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PubMed2005

Thalamic neuronal activity in dopamine-depleted primates: evidence for a loss of functional segregation within basal ganglia circuits.

Different analyses of neuronal activity in primate models of Parkinson's disease (PD) have resulted in two different views on the effects of dopamine depletion. The first is based on the higher firing rate and bursty firing pattern, and assumes that dopamine depletion results in a hyperactivity of basal ganglia (BG) output structures. The second is based on the less-specific responses to passive joint manipulation and the excessive correlations between neuronal discharges, and assumes that dopamine depletion results in a loss of functional segregation in cortico-BG circuits. The aim of the present study was to test out the predictions of these two different views on thalamic neuronal activity. Three male vervet monkeys (Cercopithecus aethiops) were progressively intoxicated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Neuronal activities were characterized using standard analyses (firing rates and patterns, receptive fields, and cross-correlations) and compared between the normal, asymptomatic (before the stabilization of motor symptoms), and parkinsonian (with persistent akinesia and rigidity) stages of MPTP intoxication. The pallidonigral thalamus (receiving projections from the BG) was characterized in both the asymptomatic and parkinsonian states by (1) an unchanged firing rate and pattern and (2) a proliferation of nonspecific neurons and correlated pairs. In contrast, the cerebellar thalamus (receiving projections from the cerebellum), was characterized by no change (asymptomatic state) or minor changes (symptomatic state). Thus the major dysfunction after dopamine depletion appeared to be the loss of functional segregation within cortico-BG circuits, which could also be at the heart of parkinsonian pathophysiology.

Action Potentials↗
PubMed2005

Selective glial cell line-derived neurotrophic factor production in adult dopaminergic carotid body cells in situ and after intrastriatal transplantation.

Glial cell line-derived neurotrophic factor (GDNF) exerts a notable protective effect on dopaminergic neurons in rodent and primate models of Parkinson's disease (PD). The clinical applicability of this therapy is, however, hampered by the need of a durable and stable GDNF source allowing the safe and continuous delivery of the trophic factor into the brain parenchyma. Intrastriatal carotid body (CB) autografting is a neuroprotective therapy potentially useful in PD. It induces long-term recovery of parkinsonian animals through a trophic effect on nigrostriatal neurons and causes amelioration of symptoms in some PD patients. Moreover, the adult rodent CB has been shown to express GDNF. Here we show, using heterozygous GDNF/lacZ knock-out mice, that unexpectedly CB dopaminergic glomus, or type I, cells are the source of CB GDNF. Among the neural or paraneural cells tested, glomus cells are those that synthesize and release the highest amount of GDNF in the adult rodent (as measured by standard and in situ ELISA). Furthermore, GDNF expression by glomus cells is maintained after intrastriatal grafting and in CB of aged and parkinsonian 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated animals. Thus, glomus cells appear to be prototypical abundant sources of GDNF, ideally suited to be used as biological pumps for the endogenous delivery of trophic factors in PD and other neurodegenerative diseases.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2005

Quantitative 1H magnetic resonance spectroscopic imaging determines therapeutic immunization efficacy in an animal model of Parkinson's disease.

Nigrostriatal degeneration, the pathological hallmark of Parkinson's disease (PD), is mirrored by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. MPTP-treated animals show the common behavioral, motor, and pathological features of human disease. We demonstrated previously that adoptive transfer of Copaxone (Cop-1) immune cells protected the nigrostriatal dopaminergic pathway in MPTP-intoxicated mice. Herein, we evaluated this protection by quantitative proton magnetic resonance spectroscopic imaging (1H MRSI). 1H MRSI performed in MPTP-treated mice demonstrated that N-acetyl aspartate (NAA) was significantly diminished in the substantia nigra pars compacta (SNpc) and striatum, regions most affected in human disease. When the same regions were coregistered with immunohistochemical stains for tyrosine hydroxylase, numbers of neuronal bodies and termini were similarly diminished. MPTP-intoxicated animals that received Cop-1 immune cells showed NAA levels, in the SNpc and striatum, nearly equivalent to PBS-treated animals. Moreover, adoptive transfer of immune cells from ovalbumin-immunized to MPTP-treated mice failed to alter NAA levels or protect dopaminergic neurons and their projections. These results demonstrate that 1H MRSI can evaluate dopaminergic degeneration and its protection by Cop-1 immunization strategies. Most importantly, the results provide a monitoring system to assess therapeutic outcomes for PD.

Adoptive Transfer↗
PubMed2006

Enhanced de novo neurogenesis and dopaminergic neurogenesis in the substantia nigra of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease-like mice.

Research reports on de novo neurogenesis, particularly dopaminergic (DA) neurogenesis in the adult mammalian substantia nigra (SN), remain very controversial. For this reason, we used the nestin second intron enhancer-controlled LacZ reporter transgenic mouse model coupled with the 1-methyl-4-phyenyl-1,2,3,6-tetrahydropyridine (MPTP) lesion system to investigate whether there are neurogenesis and DA neurogenesis in the SN of the adult normal and Parkinson's disease (PD)-like mice. First, we demonstrated the presence of neural progenitor cells (NPCs), basal levels of neurogenesis, and DA neurogenesis in the normal adult mouse SN. Second, we showed that there is not only a significant increase in the number of NPCs but also a dramatic increase of neurogenesis from the NPCs in the SN and the midline region adjacent to the SN of the PD-like mice compared with that of normal controls. More importantly, we also demonstrated that there is an increase of DA neurogenesis in the SN of the MPTP-lesioned mice. Third, we showed that the increased DA neurogenesis in the MPTP-lesioned mice was derived from the NPCs and 5-bromodeoxyuridine-positive cells, suggesting that multiple stem cell lineages may contribute to the enhanced neurogenesis in the adult SN. Taken together, these results establish that there are basal levels, albeit low, and increased levels of de novo neurogenesis and DA neurogenesis in the SN of the adult normal and PD-like mice, respectively. The increased NPCs in the MPTP-lesioned mice further suggest that experimental approaches to promote de novo neurogenesis may provide an effective therapy for PD by functional replacement of degenerated DA neurons.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2003

Rest tremor in rhesus monkeys with MPTP-induced parkinsonism.

Rest tremor (RTr) is a typical feature of Parkinson's diseases (PD). Animal models of PD presenting with RTr are indispensable for understanding the pathophysiology of human RTr and the development of new therapeutic agents. In this report we studied the occurrence of tremor on rhesus monkeys rendered parkinsonian by an intracarotid (ICA) infusion followed by 2-4 iv. doses of n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The animals' parkinsonism was assessed using a rating scale, activity monitors and a novel tremor monitor. The animals manifested bilateral parkinsonism with more severe clinical signs on the side of the body contralateral to the ICA infusion. The RTr in these animals had a mean peak frequency of 7.9 Hz (S.E.: 0.12), and a mean amplitude of 5.1/d/s/rtz (S.E.: 0.69). Substantial reduction in RTr amplitude (80.4%) was observed after oral L-DOPA administration. Our results suggest that: 1) RTr is present after the combined administration of ICA and iv. MPTP. 2) The mean RTr frequency in rhesus monkeys may be higher than in parkinsonian patients. However, as in PD, RTr frequency in the monkey was maintained within a narrow band width. 3) As in PD, L-DOPA administration to MPTP-treated monkeys reduced the amplitude of RTr and improved the parkinsonian features. Monitoring and quantifying the RTr in the MPTP-parkinsonian monkeys provide an objective, non invasive way to measure the outcome of therapeutic interventions and, further support the concept that loss of dopaminergic innervation contributes to the occurrence of RTr.

Animals↗
PubMed2007

Mitochondrial toxins and neurodegenerative diseases.

The selective loss of a particular subset of neurons is a common feature of neurodegenerative disorders. A failure in respiratory chain complex activities in mitochondria seems to be a causative factor. The aim of this review is to describe the most important toxins affecting the mitochondrial function, which could be involved in the incidence of some of these diseases: MPTP, rotenone and 3-nitropropionic (3-NPA).

Animals↗
PubMed1999

Reversal of experimental parkinsonism by using selective chemical ablation of the medial globus pallidus.

OBJECT: Symptoms from Parkinson's disease improve after surgical ablation of the medial globus pallidus (GPm). Although, in theory, selective chemical ablation of neurons in the GPm could preserve vital structures jeopardized by surgery, the potential of this approach is limited when using traditional techniques of drug delivery. The authors examined the feasibility of convection-enhanced distribution of a neurotoxin by high-flow microinfusion to ablate the neurons of the GPm selectively and reverse experimental Parkinson's disease (akinesia, tremor, and rigidity). METHODS: Initially, to test the feasibility of this approach, the GPms of two naive rhesus macaques were infused with kainic acid or ibotenic acid through two cannulas that had been placed using the magnetic resonance imaging-guided stereotactic technique. Two weeks later the animals were killed and their brains were examined histologically to determine the presence of neurons in the GPm and the integrity of the optic tract and the internal capsule. To examine the therapeutic potential of this paradigm, unilateral experimental Parkinson's disease was induced in six macaques by intracarotid infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and their behavior was studied for 12 weeks after chemopallidotomy was performed using kainic acid (three animals) or control infusion (three animals). CONCLUSIONS: Chemopallidotomy using kainic acid permanently reversed the stigmata of MPTP-induced parkinsonism. By contrast, the control animals exhibited a transient recovery following intrapallidal infusion and then relapsed back to their baseline state. The use of high-flow microinfusion of selectively active toxins has the potential for treatment of Parkinson's disease and, by expanding the range of approachable targets to include large nuclei, for broad applications in clinical and experimental neuroscience.

Animals↗
PubMed2001

Increased burst firing in substantia nigra pars reticulata neurons and enhanced response to selective D2 agonist in hemiparkinsonian rats after repeated administration of apomorphine.

Intermittent administrations of dopaminergic agents in hemiparkinsonian rat enhances the behavioral response to subsequent administration of the drugs. This phenomenon is known as "priming" and thought as comparable to drug-induced dyskinesia in patients with Parkinson's disease. We investigated the behavioral and electrophysiological changes in 6-hydroxydopamine (6-OHDA)-lesioned hemiparkinsonian rats after repeated administrations of apomorphine. Administration of apomorphine (0.32 mg/kg, intraperitoneal, i.p.) twice daily for 6 days enhanced the rotation induced by apomorphine from 341 turns/hour at the beginning to 755 turns/hr at the end. At the same time, the response to selective D2 agonist quinpirole (0.26 mg/kg, i.p.) was also enhanced from 203 to 555 turns/hr. Extracellular single unit recording revealed no significant difference in the basal firing rates of substantia nigra pars reticulata (SNr) neurons between the ipsilateral and contralateral side of the 6-OHDA lesion regardless of the repeated administrations of apomorphine. In SNr of the lesion side, the units with burst firing pattern were found more frequently after repeated administrations of apomorphine and the suppressive effect of quinpirole on the firing rate was enhanced. These findings suggest that the increased percentage of the burst units is the important electrophysiological change in the development of enhanced response to selective D2 agonist.

Animals↗
PubMed2005

Neural stem cells implanted into MPTP-treated monkeys increase the size of endogenous tyrosine hydroxylase-positive cells found in the striatum: a return to control measures.

Neural stem cells (NSC) have been shown to migrate towards damaged areas, produce trophic factors, and replace lost cells in ways that might be therapeutic for Parkinson's disease (PD). However, there is very little information on the effects of NSC on endogenous cell populations. In the current study, effects of implanted human NSC (hNSC) on endogenous tyrosine hydroxylase-positive cells (TH+ cells) after treatment with 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) were explored in nonhuman primates. After MPTP damage and in PD, the primate brain is characterized by decreased numbers of dopamine neurons in the substantia nigra (SN) and an increase in neurons expressing TH in the caudate nucleus. To determine how implanted NSC might affect these cell populations, 11 St. Kitts African green monkeys were treated with the selective dopaminergic neurotoxin, MPTP. Human NSC were implanted into the left and right caudate nucleus and the right SN of eight of the MPTP-treated monkeys. At either 4 or 7 months after NSC implants, the brains were removed and the size and number of TH+ cells in the target areas were assessed. The results were compared to data obtained from normal untreated control monkeys and to the three unimplanted MPTP-treated monkeys. The majority of hNSC were found bilaterally along the nigrostriatal pathway and in the substantia nigra, while relatively few were found in the caudate. In the presence of NSC, the number and size of caudate TH+ cells returned to non-MPTP-treated control levels. MPTP-induced and hNSC-induced changes in the putamen were less apparent. We conclude that after MPTP treatment in the primate, hNSC prevent the MPTP-induced upregulation of TH+ cells in the caudate and putamen, indicating that hNSC may be beneficial to maintaining a normal striatal environment.

Animals↗
PubMed2003

Post intoxicative therapeutic immunization with myelin oligodendrocyte glycoproteine (MOG 35-55) suppresses spontaneous regeneration of dopaminergic neurons injured with 1-methyl-4 phenyl-1,2,3,6-tetrahydropiridine (MPTP).

The pathological process of neurodegeneration is accompanied by an inflammatory reaction that is believed to contribute to the pathogenesis of neurodegenerative diseases. The aim of our study was to evaluate the influence of autoimmune reaction induced by post-traumatic vaccination with myelin self-antigen on spontaneous regeneration of dopaminergic neurons, injured with MPTP. C57BL mice were intoxicated with 40 mg/kg MPTP and seven days later immunized with MOG 35-55 peptide in CFA. On the 7th day following intoxication, the MPTP treated mice showed decrease of the dopamine level by 63% as compared to the control mice. However, starting from the 14th day following intoxication, a spectacular increase of dopamine content was observed. Immunization with MOG resulted in a statistically significant reduction of the increase in striatum as compared to non-immunized animals, and was lower by 23%, 17% and 15% on days 14, 28 and 50, respectively. Our results show suppressive influence of autoimmune reaction induced after injury on regeneration of dopamine cells intoxicated with MPTP.

Animals↗
PubMed1998

[Metabolic activation of azaheterocyclics induced dopaminergic toxicity: possible candidate neurotoxins underlying idiopathic Parkinson's disease].

In 1983, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a contaminant of "synthetic heroin", has been reported to induce parkinsonian symptoms in humans, who were responsive to L-DOPA therapy, as a result of the degeneration of nigrostriatal neurons. The "MPTP story" hypothesizes that Parkinson's disease may be initiated or percipitated by environmental and/or endogenous toxins by a mechanism similar to that of MPTP in genetically-predisposed individuals. Several classes of heterocyclic molecules structurally related to MPTP have been advanced as possible neurotoxicant precursors underlying the nigrostriatal degeneration in Parkinson's disease. Indoleamine-related beta-carbolines (beta Cs), a class of heterocyclics which are basically plant alkaloids, are proposed as the most promising natural MPTP-like toxicants or protoxicants. In this article, beta Cs and N-methylated beta C cations are reviewed with regards to their formation, bioactivation, toxicity and presence in the human central nervous system. The enzymes in mammalian brain particulate fractions methylate beta Cs, sequentially forming 2-mono-[N]-methylated (2-Me beta C+s) and neurotoxic 2,9-di-[N, N']-methylated (2,9-Me2 beta C+s) beta-carbolinium cations. These beta C+s are structural analogs of 1-methyl-4-phenylpyridinium ion (MPP+), an active metabolite of MPTP, with a nitrogen bridge. The beta C+s not only inhibit DA reuptake and tyrosine hydroxylase, but also function as NADH-linked respiratory inhibitors in isolated mitochondria. The quarternization of beta C strikingly increased the affinity for dopamine transporter with 2-10 times greater Km and 10 times smaller Vmax values than MPP+. Furthermore, we have found higher concentrations of beta C+s localized in the nigra than in the cortex, and observed the S-adenosyl-L-methionine-dependent methylation of 2[beta]- and 9[indole]-nitrogens of beta Cs in non-parkinsonian human brains. Moreover, the cerebrospinal fluid levels of these beta C+s are higher in parkinsonian than non-parkinsonian patients. Simple beta-carboline induced parkinsonian-like symptoms in mice via N-methylation. These results indicated that beta C is a selective dopaminergic toxin precursor, that is sequentially methylated to form 2,9-Me2 beta C+ that could be an underlying factor in idiopathic Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMedDate not supplied

Enzyme-catalyzed bioactivation of cyclic tertiary amines to form potential neurotoxins.

The pyridinium metabolites formed in the MAO-B catalyzed oxidation of 1-methyl-4-substituted-1,2,3,6-tetrahydropyridinyl derivatives, such as the parkinsonian inducing agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), cause the selective degeneration of nigrostriatal neurons, presumably by inhibition of mitochondrial respiration and depletion of ATP stores. The possibility that other partially oxidized piperidinyl derivatives also may be biotransformed to toxic pyridinium metabolites has led us to examine the metabolic fate of the neuroleptic agent haloperidol (HP) and its tetrahydropyridinyl dehydration product 4-(4-chlorophenyl)-1[4-(4-fluorophenyl)-4-oxobutyl]- 1,2,3,6-tetrahydropyridine (HPTP). In vitro metabolic studies employing tissue preparations isolated from rodents, baboons and humans have documented that cytochrome P4503A enzymes catalyze the biotransformation of both HP and HPTP to yield the corresponding pyridinium metabolite HPP+. An analogous biotransformation profile has been observed with "reduced haloperidol" (RHP), an abundant, circulating metabolite of HP formed by the stereospecific reduction of the benzoyl carbonyl group of HP. In vivo studies also have documented these pathways in humans, baboons and rodents. Although both HPP+ and RHPP+ are found in the urine and plasma of HP treated patients and HP or HPTP treated baboons, attempts to identify an MPTP-type lesion in baboons following long-term treatment with HPTP have failed. On the other hand, evidence for a lesion of the nucleus basalis of Meynert has been obtained. Additionally, the urinary excretion of abnormal organic acids and acylcarnitine conjugates suggests that HP and/or metabolites derived from HP interfere with energy production pathways.

Amines↗
PubMed1999

Differing effects of N-methyl-D-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine monkeys.

The antiparkinsonian and antidyskinetic profile of two N-methyl-D-aspartate (NMDA) receptor antagonists, a competitive antagonist, (R)-4-oxo-5-phosphononorvaline (MDL 100,453), and a novel noncompetitive allosteric site antagonist, 4-hydroxy-N-[2-(4-hydroxyphenoxy)ethyl]-4-(4-methylbenzyl)piper idi ne (Co 101244/PD 174494), was assessed in six levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine-lesioned parkinsonian monkeys. The effects on motor function of these two drugs, alone and in combination with levodopa, were then correlated with NMDA subtype selectivity and apparent affinity for four diheteromeric NMDA receptor subunit combinations expressed in Xenopus oocytes. MDL 100, 453 (300 mg/kg s.c.) by itself increased global motor activity (p =. 0005 versus vehicle) and administered 15 min after a low dose of levodopa/benserazide s.c., MDL 100,453 (50, 300 mg/kg s.c.) showed dose-dependent potentiation of antiparkinsonian responses and also produced dyskinesias. Following injection of a fully effective dose of levodopa, MDL 100,453 (300 mg/kg s.c.) also produced a 25% increase in mean dyskinesia score (p =.04). In contrast, Co 101244 did not change motor activity by itself and only showed a tendency to potentiate the antiparkinsonian response when given in combination with a low dose of levodopa, which did not attain statistical significance. However, with a high dose of levodopa, Co 101244 (0.1, 1 mg/kg s.c.) displayed antidyskinetic effects (67 and 71% reduction, respectively) while sparing levodopa motor benefit. In vitro, MDL 100,453 was an NMDA glutamate-site antagonist, with approximately 5- to 10-fold selectivity for the NR1A/NR2A subtype combination (K(b) = 0.6 microM) versus NR1A in combination with 2B, 2C, or 2D. In contrast, the allosteric site antagonist Co 101244 showed approximately 10,000-fold selectivity for the NR1A/NR2B (IC(50) = 0.026 microM) versus the other three subunit combinations tested. Taken together, the data suggest that the NR2 subunit selectivity profile of NMDA receptor antagonists can play an important role in predicting behavioral outcome and offer more evidence that NR2B-selective NMDA receptor antagonists may be useful agents in the treatment of Parkinson's disease.

Animals↗
PubMedDate not supplied

Effect of the selective D1 antagonists SCH 23390 and NNC 01-0112 on the delay, duration, and improvement of behavioral responses to dopaminergic agents in MPTP-treated monkeys.

We assessed the antiparkinsonian response in MPTP-treated monkeys after acute or repeated treatment with oral L-Dopa, subcutaneous administration of L-Dopa methyl ester (LDME) or apomorphine, alone and in combination with D1 antagonists SCH 23390 (SCH) or NNC 01-0112 (NNC). When given alone, the L-Dopa effect occurred within the first hour after treatment. Coadministration of SCH or NNC with L-Dopa significantly delayed the onset of action. The response duration remained unchanged, as did the extent of the antiparkinsonian effect, after SCH, whereas the former became shorter at the higher doses of NNC tested. Bypass of the gastrointestinal tract using parenteral injections of LDME and apomorphine allowed the rapid turning "on" of the animals. Both D1 antagonists administered with LDME delayed the onset and shortened the duration of the therapeutic effect as the dose increased. Pretreatment with SCH failed to block the antiparkinsonian effect induced by apomorphine, but reduced the response duration markedly in a dose-related fashion. Repeated treatment of one monkey with SCH combined with the same dopaminergic drugs produced results similar to those obtained after acute treatment in four animals. The results obtained with parenteral administration of LDME and apomorphine most probably involve pharmacodynamic actions resulting in increased threshold of response. The delay observed with L-Dopa suggests pharmacokinetic interference possibly mediated via dopamine receptors located at the level of the gut.

Animals↗
PubMedDate not supplied

[The method of the integral evaluation of the behavioral depression in rats].

A new method of the evaluation of behavioral depression was developed based on a ranged scale of changes in a number of depressive symptoms in behavior and general state of animals. The method makes it possible to evaluate the individual expression of depressive symptoms in rats and can be used for revealing a correlation between the decrease in motivation level in depressive animals and alterations of some pathophysiological parameters.

Animals↗
PubMed2000

Mice deficient in cellular glutathione peroxidase show increased vulnerability to malonate, 3-nitropropionic acid, and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine.

Glutathione peroxidase (GSHPx) is a critical intracellular enzyme involved in detoxification of hydrogen peroxide (H(2)O(2)) to water. In the present study we examined the susceptibility of mice with a disruption of the glutathione peroxidase gene to the neurotoxic effects of malonate, 3-nitropropionic acid (3-NP), and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP). Glutathione peroxidase knock-out mice showed no evidence of neuropathological or behavioral abnormalities at 2-3 months of age. Intrastriatal injections of malonate resulted in a significant twofold increase in lesion volume in homozygote GSHPx knock-out mice as compared to both heterozygote GSHPx knock-out and wild-type control mice. Malonate-induced increases in conversion of salicylate to 2,3- and 2, 5-dihydroxybenzoic acid, an index of hydroxyl radical generation, were greater in homozygote GSHPx knock-out mice as compared with both heterozygote GSHPx knock-out and wild-type control mice. Administration of MPTP resulted in significantly greater depletions of dopamine, 3,4-dihydroxybenzoic acid, and homovanillic acid in GSHPx knock-out mice than those seen in wild-type control mice. Striatal 3-nitrotyrosine (3-NT) concentrations after MPTP were significantly increased in GSHPx knock-out mice as compared with wild-type control mice. Systemic 3-NP administration resulted in significantly greater striatal damage and increases in 3-NT in GSHPx knock-out mice as compared to wild-type control mice. The present results indicate that a knock-out of GSHPx may be adequately compensated under nonstressed conditions, but that after administration of mitochondrial toxins GSHPx plays an important role in detoxifying increases in oxygen radicals.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗