetamine-induced neurotoxicity upon the nigrostriatal dopaminergic system. Similar results were observed for the potassium-stimulated dopamine outputs from these treatment conditions as evaluated with in vitro superfusion, although a difference between the two measures for the estrogen+methamphetamine treated group was obtained in Experiment 1. These results have important implications for estrogen-tamoxifen interactions upon the nigrostriatal dopaminergic system and the gender differences which are observed in Parkinson's disease and animal models of nigrostriatal dopaminergic neurotoxicity as well as for the proposed use of tamoxifen in pre-menopausal women at risk for breast cancer.

The effect of testosterone upon methamphetamine neurotoxicity of the nigrostriatal dopaminergic system

The gonadal steroid hormone estrogen (E) can function as a neuroprotectant of nigrostriatal dopaminergic (NSDA) neurotoxicity, however, there exists very limited information on the role of testosterone (T) in this capacity. In the present report, the effects of T on methamphetamine (MA) induced neurotoxicity of the NSDA system were examined in gonadectomized female and male CD-1 mice. In Experiment 1, striatal dopamine (DA) concentrations and output from T-treated ovariectomized mice were not significantly different from that of non-T-treated mice following MA. These results suggest that T is not functioning as a modulator of MA-induced NSDA neurotoxicity in ovariectomized CD-1 mice. In Experiment 2, there were no significant differences in DA concentrations or output among T-treated, non-T-treated as well as E-treated orchidectomized mice following MA. The results of Experiment 2 indicate that the neuroprotective effect of E reported within ovariectomized mice is not seen in male mice. Nor does T appear to function as a modulator of MA neurotoxicity in male mice. These effects of T and E upon the MA induced neurotoxicity of the NSDA system have important implications for the gender differences which are observed in animal models of NSDA neurotoxicity and in Parkinson’s disease.

Nigrostriatal dopaminergic neurotoxicity of L-cysteine after stereotaxic administration into the substantia nigra of rats: Potential implications for MPTP-induced neurotoxicity and parkinson’s disease

Stereotaxic administration of L-cysteine (CySH) into the rat substantia nigra pars compacta (SNC) evokes a dose-dependent fall of striatal levels of dopamine. This, together with decreased tyrosine hydroxylase immunoreactivity in the striatum and SNcand decreased nigral staining for Niss1 substance indicate that CySH is a dopaminergic neurotoxin. The neurotoxic effects of CySH infusion into the rat SNC were blocked by prior administration of the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801. Previous studies have demonstrated that administration of the neurotoxin l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) not only evokes the degeneration of nigrostriatal dopamine neurons but also causes a significant fall of glutathione (GSH) without corresponding increases of glutathione disulfide (GSSG). Furthermore, microdialysis studies have demonstrated that when perfusions of l-methyl-4-phenylpyridinium (MPP+), the active metabolite of MPTP, into the rat SNC are discontinued extracellular levels of GSH massively but transiently increase followed by a prolonged elevation of extracellular CySH, the latter effect being blocked by inhibition of γ-glutamyl transpeptidase (γ-GT). These observations, together with the present results, suggest that the delayed but prolonged elevation of extracellular CySH that occurs as a MPP+-induced dopaminergic SNccell energy impairment begins to subside might evoke NMDA receptor mediated excitotoxicity. The potential roles of elevated extracellular CySH in MPTP/MPP+-induced dopaminergic neurotoxicity and in the pathogenesis of Parkinson’s disease are discussed.

Involvement of monoamine oxidase inhibition in neuroprotective and neurorestorative effects of ginkgo biloba extract against MPTP-induced nigrostriatal dopaminergic toxicity in C57 mice

The present study investigated the neuroprotective and neurorestorative effects of Ginkgo biloba extract (EGb 761) and its two components ginkgolides A (BN52020) and B (BN52021) in mice. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg/kg/d ip for six days) significantly reduced striatal dopamine (DA) levels in C57 mice measured by high performance liquid chromatography with electrochemical detection (HPLC-EC). When C57 mice were pretreated with EGb 761 (20, 50, 100 mg/kg/d ip) for 7 days and then treated with the same extract 30 min before MPTP injection for 6 days, the neurotoxic effect of MPTP was antagonized in a dose-dependent fashion. Similar treatment with ginkgolides A and B (5, 10, 50 mg/kg/d ip) showed no protective effect. When C57 mice were treated with EGb 761 (50 mg/kg/d ip) after MPTP-lesion, the recovery of striatal dopamine (DA) levels was accelerated. However, similar treatment with ginkgolides A or B (10 mg/kg/d ip) did not show any effect. EGb 761, but not ginkgolides A and B, nonselectively inhibited mouse brain MAO activity in vitro (IC 50 = 36.45 ± 1.56 μg/ml tested by an improved fluorimetric assay. The results demonstrate that EGb 761 administered before or after MPTP treatment effectively protects against MPTP-induced nigrostriatal dopaminergic neurotoxicity and that the inhibitory effect of EGb 761 on brain MAO may be involved in its neuroprotective effect.

Estrogen as a neuromodulator of MPTP-induced neurotoxicity: effects upon striatal dopamine release

The effects of estrogen upon MPTP-induced neurotoxicity were examined using in vitro superfusion. In Experiment 1, striatal tissue from ovariectomized rats was infused with MPP + (10 μM), a combination of MPP + and 17β-estradiol (300 nM), the same dose of estradiol preceding MPP +, or no treatment infusion. The effects of these treatments on dopamine release rates during the infusion periods were determined. Infusion of MPP + resulted in a significant increase in dopamine release as compared to the control. Estradiol added to the MPP + infusion significantly attenuated this dopamine (DA) release, while estradiol treatment preceding the MPP + had no effect. In Experiment 2, three different doses of estradiol (0.3, 3, or 300 nM) were infused simultaneously with the MPP +. Doses of estradiol below 300 nM did not attenuate the DA release. In Experiment 3, estradiol alone (300 nM) was infused, to determine dopamine release rate effects of the hormone itself. There was no difference between estradiol treated and non-infused control groups. These results demonstrate that the gonadal steroid hormone estradiol can modulate responses of striatal dopamine neurons to MPP + by altering the immediate increase in dopamine release which occurs in response to this neurotoxin. These modulating effects of estradiol are dose-dependent, and represent a direct effect upon striatal neurons, most likely involving a non-genomic mechanism of action. These results implicate that hormonal modulation of nigrostriatal dopaminergic neurotoxicity may represent an important variable responsible for the sex differences which are reported in Parkinson's disease.

Effects of testosterone upon MPTP-induced neurotoxicity of the nigrostriatal dopaminergic system of C57/B1 mice

We have recently reported that treatment of gonadectomized female and male C57/B1 mice with the gonadal steroid hormone, estrogen, reduced nigrostriatal dopaminergic neurotoxicity resulting from the Parkinson's-like inducing agent 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). In the present report we examined whether the predominantly male gonadal steroid hormone, testosterone, would similarly modulate MPTP-induced neurotoxicity. Male C57/B1 mice were assigned to one of the following five treatment conditions: (1) Intact, (2) Orchidectomized, (3) Intact + MPTP, (4) Orchidectomized + Testosterone + MPTP and (5) Orchidectomized + MPTP. Corpus striatal and olfactory tubercle dopamine, DOP AC and norepinephrine concentrations were determined from the animals within each of the five treatment conditions. Orchidectomy alone failed to alter striatal dopamine and DOPAC concentrations, with levels obtained being similar to that of Intact animals. MPTP treatment significantly reduced striatal dopamine and DOPAC concentrations, regardless of hormonal condition of the animal. Similar results were obtained for olfactory tubercle determinations, with the exception that DOPAC levels from Orchidectomized mice were significantly greater than Intact males. No significant differences were obtained for norepinephrine within either brain area sampled. These results show that unlike estrogen, testosterone is devoid of any capacity to modulate nigrostriatal dopaminergic neurotoxicity resulting from MPTP. These findings may be related to the gender differences which exist in the prevalence of Parkinson's disease.

Studies with the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and several of its analogs

The nigrostriatal dopaminergic neurotoxicity of MPTP was prevented in mice in a dose-dependent manner by the monoamine oxidase-B (MAO-B) inhibitor deprenyl. This finding, combined with other observations, points out the important role of MAO-B in the bioactivation of MPTP. In the present study, some comparisons between MPTP and several of its structural analogs will be presented.

Time-dependent inhibition of rat brain monoamine oxidase by an analogue of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP),4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine

Inhibitory effects of some MPTP and MPP + analogues on rat brain MAO activity were studied to further clarify the structure-activity relationships of MPTP neurotoxicity. Of the analogues tested, 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (CPTP), 4-(4-chlorobenzyl)-pyridine (CBP), 4-benzylpyridine (BPY) and 4-benzylpiperidine (BPIP) dose-dependently inhibited both MAO-A and -B activities. CPTP, BPY and BPIP showed a higher MAO-A selectivity, while CBP was a selective MAO-B inhibitor. In preincubation studies, only CPTP greatly enhanced the degree of inhibition of MAO-B when the preincubation time was increased, but inhibition of MAO-A was not enhanced. Together with our previous MPTP and MPP + analogue findings, the present results indicate that, in these chemical structures, a 4-phenyl-1,2,3,6-tetrahydropyridine ring is most essential for time-dependent inhibition of MAO. This chemical requirement is consistent with the ability to cause nigrostriatal dopaminergic neurotoxicity.