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At least 649 records · Page 36Linked to original sources
PubMed2000

Acute ultrastructural effects of MPTP on the nigrostriatal pathway of the C57BL/6 adult mouse: evidence of compensatory plasticity in nigrostriatal neurons.

Acute doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) elicited degenerative and apparently compensatory changes in the nigrostriatum of injected animals within 1 day of treatment. In the substantia nigra pars compacta (SNc), low-dose (20 mg/kg) administration elicited early degeneration of mitochondria in the absence of other effects. In the striatum, a low MPTP dose resulted in myelin unwinding, demyelination, cytoplasmic shrinkage, and disturbance of synaptic communication, as evinced by a profound reduction in synaptic vesicle production. High-dose (40 mg/kg) administration generated more drastic axonal degeneration leading to cell elimination in the striatum. At neither dose was mitochondrial disturbance evident in the striatum. Evidence is presented that darkened synaptic boutons, visible at this level of MPTP administration, were part of healthy enlarged axons with an elevated number of synaptic contacts. These spared neuronal processes, therefore, were hypothesized to compensate for the MPTP-induced death of dopaminergic neurons by adaptive structural modifications that would serve to enhance their functional capability.

Animals↗
PubMed1999

Effect of MPTP on brain mitochondrial H2O2 and ATP production and on dopamine and DOPAC in the striatum.

An experimental rat model of Parkinson's disease was established by injecting rats directly in the striatum with the neurotoxic agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In order to study the action mechanism of this neurotoxic agent, MPTP and its main metabolite 1-methyl-4-phenylpyridinium (MPP+) were also added to suspensions of pyruvate/malate-supplemented nonsynaptic brain mitochondria, and the rates of hydrogen peroxide and ATP production were measured. Intrastriatal administration of MPTP produced a pronounced decrease in striatal dopamine levels (p < 0.005) and a strong increase in 3,4-hydroxiphenylacetic acid/dopamine ratio (an indicator of dopamine catabolism; p < 0.005) in relation to controls, as evaluated by in situ microdialysis. MPTP addition to rat brain mitochondria increased hydrogen peroxide production by 90%, from 1.37+/-0.35 to 2.59+/-0.48 nanomoles of H2O2/minute . mg of protein (p < 0.01). The metabolite MPP+ produced a marked decrease on the rate of ATP production of brain mitochondria (p < 0.005). These findings support the mitochondria-oxidative stress-energy failure hypothesis of MPTP-induced brain neurotoxicity.

1-Methyl-4-phenylpyridinium↗
PubMed2000

Factors influencing the onset and persistence of dyskinesia in MPTP-treated primates.

The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated primate model of Parkinson's disease provides a unique opportunity to study factors influencing the onset and persistence of dyskinesia induced by levodopa or dopamine agonist treatment. Contrary to popular belief, denervation is not essential for the induction of dyskinesia, and both D1 and D2 dopamine agonist drugs are able to initiate dyskinetic movements. However, their ability to do so is currently attributed to their pharmacokinetic and pharmacodynamic properties rather than to their receptor selectivity, although this view is challenged in this article. Short-acting pulsatile dopamine agonists are more likely to induce dyskinesia than drugs that have a long duration of effect and produce continuous receptor stimulation. The induction of dyskinesia does not seem to be associated with any obvious change in the number or sensitivity of post-synaptic dopamine receptors, but rather to downstream events associated with the indirect and direct output pathways. Currently, there is evidence for the involvement of both pathways in the genesis of dyskinesia and so there is no clear explanation for the onset of involuntary movements or for the priming process that initiates dyskinesia. However, a variety of therapeutic strategies primarily related to the use of non-dopaminergic agents may be able to prevent dyskinesia from occurring, and the actions of neurotropic factors, such as glial-derived neurotropic factor, may be effective in reversing established involuntary movements.

Animals↗
PubMed1998

[A pathological study on the autotransplantation of monkey's cervical sympathetic ganglion into brain for the treatment of Parkinson's disease].

OBJECTIVE: In order to find out evidences in explicating whether the transplanted ganglion cells can be kept surviving longer in the brain and to find out an ideal transplantation way for the surgical treatment of Parkinson's disease. METHODS: Cervical sympathetic ganglions autotransplantation into the caudate nuclei of the brain in 9 rhesus monkeys known to have the symptoms and signs of the Parkinson's disease beforehand induced by using 1-methy1-4-phen-1, 2, 3, 6-tetrahydropynidne (MPTP) and in addition, muscle tendon tissue was also grafted for comparison. The experimental animals were followed up for 2 years. All the specimens taken were processed and prepared in continuous frozen sections for H & E, glyoxlyic acid induced dopamine fluorescence and immunochemistry stainings including anti-chromogranin A, synaptophysin, neurofilament, NSE, GFAP as markers. RESULTS: Two years after the autotransplantation operation, there were still surviving ganglion cells left in the caudate nuclei. The grafted ganglion cells were connected by the neurodendrites with the brain tissue which showed dopamine fluorescence positive and also had expression of chromogramin A, synaptophysin and neurofilaments. CONCLUSIONS: The grafted cells survived in the brain over 2 years. It's considered that the sympathetic ganglion is the first choice in comparing with other tissues as the graft for the surgical treatment of Parkinson's disease. Continuous frozen sections accompanying with inducing fluorescence and immunohistochemistry staining are seemed reliable as the parameters in checking the result after neural transplantation.

Animals↗
PubMedDate not supplied

Idiopathic Parkinson's disease: a review of clinical types and pathology.

Parkinsonism occurs in a variety of disorders, involving the central nervous system. The basic pathology in this disorder is the destruction of the pigmented neuronal pathway of the brain stem. The major site of damage is the nigrostriatal pathway. There is associated cytoplasmic neuronal changes, the most specific is the formation of an intracytoplasmic inclusion body, the Lewy body. This varies from other forms of neurofibrillary degeneration. Other neuropathological changes which may be age related are also found. This paper is an overview of the idiopathic Parkinson's disease.

Central Nervous System↗
PubMed2002

[The role of substantia nigra in the cognitive activity in cats].

The role of substantia nigra (SN) in the cat cognitive activity of different complexity degree, was investigated by original technique. Neurosurgery or neurochemical SN switching off leads to reliable disturbances of condition, reflexes, generalization and abstraction. Rehabilitation was possible after pharmacological stimulation of dopaminergic, partly GABA-ergic, and cholinergic systems. Stimulation of serotonin system was ineffective.

5-Hydroxytryptophan↗
PubMed2002

[Neuroprotective effects of semax in MPTP-induced disturbances of brain dopamine system].

Effects of an ACTH (4-10) analogue Semax (MEHFPGP) on behaviour of white rats with MPTP-induced disturbances of brain DA-system have been studied. It was shown that MPTP administration (25 mg/kg) reduced motor activity and auhmented the anxiety level in rats. Semax administration (daily intranasal 0.2 mg/kg) attenuated behaviour disturbances induced by neurotoxin. The observed protective action of Semax in rats with MFTP-induced DA system disturbances may be due to both its modulating influence on the brain DA system and peptide neuroprotective effects.

Administration, Intranasal↗
PubMed2003

[Recombinant adenovirus carrying glial cell line-derived neurotrophic factor gene protect midbrain dopaminergic neurons in mice].

OBJECTIVE: To observe the protective effects of recombinant adenovirus expressing glial cell line-derived neurotrophic factor (Ad-rGDNF) on the midbrain dopaminergic neurons against MPTP damage. METHODS: Recombinant adenovirus carrying LacZ gene (Ad-LacZ) was injected into the murine striatum using the stereotaxic apparatus. The murine brains were perfused and dissected, then stained with X-Gal subsequently at 24 hours, 72 hours, 10 days and 30 days after injection. In another experiment, MPTP was injected subcutaneously into the mice 72 hours after the intrastriatal injection of Ad-rGDNF (1 x 10(8) pfu.ml-1). The murine striatum was removed to evaluate the content of DA, DOPAC and HVA by HPLC-ECD 1 week later. RESULTS: X-Gal staining indicated the expression of LacZ gene 24 hours after injection of Ad-LacZ. Stronger expression was also detected at the end of 72 hours and 10 days, but decreased 30 days later. In addition, the LacZ gene expression was localized and detectable in both neurons and glial cells. There was no apparent cytotoxic effect induced by Ad-LacZ alone. In MPTP-treated mice, the content of dopamine decreased 80% compared to that in the saline-treated ones. The DA content of MPTP + Ad-rGDNF group on injected side was significantly higher than that of MPTP alone group and MPTP + Ad-LacZ group. Changes in the content of DOPAC and HVA followed the same pattern. The ratio of DOPAC/DA and HVA/DA on injected side also decreased significantly. However, no significant change was observed on uninjected side. CONCLUSION: The results suggested that recombinant adenoviral vector expressing rGDNF can protect DA neurons against MPTP injury.

Adenoviridae↗
PubMed1992

Characterization of 2,4,5-trihydroxyphenylalanine neurotoxicity in vitro and protective effects of ganglioside GM1: implications for Parkinson's disease.

The neurotoxic properties of 2,4,5-trihydroxyphenylalanine (TOPA; the 6-hydroxylated derivative of dopa) was investigated in cultures of central neurons. Application of solutions of TOPA to cerebellar granule cells resulted in a concentration- and time-dependent neuronal death, with prolonged (24 hr) exposure producing a clear left-handed shift in the dose-response relationship from the one observed with a 60-min exposure (LD50: 4 and 29 microM, respectively). This toxicity was largely blocked by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Solutions of TOPA were also toxic to mesencephalic neurons after acute or chronic exposure, displaying the same leftward shift in LD50. This latter preparation contained a minor population of dopaminergic, tyrosine hydroxylase immunopositive cells which were likewise sensitive to the excitotoxic effects of TOPA. Neurotoxic activity of TOPA appeared to depend upon its oxidation in solution, as judged using chemical analysis and reducing agents. The monosialoganglioside GM1 was effective in protecting against neurodegeneration induced by brief or prolonged exposure to solutions of TOPA. These results suggest that an abnormal production or accumulation of TOPA or its oxidation product(s) might be involved in excitotoxicity directed to areas of the brain with dopaminergic innervation, and in other brain areas in Parkinson's disease patients on long-term dopa therapy. The selective action of gangliosides in disrupting the pathological consequences of glutamate receptor activation proposes their use as chemoprophylactic agents for preventing or arresting the neuronal losses accompanying such situations.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1992

Comparative studies of the neurotoxicity of MPTP in rats of different ages.

The present study investigated the neurotoxic effects of repeated MPTP injections on monoamine neurotransmitters and locomotor activity in rats of different ages. We also examined the mortality of MPTP-treated rats at different ages. Male Sprague-Dawley rats were used in all experiments. In the first experiment, we examined the mortality of rats (11-12 month old) subject to different doses of MPTP. In the second experiment, rats of 2-3 months old were randomly divided into five groups. Group 1 served as the control; Groups 2,3,4 and 5 received daily MPTP injections (30 mg/kg, ip) for a continuation of 7 days. Biochemical and behavioral assays were conducted at 1,7,14 and 28 days after withdrawal of MPTP, respectively. In the third and fourth experiments, the same experimental design was adopted except that rats of 5-6 months old and rats of 11-12 months old were used, respectively. Besides, the doses of MPTP used were 22.5 mg/kg and 12.5 mg/kg, respectively. Immunohistochemical experiments were always conducted 7 days after withdrawal of MPTP. Results indicated that, in young rats, repeated MPTP injections did not significantly decrease DA, and 5HT levels as well as TH and DBH immunoreactivities although it impaired locomotor activity. The same treatment significantly depleted DA, NE and 5HT levels in the middle-aged rats. It also decreased the density of TH and DBH immunoreactivities and altered the morphology of DA and NE neurons. Meanwhile, it impaired locomotor activity. In old rats, MPTP injections produced effects similar to those observed in the middle-age rats except that the hippocampal serotonergic system was also affected. However, all these effects recovered 28 days after withdrawal of MPTP injection. Finally, the dose of MPTP required to exert similar extent of neurotoxicity decreased as the age of rats increased, and the dose required to result in mortality markedly decreased in old rats. These results together suggest that MPTP does exert a toxicity on DA, NE and 5HT neurons and impair motor activity in rats. These effects are age-dependent while the irreversibility of MPTP's toxicity in rats requires further investigation.

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

[Experimental model of Parkinson disease: mechanisms and anatomo- pathological characteristics of MPTP neurotoxicity].

MPTP administration induces a fairly selective lesion of substantia nigra dopaminergic neurons both in animals and humans. This characteristic of MPTP has led to the best available model of Parkinson's disease and neuronal degenerations. MPTP toxicity is actually provoked by MPP+ which results after oxidation by MAO-B. Possible mechanism of action of MPP+ include: 1) Mitochondrial lesion. 2) Free radicals generation. 3) Trapping of MPP+ by highly melanized neurons. This article reviews the mechanisms of toxicity by MPTP and its neuropathological characteristics.

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

[The roles of dopamine 4 receptor in MPTP-induced gastrointestinal mucosal injury in rats].

OBJECTIVE: Using the dopamine 4 receptor (D(4)) agonist quinpirole (Q.) and antagonist clozapine (C.) to investigate the role of D(4) in MPTP induced gastrointestinal injury in rat. METHODS: SD rats were randomly divided into 8 groups (n = 5 approximately 9 each group): NS as control; Q. 0.5 mg/kg; Q. 1 mg/kg; C. 10 mg/kg; Q. 0.5 mg/kg + MPTP; Q. 1 mg/kg + MPTP; and MPTP l mg/100 g. After treated with the different chemicals, the gastric and duodenal mucosa lesion index (LI) was recorded. Gastric and duodenal mucosa was collected to assay NO and iNOS by spectrophotometer. RESULTS: (1) MPTP peritoneal injection induced significant gastro-duodenal mucosa injury; both gastric and duodenal LI were 5 approximately 6-fold higher than control group (P < 0.01). (2) Q. or C. used alone showed no effect on gastro-duodenal mucosa, Q. used before MPTP could resist the MPTP-induced mucosa injury, especially in duodenum (P < 0.01). This effectiveness is dose dependent. C. had no effect on gastro-duodenal mucosa protection. (3) The mucosal NO concentration and iNOS activity in MPTP group were lower than that in control, especially in duodenum (P < 0.05). They were negative correlated with LI. CONCLUSION: MPTP peritoneal injection induced significant gastro-duodenal mucosa injury in rat, mediated partially by decreasing the activity of mucosa iNOS and NO concentration. D(4) agonist Q. could resist the effectiveness of MPTP-induced mucosa injury, while the antagonist C. had no effect.

Animals↗
PubMed2003

Survival and differentiation of transplanted neural stem cells in mice brain with MPTP-induced Parkinson disease.

AIM: To determine survival and differentiation of cultured neural stem cells (NSCs) into viable and functional neurons upon transplantation into mice brain of MPTP-induced Parkinson disease (PD). METHODS: Mouse model of PD was established with two subcutaneous (sc) injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 40 mg/kg) twice, 16 h apart. NSCs isolated from rat embryo midbrain were cultured in clonal density. After labeled with 5-bromo-2'-deoxyuridine (BrdU), the NSCs were transplanted into the uni- or bi-lateral striatum of PD mouse. Tyrosine hydroxylase (TH) immunofluorescence was used to evaluate the toxicity of MPTP on the neural cells in the substantia nigra. Immunohistology and laser confocal microscope were used to detect the survival and differentiation of transplanted NSCs. RESULTS: The cultured NSCs generated neurospheres and differentiated into neuron and astrocyte. It indicated that the cultured NSCs were multipotent and self-renewal in vitro. TH-positive neural cells were significantly reduced in the substantia nigra. Immunohistology showed that the uni- or bi-lateral transplanted NSCs survived in the brain of PD model mouse. Laser confocal microscope indicated that some transplanted NSCs could properly differentiate into targeted TH-positive neural cells in vivo. CONCLUSION: The transplanted multipotent NSCs could survive and differentiate into functional dopamine neurons.

Animals↗