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PubMed2006

Quantification of MPTP-induced dopaminergic neurodegeneration in the mouse substantia nigra by laser capture microdissection.

The neurotoxin MPTP is widely used to cause damage to the dopaminergic system in rodents and non-human primates to model various aspects of Parkinson's disease. In mice, depletion of striatal dopamine is the commonly used endpoint to assess neuronal damage. However, it has proved technically challenging to quantify dopaminergic cell bodies as an index of neuronal integrity. To meet this challenge, we applied laser pressure catapult microdissection (LCM) of the substantia nigra in combination with quantitative Western blot to provide an index of dopamine neurodegeneration in mice treated with MPTP. Seven days following initiation of MPTP treatment, striatal dopamine depletion was maximal and there was histological evidence of neuronal degeneration in the substantia nigra. To index the integrity of dopamine cell bodies, tyrosine hydroxylase (TH) and beta-actin were quantified by Western blot in LCM extracts. In untreated mice, TH was detected in LCM extracts of substantia nigra but was undetectable in equivalently sized extracts of cortex from the same animals. In MPTP-treated mice, there was a significant 70% reduction in TH relative to beta-actin in LCM extracts as compared to vehicle-injected controls. This reduction corresponded to decreases in striatal dopamine and loss of immunocytochemically detected TH but not beta-actin in the substantia nigra (SN). Thus, this method provides a quantitative means to measure dopamine neuron toxicity in the substantia nigra and, as such has potential application in evaluating regimens that may be neuroprotective or neurorestorative for dopaminergic neurons.

Animals↗
PubMed2005

Interleukine-1beta and interleukine-6 levels in striatum and other brain structures after MPTP treatment: influence of behavioral lateralization.

MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces diminution of the dopamine in nigrostriatal pathway and cognitive deficits in mice. MPTP treatment also increases pro-inflammatory cytokine production in substantia nigra and striatum. Since, pro-inflammatory cytokines influence striatal dopamine content and provoke cognitive impairments, the cognitive defects induced by MPTP may be partly due to brain cytokine induction in other structures than nigrostriatal pathway. Furthermore, behavioral lateralization, as assessed by paw preference, influences cytokine production at the periphery and in the central nervous system. Behavioral lateralization may thus influence brain cytokine levels after MPTP. In order to address these issues, mice selected for paw preference were injected with 25 mg/kg MPTP i.p. for five consecutive days after which striatal dopamine and DOPAC contents were measured by HPLC and IL-1beta and IL-6 quantified by ELISA in the striatum, cerebral cortex, hippocampus and hypothalamus. The results showed that MPTP treatment induced dramatic loss of DA in striatum, simultaneously, IL-6 levels decreased in the striatum and increased in hippocampus and hypothalamus, while IL-1beta levels decreased in the striatum, cerebral cortex and hippocampus. Interestingly, striatal dopamine turnover under basal conditions as well as striatal IL-1beta and IL-6 levels under basal conditions and after MPTP depended on behavioral lateralization. Left pawed mice showed a higher decrease in dopamine turnover and lower cytokine levels as compared to right pawed animals. Behavioral lateralization also influenced IL-6 hippocampal levels under basal conditions and IL-1beta cortical levels after MPTP. From these results, it can be concluded that MPTP-induced cognitive defects are accompanied by an alteration of pro-inflammatory cytokine levels in brain structures other than those involved in the nigrostriatal pathway. In addition, MPTP-induced dopamine decrease is influenced by behavioral lateralization, possibly through an effect on brain cytokine levels.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Enhanced neuroprotective effect by combination of bromocriptine and Hypericum perforatum extract against MPTP-induced neurotoxicity in mice.

The present study has been designed to evaluate the combined effect of bromocriptine (BRC) and Hypericum perforatum extract (HPE) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease in male Swiss Albino mice, which were randomly divided into seven groups of six animals each. Group I served as control. Groups II and III were given 300 mg/kg HPE (po) and 10 mg/kg BRC (i.p.) respectively, once daily for 7 days. The four doses of MPTP (20 mg/kg) were administered intraperitoneally with an interval of 2 h to the groups IV, V, VI and VII. The drug treatment was given to fifth group (10 mg/kg BRC; i.p), sixth group (300 mg/kg HPE; po) and seventh group (300 mg/kg HPE; po and 10 mg/kg BRC; i.p.) once in a day for 7 days and the dose on the first day was given 30 min prior to first MPTP injection. The rotarod test, hang test and forepaw stride length revealed significant improvement by the combined treatment. Dopamine and DOPAC levels were significantly improved (p<0.05). There was a significant reduction in lipid peroxidation after the combined treatment (p<0.05) and the antioxidant status was improved. These findings suggest that the combined effect of BRC and HPE was more pronounced than BRC or HPE alone. So it is concluded that the combined treatment might be preferable to either BRC (or) HPE alone in the effective clinical management of Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2004

Acetyl-L-carnitine prevents total body hydroxyl free radical and uric acid production induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the rat.

Acetyl-L-carnitine (ALCAR) is intimately involved in the transport of long chain fatty acids across the inner mitochondrial membrane during oxidative phosphorylation. ALCAR also has been reported to attenuate the occurrence of parkinsonian symptoms associated with 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) in vivo, and protects in vitro against the toxicity of the neurotoxic 1-methyl-4-phenylpyridinium (MPP+) metabolite of MPTP. The mechanism for these protective effects remains unclear. ALCAR may attenuate hydroxyl (HO*) free radical production in the MPTP/MPP+ neurotoxic pathway through several mechanisms. Most studies on MPTP/MPP+ toxicity and protection by ALCAR have focused on in vivo brain chemistry and in vitro neuronal culture studies. The present study investigates the attenuative effects of ALCAR on whole body oxidative stress markers in the urine of rats treated with MPTP. In a first study, ALCAR totally prevented the MPTP-induced formation of HO* measured by salicylate radical trapping. In a second study, the production of uric acid after MPTP administration-a measure of oxidative stress mediated through xanthine oxidase-was also prevented by ALCAR. Because ALCAR is unlikely to be a potent radical scavenger, these studies suggest that ALCAR protects against MPTP/MPP+-mediated oxidative stress through other mechanisms. We speculate that ALCAR may operate through interference with organic cation transporters such as OCTN2 and/or carnitine-acylcarnitine translocase (CACT), based partly on the above findings and on semi-empirical electronic similarity calculations on ALCAR, MPP+, and two other substrates for these transporters.

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

Environmental enrichment in adulthood eliminates neuronal death in experimental Parkinsonism.

Idiopathic Parkinson's disease (PD) affects 2% of adults over 50 years of age. PD patients demonstrate a progressive loss of dopamine neurons in the substantia nigra pars compacta (SNpc). One model that recapitulates the pathology of PD is the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here we show that exposure to an enriched environment (EE) (a combination of exercise, social interactions and learning) or exercise alone during adulthood, totally protects against MPTP-induced Parkinsonism. Furthermore, changes in mRNA expression would suggest that increases in glia-derived neurotrophic factors, coupled with a decrease of dopamine-related transporters (e.g. dopamine transporter, DAT; vesicular monoamine transporter, VMAT2), contribute to the observed neuroprotection of dopamine neurons in the nigrostriatal system following MPTP exposure. This non-pharmacological approach presents significant implications for the prevention and/or treatment of PD.

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

Metallothionein-mediated neuroprotection in genetically engineered mouse models of Parkinson's disease.

Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra zona compacta, and in other sub-cortical nuclei associated with a widespread occurrence of Lewy bodies. The cause of cell death in Parkinson's disease is still poorly understood, but a defect in mitochondrial oxidative phosphorylation and enhanced oxidative and nitrative stresses have been proposed. We have studied control(wt) (C57B1/6), metallothionein transgenic (MTtrans), metallothionein double gene knock (MTdko), alpha-synuclein knock out (alpha-syn(ko)), alpha-synuclein-metallothionein triple knock out (alpha-syn-MTtko), weaver mutant (wv/wv) mice, and Ames dwarf mice to examine the role of peroxynitrite in the etiopathogenesis of Parkinson's disease and aging. Although MTdko mice were genetically susceptible to 1, methyl, 4-phenyl, 1,2,3,6-tetrahydropyridine (MPTP) Parkinsonism, they did not exhibit any overt clinical symptoms of neurodegeneration and gross neuropathological changes as observed in wv/wv mice. Progressive neurodegenerative changes were associated with typical Parkinsonism in wv/wv mice. Neurodegenerative changes in wv/wv mice were observed primarily in the striatum, hippocampus and cerebellum. Various hallmarks of apoptosis including caspase-3, TNFalpha, NFkappaB, metallothioneins (MT-1, 2) and complex-1 nitration were increased; whereas glutathione, complex-1, ATP, and Ser(40)-phosphorylation of tyrosine hydroxylase, and striatal 18F-DOPA uptake were reduced in wv/wv mice as compared to other experimental genotypes. Striatal neurons of wv/wv mice exhibited age-dependent increase in dense cored intra-neuronal inclusions, cellular aggregation, proto-oncogenes (c-fos, c-jun, caspase-3, and GAPDH) induction, inter-nucleosomal DNA fragmentation, and neuro-apoptosis. MTtrans and alpha-Syn(ko) mice were genetically resistant to MPTP-Parkinsonism and Ames dwarf mice possessed significantly higher concentrations of striatal coenzyme Q10 and metallothioneins (MT 1, 2) and lived almost 2.5 times longer as compared to control(wt) mice. A potent peroxynitrite ion generator, 3-morpholinosydnonimine (SIN-1)-induced apoptosis was significantly attenuated in MTtrans fetal stem cells. These data are interpreted to suggest that peroxynitrite ions are involved in the etiopathogenesis of Parkinson's disease, and metallothionein-mediated coenzyme Q10 synthesis may provide neuroprotection.

Animals↗
PubMed2005

A role of IL-1 in MPTP-induced changes in striatal dopaminergic and serotoninergic transporter binding: clues from interleukin-1 type I receptor-deficient mice.

In mice, the MPTP-induced striatal dopaminergic denervation is followed by a spontaneous partial DAT recovery and by serotoninergic hyperinnervation. We show that IL-1RI-deficient mice have a higher DAT decrease in the ventromedial striatum after MPTP and a higher basal serotoninergic innervation of the whole striatum. These data point to a possible role of IL-1RI in the early MPTP-induced structural or functional remodeling of the nigrostriatal dopamine system.

Analysis of Variance↗
PubMed2005

Absence of inclusion body formation in the MPTP mouse model of Parkinson's disease.

Formation of alpha-synuclein aggregation and Lewy bodies (LBs) are hallmarks of Parkinson's disease (PD) and other related diseases. The dopaminergic neurotoxin, MPTP, replicates many of the pathological signs and motoric features of PD in primates and rodents by selective destruction of dopamine (DA) neurons of the substantia nigra. In this study, groups of adult wild-type C57BL6 mice were treated with MPTP either acutely (20 mg/kg, every 2 h x 4 for 1 day), semi-chronically (30 mg/kg/day for 5 days), or chronically (25 mg/kg MPTP with 250 mg/kg probenecid 2 times/week for 5 weeks). Mice brains were collected and processed at various time points for immunohistochemistry and HPLC assays. Our data showed that although there is a significant decrease in DA content and its metabolites and tyrosine hydroxylase immunoreactivity, there is no inclusion body formation following the various MPTP treatment regimens.

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

Neuroprotection of MPTP-induced toxicity in zebrafish dopaminergic neurons.

Parkinson's disease is characterized by a severe loss of dopaminergic neurons resulting in a range of motor deficits. The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is known to cause a similar loss of dopaminergic neurons in the human midbrain with corresponding Parkinsonian symptoms. Several animal species have also shown sensitivity to MPTP, including primates, mice, goldfish, and, most recently, zebrafish. This study demonstrates that the effect of MPTP on dopaminergic neurons in zebrafish larvae is mediated by the same pathways that have been demonstrated in mammalian species. MPTP-induced neurodegeneration was prevented by co-incubation with either the monoamine oxidase-B (MAO-B) inhibitor l-deprenyl or the dopamine transporter (DAT) inhibitor nomifensine. Furthermore, targeted inactivation of the DAT gene by antisense morpholinos also protected neurons from MPTP damage. Thus, the mechanism for MPTP-induced dopaminergic neuron toxicity in mammals is conserved in zebrafish larvae. Effects on swimming behavior and touch response that result from MPTP damage are partially ameliorated by both l-deprenyl and DAT knockdown.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Neuroprotective mechanisms of creatine occur in the absence of mitochondrial creatine kinase.

There is substantial evidence that creatine administration exerts neuroprotective effects both in vitro and in vivo. The precise mechanisms for these neuroprotective effects however are as yet unclear. We investigated whether creatine administration could exert neuroprotective effects in mice deficient in ubiquitous mitochondrial creatine kinase (UbMi-CK). UbMi-CK-deficient mice showed increased sensitivity to 1-methyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopamine depletion and loss of tyrosine hydroxylase (TH) stained neurons. Isolated mitochondria from these mice showed no alterations in calcium retention, oxygen utilization, membrane potential, or swelling in response to a calcium challenge. Creatine administration significantly increased brain concentrations of both creatine and PCr in the UbMi-CK knockout mice. Creatine administration to the UbMi-CK-deficient mice exerted significant neuroprotective effects against MPTP toxicity that were comparable in magnitude to those seen in wild-type mice. These results suggest that the neuroprotective effects of creatine are not mediated by an effect on UbMi-CK to inhibit the mitochondrial permeability transition, and are more likely to be mediated by maintenance of appropriate ATP/ADP and PCr/Cr levels.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

Transforming growth factor beta2 haploinsufficient mice develop age-related nigrostriatal dopamine deficits.

The transforming growth factor-betas (TGF-betas) regulate the induction of dopaminergic neurons and are elevated in the CSF of Parkinson's patients. We report here that mice with TGF-beta2 haploinsufficiency (TGF-beta2+/-) have subclinical defects in the dopaminergic neurons of their substantia nigra pars compacta. At 6 weeks of age, the TGF-beta2+/- mice had 12% fewer dopaminergic neurons than wild-type littermates. No additional loss of neurons occurred during the next 5 months, although striatal dopamine declined to 70% of normal. The level of 3,4-dihydroxphenylacetic acid was normal in the TGF-beta2+/- mice, indicating that a compensatory mechanism maintains dopamine stimulation of their striatum. The TGF-beta2+/- mice had normal sensitivity to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, despite having reduced levels of monoamine oxidase-B. These results raise the possibility that people with naturally low levels of TGF-beta2 may have less functional reserve in their nigrostriatal pathway, causing them to be at increased risk of developing Parkinson disease.

Age Factors↗
PubMed2004

Modafinil prevents the MPTP-induced increase in GABAA receptor binding in the internal globus pallidus of MPTP-treated common marmosets.

The psychostimulant drug modafinil induces a reversal of motor deficits in MPTP treated primates and prevents MPTP toxicity to substantia nigra but its mechanism of action is not clear. In common marmosets acutely treated with MPTP in the presence or absence of modafinil, we have studied changes in GABA(A) receptor binding in the basal ganglia. MPTP treatment had no effect on [(3)H]-flunitrazepam (FNZ) binding density in the striatum or external globus pallidus (GPe) but increased [(3)H]-FNZ binding density in the internal globus pallidus (GPi). Administration of modafinil (10-100 mg/kg) with MPTP did not alter [(3)H]-FNZ binding density in the striatum or GPe. Low doses of modafinil (10 and 30 mg/kg) had no effect on the increased [(3)H]-FNZ binding density in the GPi but high dose modafinil (100 mg/kg) significantly decreased [(3)H]-FNZ binding density in GPi. These findings suggest that modafinil can selectively alter GABA binding density in the GPi either by preventing MPTP-induced toxicity or through an action on striatal output pathway related to its antiparkinsonian activity and its ability to inhibit MPTP toxicity.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

TorsinA, the gene linked to early-onset dystonia, is upregulated by the dopaminergic toxin MPTP in mice.

Early-onset torsion dystonias are caused by a mutation in TorsinA, a protein widely expressed in the nervous system. Here we report the cloning of the murine TorsinA cDNA and a mRNA in situ hybridization analysis of the expression patterns of TorsinA over developmental periods relevant to the etiology of early-onset dystonias. Several studies have demonstrated a functional involvement of the nigrostriatal dopaminergic system in pathological mechanisms underlying dystonia. In this study, we show that the expression of TorsinA is significantly increased in the brain within hours of treatment with the dopaminergic toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice, suggesting that the TorsinA gene is regulated by cellular stress. These results provide insights into the pathophysiology of early-onset dystonia and strengthen links between the dopaminergic system and dystonia.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2004

Preventive effect of antioxidants in MPTP-induced mouse model of Parkinson's disease.

Oxidative stress to dopaminergic neurons is believed to be one of the causes of neurodegeneration in Parkinson's disease (PD). It was investigated whether N-acetylcysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) have a preventive effect in an oxidative stress-induced model of PD. We found that NAC and OTC prevent degradation of PARP during auto-oxidized dopamine- or auto-oxidized L-DOPA-induced apoptosis in PC12 cells. In an animal model study, NAC and OTC showed a preventive effect against MPTP-induced loss of tyrosine hydroxylase-positive neurons, and suppressed the nuclear translocation of c-jun N-terminal kinase (JNK), suggesting that NAC and OTC can prevent MPTP-induced apoptosis by suppressing JNK activation. Therefore, these results suggest that NAC and OTC can be used as potential agents to prevent the progression of PD.

Acetylcysteine↗
PubMed2005

A synthetic human proline-rich-polypeptide enhances hydroxyl radical generation and fails to protect dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced toxicity in mice.

Some of the proline-rich-polypeptides (PRPs) are shown to afford protection against spinal cord transection or crush syndrome-induced neurodegeneration in the brain. In the present study a synthetic proline-rich-polypeptide of human hypothalamus origin (h-PRP) has been examined for its potency to protect against dopaminergic neuronal damage caused by the parkinsonian neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Effect of h-PRP on hydroxyl radical (*OH) generation in a Fenton-like reaction was monitored, employing a sensitive salicylate hydroxylation procedure. Balb/c mice treated twice with MPTP (30 mg/kg. i.p., twice, 16 h apart) or h-PRP (20 microg/animal, twice, 16 h apart) showed significant loss of striatal dopamine as assayed by HPLC with electrochemical detection. h-PRP pretreatment failed to attenuate MPTP-induced striatal dopamine depletion. A dose-dependent increase in the generation of *OH by h-PRP suggests its pro-oxidant action, and explains its failure to protect against MPTP-induced parkinsonism in mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Use-dependent behavioral and neurochemical asymmetry in MPTP mice.

Early in Parkinson's disease (PD) physical activity becomes difficult resulting in a more sedentary lifestyle. Clinical and experimental studies have found that increased activity following striatal dopamine loss leads to increased motor function. Decreased physical activity early in PD along with findings that increased physical activity results in functional improvement suggested to us that decreased physical activity during the period of nigrostriatal degeneration may not only be a symptom of the injury, but may also act to potentiate the degeneration. Using the bilateral MPTP mouse model of PD, we restricted use of one forelimb for the first 7 days post-injection. This transient behavioral manipulation during the period of dopamine degeneration resulted in a long-lasting deficit of the restricted forelimb. This was manifested as sustained asymmetrical use of the forelimbs during wall exploration, as well as a neurochemical imbalance between striatal hemispheres measured by immunoreactivity of the dopamine terminal markers, DAT, VMAT2 and TH. These results show a significant interaction between behavior and neurochemistry and suggest that a reduction in activity level may further exacerbate degeneration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

In vitro and in vivo neuroprotection by gamma-glutamylcysteine ethyl ester against MPTP: relevance to the role of glutathione in Parkinson's disease.

Glutathione is an abundant intracellular thiol antioxidant whose levels are reduced both in Parkinson's disease itself and in a widely used animal model of the disorder, systemic MPTP administration. Previous in vitro work from our laboratory has suggested that glutathione depletion may be directly responsible for mitochondrial dysfunction, which ultimately leads to dopaminergic cell death associated with the disease. Here, we demonstrate the ability of gamma-glutamylcysteine ethyl ester, a lipid permeable derivative of the major substrate for scavenger glutathione synthesis, to counteract glutathione loss and neurodegeneration associated with in vitro and in vivo administration of MPTP or its derivatives. This data suggests that prevention of glutathione depletion is a likely therapeutic target for the disease.

Analysis of Variance↗
PubMed2004

SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson's disease.

Increasing evidence suggests that c-Jun N-terminal kinase (JNK) is an important kinase mediating neuronal apoptosis in Parkinson's disease (PD) model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In order to study roles of JNK activity in neuronal apoptosis in this model, we blocked JNK activity in vivo using a specific inhibitor of JNK, SP600125. Our data showed that MPTP-induced phospho-c-Jun of substantial nigral neurons, caused apoptosis of dopaminergic neurons, and decreased the dopamine level in striatal area. We found that inhibiting JNK with SP600125 reduced the levels of c-Jun phosphorylation, protected dopaminergic neurons from apoptosis, and partly restored the level of dopamine in MPTP-induced PD in C57BL/6N mice. These results indicate that JNK pathway is the major mediator of the neurotoxic effects of MPTP in vivo and inhibiting JNK activity may represent a new and effective strategy to treat PD.

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