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PubMed2002

Quantitative [18F]fluorodopa/PET and histology of fetal mesencephalic dopaminergic grafts to the striatum of MPTP-poisoned minipigs.

The functional restoration of the dopamine innervation of striatum in MPTP-poisoned Göttingen minipigs was assessed for 6 months following grafting of fetal pig mesencephalic neurons. Pigs were assigned to a normal control group and a MPTP-poisoned group, members of which received no further treatment, or which received bilateral grafts to the striatum of tissue blocks harvested from E28 fetal pig mesencephalon with and without immunosuppressive treatment after grafting, or with additional co-grafting with immortalized rat neural cells transfected to produce GDNF. In the baseline condition, and again at 3 and 6 months postsurgery, all animals were subjected to quantitative [18F]fluorodopa PET scans and testing for motor impairment. At the end of 6 months, tyrosine hydroxylase (TH)-containing neurons were counted in the grafts by stereological methods. The MPTP poisoning persistently reduced the magnitude of k3(D), the relative activity of DOPA decarboxylase in striatum, by 60%. Grafting restored the rate of [18F]fluorodopa decarboxylation to the normal range, and normalized the scores in motor function. The biochemical and functional recovery was associated with survival of approximately 100,000 TH-positive graft neurons in each hemisphere. Immunosuppression did not impart a greater recovery of [18F]fluorodopa uptake, nor were the number of TH-positive graft neurons or the volumes of the grafts increased in the immunosuppressed group. Contrary to expectation, co-grafting of transfected GDNF-expressing HiB5 cells, a rat-derived neural cell line, tended to impair the survival of the grafts with the lowest values for graft volumes, TH-positive cell numbers, behavioral scores, and relative DOPA decarboxylase activity. From the results we conclude that pig ventral mesencephalic allografts can restore functional dopamine innervation in adult MPTP-lesioned minipigs.

Animals↗
PubMedDate not supplied

The DaNeX study of embryonic mesencephalic, dopaminergic tissue grafted to a minipig model of Parkinson's disease: preliminary findings of effect of MPTP poisoning on striatal dopaminergic markers.

A multicenter study is under way to investigate the efficacy of allografting of embryonic mesencephalic neurons in a pig model of Parkinson's disease. We have first established that a stable parkinsonian syndrome can be established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of adult male Göttingen minipigs. We are now using positron emission tomography (PET) methods for testing the physiological responses to MPTP intoxication and the time course of the response to several treatment strategies. We now report preliminary results obtained in 11 pigs employed in the initial phase of the study; the completed study shall ultimately include 30 pigs. Animals were randomly assigned to one of five groups: 1) Control, 2) MPTP intoxication, 3) MPTP intoxication followed by allograft, 4) MPTP intoxication followed by allograft with immunosuppression, and 5) MPTP intoxication followed by allograft with immunosuppression and co-grafting of immortalized HiB5 cells, which had been manipulated to secrete glia cell line-derived neurotrophic factor (GDNF) (approximately 2 ng GDNF/h/10(5) cells). MPTP was administered (1 mg/kg/day, SC) for 7-10 days until the pigs had developed mild parkinsonian symptoms of muscle rigidity, hypokinesia, and impaired coordination, especially of the hind limbs. Approximately 2 weeks after the last MPTP dose, animals received a T1-weighted magnetic resonance imaging (MRI) scan, and a series of dynamic PET recordings. After the first series of PET scans, four grafts of porcine embryonic mesencephalic tissue (E28 days) were placed in each striatum of some MPTP-intoxicated pigs, using MRI-based stereotactic techniques. Immunosuppression of some animals with cyclosporin and prednisolone began just prior to surgery. Two more series of PET scans were performed at 4-month intervals after surgery. After the last scans, pigs were killed and the brains were perfused for unbiased stereological examination of cytological and histochemical markers in striatum and substantial nigra. The behavioral impairment of the animals (the "Parkinson's score") had been evaluated throughout the 8-month period. Kinetic analysis of the first set of PET scans has indicated that the rate constant for the decarboxylation of FDOPA in catecholamine fibers was reduced by 33% in striatum of the mildly parkinsonian pigs. The rate of association of [11C]NS-2214 to catecholamine uptake sites was reduced by 62% in the same groups of pigs. No significant difference was found in the binding potential of [11C]raclopride to the dopamine D2-like receptors in striatum of the MPTP-intoxicated versus control pigs. These preliminary results are suggestive that the activity of DOPA decarboxylase may be upregulated in the partially denervated pig striatum.

Animals↗
PubMed1987

Effects of MPTP poisoning on central somatostatin and substance P levels in the mouse.

The effects of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) on the levels of the neuropeptides somatostatin and substance P, were examined in various brain regions of C57 mice. Two weeks after injections of MPTP (2 X 30, 2 X 40 and 2 X 50 mg/kg i.p.) a dose-dependent decrease in striatal catecholamine levels was observed. There was also a dose-dependent increase in nigral somatostatin immunoreactivity and no reduction in striatonigral substance P levels. These results are in contrast with the changes observed in peptide levels in post-mortem Parkinson's brains.

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

Pig brain stereotaxic standard space: mapping of cerebral blood flow normative values and effect of MPTP-lesioning.

The analysis of physiological processes in brain by position emission tomography (PET) is facilitated when images are spatially normalized to a standard coordinate system. Thus, PET activation studies of human brain frequently employ the common stereotaxic coordinates of Talairach. We have developed an analogous stereotaxic coordinate system for the brain of the Gottingen miniature pig, based on automatic co-registration of magnetic resonance (MR) images obtained in 22 male pigs. The origin of the pig brain stereotaxic space (0, 0, 0) was arbitrarily placed in the centroid of the pineal gland as identified on the average MRI template. The orthogonal planes were imposed using the line between stereotaxic zero and the optic chiasm. A series of mean MR images in the coronal, sagittal and horizontal planes were generated. To test the utility of the common coordinate system for functional imaging studies of minipig brain, we calculated cerebral blood flow (CBF) maps from normal minipigs and from minipigs with a syndrome of parkisonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-poisoning. These maps were transformed from the native space into the common stereotaxic space. After global normalization of these maps, an undirected search for differences between the groups was then performed using statistical parametric mapping. Using this method, we detected a statistically significant focal increase in CBF in the left cerebellum of the MPTP-lesioned group. We expect the present approach to be of general use in the statistical parametric mapping of CBF and other physiological parameters in living pig brain.

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

Nicotinamide homeostasis: a xenobiotic pathway that is key to development and degenerative diseases.

Monkeys and man are very closely related genetically. Yet intellectually there are big differences and they suffer from a broad range of different diseases. For example, monkeys do not get Parkinson's or Alzheimer's disease. The former is surprising given that both get parkinsonism from MPTP poisoning and the latter initially less surprising as the cortex predominantly affected in Alzheimer's never developed as fully in the monkey. Man is an omnivore whilst other primates are predominantly herbivores. The one primate who was almost wholly carnivorous was Neanderthal man who became extinct. Red meat has a high content of Nicotinamide, Choline, and methyl donors. The enzyme NNMT converts nicotinamide to N-methyl-nicotinamide using SAM as the methyl donor. It is not present to any degree in herbivores. It has recently been shown to be present in human brain and up regulated in Parkinson's disease. Omnivores presumably need it for nicotinamide homeostasis but the production of N-methyl-nicotinamide will also be beneficial as it will reduce the export of Choline from neurones. Both will aid brain growth and development. However, as N-methyl-nicotinamide resembles MPTP it could cause parkinsonism later in life for man but not monkeys as they would be predicted not to have as much NNMT. Humans with a diet low in Nicotinamide,Choline or methyl donors early in life and low enzyme activity may be prone to Alzheimer's as their brain and therefore its reserves may never have developed as fully. The possession of NNMT plus a diet rich in Nicotinamide, Choline and methyl providers may explain many of the advantages but also the disadvantages of the human condition. One prediction is that a diet rich in these micronutrients whilst young will improve brain development and reduce the risk of Alzheimer's but that a lower dose later in life will reduce the risk of Parkinsonism. A second prediction is that it will become clear that dietary factors including vitamins are signalers and at the head of vital biochemical pathways. A time point will be reached when errors emerge that could not be deleted by evolutionary pressures. Finding and rectifying them will be the key to preventing many common diseases.

Animals↗
PubMed1992

Dissociation of serotoninergic and dopaminergic components in acute effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.

Behavioural and neurochemical effects of acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment in mice have been studied in order to determine the change in the neurotransmitter profile of the following areas of the brain: substantia nigra (SN), nucleus caudatus putamen (NCP), limbic system (LS; tuberculum olfactorium and nucleus accumbens), medulla oblongata (MO) and cerebellum (CER). Subcutaneous administration of MPTP (40 mg/kg) caused behavioural syndromes including restlessness, straub tail, hindlimb abduction, tremor, jumping, bradykinesia and akinesia in Balb/c mice. There existed a well-defined biphasic profile of motor activity comprising of an initial excitatory phase followed by an inhibitory phase lasting about two and a half and five hours, respectively. A significant rise in 5-hydroxytryptamine (5-HT) content together with a decreased 5-HT utilization as evidenced by lower 5-hydroxyindole acetic acid (5-HIAA) to 5-HT ratio in the above brain areas demarcated the excitatory phase, whereas the inhibitory phase was distinguished by a significant decrease in dopamine (DA) content along with an increased turnover of the amine as shown by a higher homovanillic acid (HVA) to DA ratio in the functionally important nuclei of the extrapyramidal system like SN, NCP and LS. Methysergide, a nonspecific 5-HT receptor blocker, but not ketanserin, a specific 5-HT2 antagonist, prevented the occurrence of the initial excitatory phase without affecting the depressive phase. Administration of apomorphine, a dopamine agonist, 30 minutes prior to MPTP was ineffective, whereas its application 90 minutes after MPTP prevented the occurrence of bradykinesia and akinesia. Interestingly, treatment with haloperidol, the dopamine (D1/D2) antagonist, before and after MPTP administration caused an early onset and prolongation of the inhibitory phase without affecting the initial hyperexcitement. The results provide direct evidence for the involvement of serotoninergic and dopaminergic mechanisms in the genesis of the early and late syndromes of acute MPTP poisoning respectively.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Anatomy and pathology of the basal ganglia.

Neurotransmitters of the basal ganglia are of three types: I, amino acids; II, amines; and III, peptides. The amino acids generally act ionotropically while the amines and peptides generally act metabotropically. There are many examples of neurotransmitter coexistence in basal ganglia neurons. Diseases of the basal ganglia are characterized by selective neuronal degeneration. Lesions of the caudate, putamen, subthalamus and substantia nigra pars compacta occur, respectively, in chorea, dystonia, hemiballismus and parkinsonism. The differing signs and symptoms of these diseases constitute strong evidence of the functions of these various nuclei. Basal ganglia diseases can be of genetic origin, as in Huntington's chorea and Wilson's disease, of infectious origin as in Sydenham's chorea and postencephalitic parkinsonism, or of toxic origin as in MPTP poisoning. Regardless of the etiology, the pathogenesis is often regionally concentrated for reasons that are poorly understood. From studies on Parkinson and Huntington disease brains, evidence is presented that a common feature may be the expression of HLA-DR antigen on reactive microglia in the region where pathological neuronal dropout is occurring.

Basal Ganglia↗
PubMed1990

Relationships between the mitochondrial transmembrane potential, ATP concentration, and cytotoxicity in isolated rat hepatocytes.

The relationships between mitochondrial transmembrane potential, ATP concentration, and cytotoxicity were evaluated after exposure of isolated rat hepatocytes to different mitochondrial poisons. Both the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its fully oxidized metabolite, the 1-methyl-4-phenylpyridinium (MPP+) ion, caused a concentration- and time-dependent depolarization of mitochondrial membranes which followed ATP depletion and preceded cytotoxicity. The effect of MPTP, but not that of MPP+, was prevented by deprenyl, an inhibitor of MPTP conversion to MPP+ via monoamine oxidase type B. Addition of fructose to the hepatocyte incubations treated with either MPTP or MPP+ counteracted the loss of mitochondrial transmembrane potential. Fructose was also effective in protecting against the mitochondrial membrane depolarization as well as ATP depletion and cytotoxicity induced by antimycin. A, carbonyl cyanide p-trifluoromethoxyphenyl hydrazone, and valinomycin. Data confirm the key role played by MPP(+)-induced mitochondrial damage in MPTP toxicity and indicate that (i) ATP produced via the glycolytic pathway can be utilized by hepatocytes to maintain mitochondrial electrochemical gradient, and (ii) a loss of mitochondrial membrane potential may occur only when supplies of ATP are depleted.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Dopamine differentiation factors increase striatal dopaminergic function in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mice.

We have previously shown that muscle-derived differentiation factors (MDF) and human recombinant acidic fibroblast growth factor (aFGF) have beneficial behavioral and neurochemical effects on the nigrostriatal dopaminergic neurons of 6-hydroxy-dopamine (6-OHDA)-lesioned rats (Jin and Iacovitti: Neurobiol Dis 2:1-12, 1995). In the present study, we determined the effects of similar treatments on mice treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Five days after unilateral striatal infusion of MDF or aFGF into MPTP-lesioned mice, striatal tyrosine hydroxylase (TH) activity and dihydroxyphenylacetic acid (DOPAC) levels were bilaterally increased (20-35%) compared to untreated (lesion only) or control (phosphate buffered saline + bovine serum albumin) mice. These increases, however, were not accompanied by change in dopamine (DA) levels, indicating an elevation of DA synthesis (TH/DA) and turnover (DOPAC/DA). The present findings that MDF and aFGF may have neurochemical effects in vivo on the lesioned nigrostriatal dopaminergic system suggest their potential pharmacological role in the treatment of Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

Regulation of connexin-43, GFAP, and FGF-2 is not accompanied by changes in astroglial coupling in MPTP-lesioned, FGF-2-treated parkinsonian mice.

Basic fibroblast growth factor (bFGF; FGF-2) has potent trophic effects on developing and toxically impaired midbrain dopaminergic (DAergic) neurons which are crucially affected in Parkinson's disease. The trophic effects of FGF-2 are largely indirect, both in vitro and in vivo, and possibly involve intermediate actions of astrocytes and other glial cells. To further investigate the cellular and molecular mechanisms underlying the restorative actions of FGF-2, and to analyse in more detail the changes within astroglial cells in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-lesioned striatum, we have studied striatal expression and regulation of connexin-43 (cx43), the principal gap junction protein of astroglial cells, along with the expression of glial fibrillary acidic protein (GFAP), FGF-2, and functional coupling. Our results show an immediate, yet transient increase in cx43 mRNA, and a sustained increase in FGF-2 mRNA, GFAP-positive cells, and cx43-immunoreactive punctata following the MPTP lesion, without any induction of functional coupling between astrocytes and other glial cells as revealed by dye coupling of patched cells. Unilateral administration of FGF-2 in a piece of gelfoam caused a further increase in cx43-positive punctata immediately adjacent to the implant, which was more pronounced than after application of a gelfoam containing the nontrophic control protein cytochrome C. These changes were parallelled by a small increase in cx43 protein determined by Western blot, but not by alterations in the coupling state of cells in the vicinity of the gelfoam implant. Although our data indicate that MPTP and exogenous FGF-2 may alter expression and protein levels of cx43, they do not support the notion that increases in cellular coupling may underly the trophic and widespread actions of FGF-2 in the MPTP-model of Parkinson's disease.

Animals↗
PubMed1999

Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease.

Parkinson's disease (PD) is an age-related disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN) and corresponding motor deficits. Oxidative stress and mitochondrial dysfunction are implicated in the neurodegenerative process in PD. Although dietary restriction (DR) extends lifespan and reduces levels of cellular oxidative stress in several different organ systems, the impact of DR on age-related neurodegenerative disorders is unknown. We report that DR in adult mice results in resistance of dopaminergic neurons in the SN to the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-induced loss of dopaminergic neurons and deficits in motor function were ameliorated in DR rats. To mimic the beneficial effect of DR on dopaminergic neurons, we administered 2-deoxy-D-glucose (2-DG; a nonmetabolizable analogue of glucose) to mice fed ad libitum. Mice receiving 2-DG exhibited reduced damage to dopaminergic neurons in the SN and improved behavioral outcome following MPTP treatment. The 2-DG treatment suppressed oxidative stress, preserved mitochondrial function, and attenuated cell death in cultured dopaminergic cells exposed to the complex I inhibitor rotenone or Fe2+. 2-DG and DR induced expression of the stress proteins heat-shock protein 70 and glucose-regulated protein 78 in dopaminergic cells, suggesting involvement of these cytoprotective proteins in the neuroprotective actions of 2-DG and DR. The striking beneficial effects of DR and 2-DG in models of PD, when considered in light of recent epidemiological data, suggest that DR may prove beneficial in reducing the incidence of PD in humans.

Animals↗
PubMed1996

Quantification of dopamine transporter density in monkeys by dynamic PET imaging of multiple injections of 11C-CFT.

Idiopathic Parkinson's disease (PD) is characterized by loss of dopaminergic terminals in the basal ganglia. The cocaine analog, CFT (WIN 35,428), has been shown to bind selectively to the pre-synaptic dopamine transporters and thus represents an important probe for monitoring disease progression. In this study, we evaluated [11C] labeled CFT as a PET ligand for the quantitative in vivo assay of dopamine transporter density in three normal rhesus monkeys (Macaca mulatta). One of the animals was studied after treatment with the neurotoxin, MPTP. Simulation studies demonstrated that a three injection protocol is necessary for quantitation of dopamine transporter density. The protocol consists of an initial high specific activity injection, a low specific activity "displacement dose" at 30 min, and a final high specific activity injection at approximately 90 min. Dynamic PET imaging and arterial blood sampling were started immediately before the first injection and continued for 2 h. Blood data were corrected for [11C] labeled CFT metabolites. Compartmental models describing the dynamics of labeled and the unlabeled ligand explicitly were fitted to the PET and metabolite corrected blood data. Prior to MPTP treatment, modeling of the striatal data required a saturable receptor term and yielded mean estimates of: B'max = 113 pmol/g and KD = 33 nm (n = 3). These values for B'max are in reasonable agreement with published values for [3H] CFT binding in vitro. After multiple treatments with MPTP (0.6 mg/kg x 3), B'max in one of the animals was reduced from 122 to 10.2 pmol/g. KD was relatively unaffected by MPTP treatment. These data provide additional basis for the use of [11C] CFT in monitoring the progression of Parkinson's disease and other conditions that are associated with the loss of dopaminergic nerve terminals.

Animals↗
PubMed1997

Nitric oxide synthase inhibition and MPTP-induced toxicity in the common marmoset.

Nitric oxide, produced following activation of N-methyl-D-aspartate (NMDA) receptors, may be involved in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity since NMDA receptor antagonists have been shown to prevent MPTP induced nigral cell loss in primates. Common marmosets were treated with either saline or MPTP or L-NGnitro arginine methyl ester (L-NAME) or MPTP and L-NAME. MPTP-treated common marmosets showed motor deficits including bradykinesia, rigidity, and tremor accompanied by a marked loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta and of [3H]-mazindol binding in the caudate-putamen. MPTP treatment also caused an increase in glial fibrillary acidic protein (GFAP) staining in the substantia nigra compared to controls. However, MPTP treatment did not alter the number of constitutive nitric oxide synthase-immunoreactive neurones in the caudate-putamen. Furthermore, neurones or glial cells immunoreactive for inducible nitric oxide synthase were not observed in the substantia nigra pars compacta following MPTP treatment. L-NAME treatment alone did not produce any behavioural changes in marmosets and did not alter the number of tyrosine hydroxylase-immunoreactive cells in the substantia nigra pars compacta, the number of constitutive nitric oxide synthase-immunoreactive neurones or [3H]-mazindol binding in the caudate-putamen compared to saline-treated control animals. Furthermore, L-NAME did not affect the motor deficits, loss of tyrosine hydroxylase-immunoreactive neurones in the substantia nigra pars compacta, loss of [3H]-mazindol binding in the caudate-putamen, or the increase in GFAP staining in the substantia nigra induced by MPTP treatment of common marmosets. The failure of L-NAME to protect against MPTP-induced toxicity in the marmoset suggests that nitric oxide does not play a major role in such toxicity and casts doubt over the involvement of the NMDA:nitric oxide system in neurodegeneration in MPTP-treated primates.

Adrenergic Uptake Inhibitors↗
PubMed1997

[123I]FP-CIT binds to the dopamine transporter as assessed by biodistribution studies in rats and SPECT studies in MPTP-lesioned monkeys.

[123I]FP-CIT (N-omega-fluoropropyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl)-tropane), a radioiodinated cocaine analogue, was evaluated as an agent for the in vivo labeling of dopamine (DA) transporters by biodistribution studies in rats and by single photon emission computed tomography (SPECT) studies in unilateral 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys. In rats, intravenous injection of [123I]FP-CIT resulted in high accumulation of radioactivity in the striatum. Less pronounced uptake was seen in brain areas with high densities of serotonergic uptake sites. While striatal uptake of radioactivity after injection of [123I]FP-CIT was displaced significantly by GBR12,909 but not by fluvoxamine, the opposite was observed in brain areas known to be rich of serotonin transporters. Monkeys which were unilaterally treated with neurotoxic doses of MPTP showed severe loss of striatal [123I]FP-CIT uptake at the side of treatment. The results of this study indicate that [123I]FP-CIT, although not being a selective radioligand, binds specifically to the striatal DA transporter in vivo and thus suggest that [123I]FP-CIT promises to be a suitable radioligand for SPECT imaging of DA transporters in humans.

Animals↗
PubMed1998

Reduced MPTP neurotoxicity in striatum of the mutant mouse tottering.

The effects of MPTP treatment (4 x 10 mg/kg, 2-h intervals) on in vivo striatal binding of (+)-alpha-[3H]dihydrotetrabenazine ((+)-[3H]DTBZ) to the vesicular monoamine transporter type 2 (VMAT2) were examined in wild type (+,+) and tottering (tg/tg) mice of the C57BL/6J strain. The tottering mutant has been previously characterized as having hyperinnervation of noradrenergic terminals in the brain, with increased concentrations of norepinephrine and increased numbers of VMAT2 binding sites. In wild-type mice, MPTP caused a significant decrease in specific striatal (+)-[3H]DTBZ binding in both males (-71%) and females (-57%), consistent with dopaminergic terminal losses. In the tottering mice, the neurotoxic effects of MPTP were diminished, with smaller losses of (+)-[3H]DTBZ binding observed both in males (-45%) and females (-26%). These results are consistent with the hypothesis that vesicular storage (as a result of hyperinnervation) offers neuroprotection toward MPTP toxicity, although the confounding effects of increases in norepinephrine concentrations or changes in calcium ion channel function (both also characteristics of the tottering mutant) cannot be ruled out. The tottering mutant does, however, offer another animal model to examine the biochemical features responsible for MPTP toxicity.

Animals↗
PubMed1999

Methamphetamine- and 1-methyl-4-phenyl- 1,2,3, 6-tetrahydropyridine-induced dopaminergic neurotoxicity in inducible nitric oxide synthase-deficient mice.

Previous studies have suggested a role for the retrograde messenger, nitric oxide (NO), in methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- induced dopaminergic neurotoxicity. Since evidence supported the involvement of the neuronal nitric oxide synthase (nNOS) isoform in the dopaminergic neurotoxicity, the present study was undertaken to investigate whether the inducible nitric oxide synthase (iNOS) isoform is also associated with METH- and MPTP-induced neurotoxicity. The administration of METH (5mg/kg x 3) to iNOS deficient mice [homozygote iNOS(-/-)] and wild type mice (C57BL/6) resulted in significantly smaller depletion of striatal dopaminergic markers in the iNOS(-/-) mice compared with the wild-type mice. METH-induced hyperthermia was also significantly lower in the iNOS(-/-) mice than in wild-type mice. In contrast to the outcome of METH administration, MPTP injections (20 mg/kg x 3) resulted in a similar decrease in striatal dopaminergic markers in iNOS(-/-) and wild-type mice. In the set of behavioral experiments, METH-induced locomotor sensitization was investigated. The acute administration of METH (1.0 mg/kg) resulted in the same intensity of locomotor activity in iNOS(-/-) and wild-type mice. Moreover, 68 to 72 h after the exposure to the high-dose METH regimen (5 mg/kg x 3), a marked sensitized response to a challenge injection of METH (1.0 mg/kg) was observed in both the iNOS(-/-) and wild-type mice. The finding that iNOS(-/-) mice were unprotected from MPTP-induced neurotoxicity suggests that the partial protection against METH-induced neurotoxicity observed was primarily associated with the diminished hyperthermic effect of METH seen in the iNOS(-/-) mice. Moreover, in contrast to nNOS deficiency, iNOS deficiency did not affect METH-induced behavioral sensitization.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2000

Dopaminergic innervation of the subthalamic nucleus in the normal state, in MPTP-treated monkeys, and in Parkinson's disease patients.

The existence of a dopaminergic innervation of the subthalamic nucleus (STN) has been demonstrated in rats but has remained controversial in primates. The aim of the present study was first to demonstrate the existence of a dopaminergic innervation of the STN in monkeys using tracing methods and then to quantify the loss of dopaminergic fibers in the parkinsonian state in monkeys and humans. Following injection of Fluoro-Gold into the STN of a vervet monkey (Cercopithecus aethiops), retrogradely labeled neurons were found to be scattered in all dopaminergic areas of the mesencephalon. Injection of biotin dextran amine into dopaminergic areas A8 and A9 of two monkeys resulted in anterogradely labeled axons located throughout the whole extent of the STN. Labeled axons that also expressed tyrosine hydroxylase (TH) were reconstructed from serial sections. Some terminal axonal arborizations had profuse branching and occupied much of the STN, and others were restricted to small portions of the nucleus. In TH-immunoreactive sections, numerous sparse, fine, and varicose TH-positive fibers were observed in the STN of normal monkeys and humans. Quantification of these TH-positive fibers revealed a 51% loss of TH-positive fibers in MPTP-intoxicated monkeys and a 65% loss in Parkinson's disease patients compared with their respective controls. These findings demonstrate the existence of a dopaminergic innervation of the STN in primates. The loss of dopaminergic innervation in MPTP-intoxicated monkeys and in Parkinson's disease patients may directly affect the activity of STN neurons and could participate in the hyperactivity of the structure.

Aged↗
PubMed2000

Stereospecific prevention by 17beta-estradiol of MPTP-induced dopamine depletion in mice.

Neuroprotective activity of estrogens is reported in Alzheimer disease and recently has also been suggested for Parkinson disease, a disease affecting more men than women. To characterize this estrogenic activity, we studied the effects of 17beta- and 17alpha-estradiol treatment (1 microg twice daily 5 days before, during the day of four MPTP (15 mg/kg) injections, and for the following 5 days) on dopamine striatal toxicity induced by the neurotoxin MPTP in retired breeder male C57BL/6 mice. Striatal dopamine concentrations and its metabolites dihydroxyphenylacetic acid and homovanillic acid measured by HPLC in MPTP mice that received 17beta-estradiol were comparable to control animals, whereas MPTP mice treated with saline or 17alpha-estradiol showed important decreases of dopamine and its metabolites. Striatal serotonin and its metabolite 5-hydroxyindoleacetic acid concentrations remained unchanged after MPTP and treatments with steroids. Striatal [(3)H]GBR 12935 binding autoradiography to the dopamine transporter was as extensively decreased and correlated with dopamine depletion in MPTP mice, whereas this transporter mRNA decrease in the substantia nigra pars compacta was less pronounced. Treatment with steroids did not significantly change [(3)H]GBR 12935 binding, whereas dopamine transporter mRNA levels were not significantly different from controls. Under the present paradigm in retired breeder male mice, our results show dopaminergic and stereospecificity of estradiol to augment dopamine levels in MPTP-lesioned mice without protecting against the extensive loss of dopamine terminals and moderate cell body loss.

3,4-Dihydroxyphenylacetic Acid↗