Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: CAS:28289-54-5 (MPTP)
 5,211 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MPTP is a neurotoxin thought to damage dopaminergic neurons through free radical formation. MPTP is metabolized in the brain to MPP(+), which is taken up into dopaminergic neurons via the dopamine transporter and assumed to impair mitochondrial function. We used striatal synaptosomes and telencephalic mitochondria to further investigate MPP(+) mechanism of action. For comparison, the respiratory toxins FCCP, a cyanide analog that uncouples mitochondrial ATP production, and rotenone, a NADH dehydrogenase inhibitor, were also tested. FCCP, MPP(+) and rotenone caused a rapid but stable decrease in [3H]dopamine (DA) uptake by striatal synaptosomes. Two free radical scavengers, the salen-manganese complex EUK-134, and the spin trap s-PBN, did not prevent MPP(+)-induced decrease in DA uptake. However, addition of ATP during synaptosome preparation resulted in partial recovery of MPP(+)-induced [3H]DA uptake decrease. Generation of oxygen free radicals by treatment of telencephalic mitochondria with MPP(+), FCCP, or rotenone, was evaluated by measuring DCF fluorescence, while light emission by the luciferin-luciferase complex was used to determine ATP levels. MPP(+), unlike rotenone, did not produce oxygen free radicals, but rather blocked ATP production in mitochondria, as did FCCP and rotenone. Taken together, these results suggest that MPP(+) toxicity, at least during its initial stages, is primarily due to a decrease in ATP synthesis by mitochondria and not to free radical formation.
 ...
PMID:Rapid reduction of ATP synthesis and lack of free radical formation by MPP+ in rat brain synaptosomes and mitochondria. 1276 10

Endogenous MPTP-like neurotoxins such as 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) have been suspected in the etiology of Parkinson's disease (PD). 1BnTIQ was found in a concentration three times higher in cerebrospinal fluid of PD brains than control subjects [J. Neurochem. 65 (6) (1995) 2633]. In the present study, we have evaluated the mechanisms of 1BnTIQ toxicity in human dopaminergic SH-SY5Y cells and tested the neuroprotective action of SKF-38393, a dopamine receptor (D(1)) agonist. 1BnTIQ dose dependently decreased cell viability in dopaminergic SH-SY5Y cells and the extent of cell death was more pronounced when compared to MPP(+). Similar to MPP(+), 1BnTIQ significantly decreased [3H]dopamine uptake. 1BnTIQ significantly increased lipid peroxidation, Bax expression, and active caspase-3 formation. Furthermore, it decreased the expression of Bcl-xL, an anti-apoptotic protein, in these cells. SKF-38393, a dopamine receptor (D(1)) agonist (1 and 10 microM) completely prevented the cell death and significantly increased cell viability. These results strongly suggest that 1BnTIQ induces dopaminergic cell death by apoptosis and dopamine receptor agonists may be useful neuroprotective agents against 1BnTIQ toxicity.
 ...
PMID:1-Benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ), an endogenous neurotoxin, induces dopaminergic cell death through apoptosis. 1278 6

Acetyl-L-carnitine (ALCAR) plays an integral role in the transport of long chain fatty acids across the inner mitochondrial membrane for oxidative phosphorylation. In non-human primates, administration of ALCAR was reported to prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurological injury to the substantia nigra. The present study investigates the effects of ALCAR against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)), the neurotoxic metabolite of MPTP, in murine brain neuroblastoma cells. MPP(+), a potent mitochondrial toxin, induced a dose-dependent reduction in mitochondrial oxygen consumption and cell viability, corresponding to an accelerated rate of cellular glucose utilization. Treatment with ALCAR, but not L-carnitine, prevented MPP(+) toxicity and partially restored intracellular ATP concentrations, but did not reverse the MPP(+)-induced loss of mitochondrial oxygen consumption. These data indicate that protective effects are independent of oxidative phosphorylation. ALCAR had a substantial glucose sparing effect in both controls and MPP(+)-treated groups, demonstrating a potential role in enhancing glucose utilization through glycolysis. Antagonizing the entry of fatty acids into the mitochondria, with either insulin or malonyl CoA, did not interfere with ALCAR protection against MPP(+). On the contrary, insulin potentiated the protective effects of ALCAR. In conclusion, these data indicate that ALCAR protects against MPP(+) toxicity, independent of mitochondrial oxidative capacity or beta-oxidation of fatty acids. In contrast, the protective effects of ALCAR appear to involve potentiation of energy derived from glucose through anaerobic glycolysis.
 ...
PMID:Acetyl-L-carnitine cytoprotection against 1-methyl-4-phenylpyridinium toxicity in neuroblastoma cells. 1282 72

It has been known that rotenone and 1-methyl-4-phenylpyridinium ion (MPP(+), a metabolite of MPTP), which inhibit mitochondrial complex I, are useful tools for parkinsonian models in vertebrates such as primates and rodents. Planarian, an invertebrate flatworm, has a high potential for regeneration, and dopamine plays a key role in its behavior. In the present study, we examined a cloned planarian, the GI strain from Dugesia japonica. Planarians that were treated with rotenone or MPTP underwent autolysis and individual death in a concentration- and time-dependent manner. In addition, these effects induced by rotenone or MPTP were inhibited by several antiparkinsonian drugs and caspase inhibitors. These results suggest that the degeneration of planarian dopaminergic system induced by rotenone or MPTP may be mediated through caspase-like activation.
 ...
PMID:Inhibitory effects of antiparkinsonian drugs and caspase inhibitors in a parkinsonian flatworm model. 1283 41

Several laboratories recently have reported that melatonin may possess neuroprotective properties. The present paper presents the results of our studies on the long term in vivo neuroprotective effects of melatonin in a well-defined neurotoxicity model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the C57BL/6 mouse. MPTP is bioactivated by brain monoamine oxidase B (MAO-B) to its neurotoxic pyridinium metabolite 1-methyl-4-phenylpyridinium (MPP(+)) which destroys dopaminergic nerve terminals leading to the depletion of neostriatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC). Our initial study compared striatal DA and DOPAC levels in MPTP-only-treated animals and animals treated with melatonin 30 min prior to and 3 times hourly post-MPTP. DA/DOPAC levels measured 7 days after MPTP were similar in both groups. A second study was designed to address the possibility that melatonin cleared from the brain prior to MPP(+). Animals, that had been administered the same regimen of melatonin as in the first study plus a fourth post-MPTP melatonin dose, were maintained on melatonin in drinking water until 5 days post-MPTP. Striatal DA/DOPAC levels of these melatonin-plus-MPTP treated animals also were the same as the MPTP-only-treated animals. In vitro studies confirmed that melatonin is not an inhibitor of MAO-B. These data demonstrate that melatonin does not have any significant protective effects against the long-term striatal DA and DOPAC depletion induced by MPTP in the C57BL/6 mouse.
 ...
PMID:Melatonin fails to protect against long-term MPTP-induced dopamine depletion in mouse striatum. 1283 94

To examine how mGlu2/3 metabotropic glutamate receptors affect nigro-striatal degeneration, we used the agonist, LY379268, and the antagonist, LY341495, in mice challenged with the nigro-striatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In control mice, high doses of MPTP (20 mg/kg, i.p., injected four times with 2 h of interval) induced a nearly total degeneration of the nigro-striatal pathway, as shown by measurements of striatal dopamine (DA) levels and by immunohistochemical analysis of tyrosine hydroxylase, high affinity dopamine transporter, and glial fibrillary acidic protein in the corpus striatum and substantia nigra. Lower cumulative doses of MPTP (30 mg/kg, i.p., injected only once) produced a partial lesion of the nigro-striatal pathway (about 50% reduction of striatal DA content). Systemic injection of LY379268 (1 mg/kg, i.p., 30 min prior to each injection of MPTP) partially reduced the extent of nigro-striatal degeneration induced by high doses of MPTP. Similar results were obtained by continuously delivering LY379268 (1 mg/kg/d for 7 d) by means of a subcutaneous osmotic minipump. The protective effect of LY379268 was antagonized by LY341495 (also delivered by the osmotic minipump). In mice challenged with the lower cumulative dose of MPTP, injection of LY379268 did not produce a significant neuroprotective effect. In contrast, the lesion was amplified by the antagonist, LY341495. Neither LY379268 nor LY341495 influenced the central bioavailability and the local half-life of MPTP, as shown by measurements of the toxin and its active metabolite, MPP(+), in the striatum. We conclude that mGlu2/3 receptors play a protective role against MPTP toxicity, and that the efficacy of the agonist, LY379268, critically depends on the extent of the nigro-striatal lesion.
 ...
PMID:Protective role of group-II metabotropic glutamate receptors against nigro-striatal degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. 1284 21

In vivo formation of 1-methyl-4-phenylpyridinium ion (MPP(+)) in the striatum, and dopaminergic neurotoxicity following systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the presence and absence of calcium channel agonist (+/-)-Bay K8644 were analyzed in Balb/c mice. We used HPLC-photodiode array detection, HPLC-electrochemical detection and spectrofluorimetric procedures to measure striatal MPP(+) and dopamine (DA) and for the assay of monoamine oxidase-B (MAO-B) activity, respectively. Systemic administration of (+/-)-Bay K8644 resulted in a significant increase in striatal MAO-B activity. An MPTP-induced decrease in striatal MAO-B activity was attenuated by pre-treatment with (+/-)-Bay K8644 initially, but not on the 3rd day. MPP(+) formation in the striatum following systemic administration of MPTP was significantly increased by the pre-treatment of the agonist initially (30 min), but was not different afterwards (at 60 and 90 min). Nevertheless, the total MPP(+) formed over a 90 min period was found to be comparable. (+/-)-Bay K8644 administration prior to MPTP failed to influence the MPTP-induced striatal DA depletion on the 3rd day. While the transient effect of (+/-)-Bay K8644 on striatal MAO-B is reflected as an immediate increase in the levels of MPP(+) in the striatum, it failed to affect MPTP-induced DA neurotoxicity in Balb/c mice.
 ...
PMID:Calcium channel agonist, (+/-)-Bay K8644, causes an immediate increase in the striatal 1-methyl-4-phenylpyridinium level following systemic administration of the dopaminergic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, in Balb/c mice. 1285 May 50

MPTP (1-methyl-1,2,3,6-tetrahydropyridine), a chemical contaminant of synthetic heroin, induces neuropathological changes with clinical features similar to idiopathic Parkinson's disease. The mechanism by which MPTP and its metabolite MPP(+)(1-methyl-4-phenylpyridinium) induces neuronal cell death remains unclear. We employed primary cortical/telencephalon neuronal cultures to investigate the potential role of caspase and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) pathways in MPP(+)-induced neuronal death. DNA fragmentation and caspase-3 activity analysis showed that cortical neuronal cells underwent apoptosis after MPP(+)treatment. However, a basal level of apoptotic cells was also observed in untreated cultures. Interestingly, JNK activity increased in untreated cultures over time, whereas it was down-regulated after MPP(+)treatment. This indicates that the JNK pathways could be differentially regulated in different apoptotic processes.
 ...
PMID:Differential regulation of JNK in caspase-3-mediated apoptosis of MPP(+)-treated primary cortical neurons. 1297 83

The novel naphtoxazine derivative and preferential D(3) vs D(2) receptor agonist, S32504, restores perturbed motor function in rodent and primate models of antiparkinsonian activity with a potency superior to those of two further, preferential D(3) receptor agonists, pramipexole and ropinirole. However, potential neuroprotective properties of S32054 have not, to date, been evaluated. Herein, employing several measures of cellular integrity, we demonstrate that S32504 robustly, concentration-dependently and completely protects terminally differentiated SH-SY5Y cells against 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in vitro. Further, S32504 was substantially more potent than pramipexole and ropinirole, the latter of which was neurotoxic at high concentrations. In vivo, subchronic treatment with low (0.25 mg/kg) and high (2.5 mg/kg) doses of S32504 prior to and during treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP, provided complete protection against MPTP-induced tyrosine hydroxylase immunoreactive (TH-IR) neuronal death in the substantia nigra pars compacta and ventral tegmental area. A high dose of ropinirole (2.5 mg/kg) provided some protection but statistical significance was not attained, and a low dose (0.25 mg/kg) was ineffective. Neither drug afforded protection against the MPTP-induced loss of DA fibers in the striatum, as measured by TH-IR and dopamine transporter immunoreactive fiber counts. In conclusion, the novel naphotoxazine and dopaminergic agonist, S32504, robustly protects dopaminergic neurones against the neurotoxic effects of MPP(+) and MPTP in in vitro and in vivo models, respectively. The underlying mechanisms and therapeutic pertinence of these actions will be of interest to further evaluate in view of its potent actions in behavioral models of antiparkinson activity.
 ...
PMID:Neuroprotective effects of the novel D3/D2 receptor agonist and antiparkinson agent, S32504, in vitro against 1-methyl-4-phenylpyridinium (MPP+) and in vivo against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): a comparison to ropinirole. 1463 9

The herbal remedy, ginseng, has recently been demonstrated to possess neurotrophic and neuroprotective properties, which may be useful in preventing various forms of neuronal cell loss including the nigrostriatal degeneration seen in Parkinson's disease (PD). In these studies, we examine the potential neuroprotective actions of the ginseng extract, G115, in two rodent models of PD. Animals received oral administration of G115 prior to and/or following exposure to the parkinsonism-inducing neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in mice, or its toxic metabolite, 1-methyl-4-phenylpyridinium (MPP(+)), in rats. Such treatment significantly and dramatically blocked tyrosine hydroxylase-positive cell loss in the substantia nigra and reduced the appearance of locomotor dysfunction. Thus, oral administration of ginseng appears to provide protection against neurotoxicity in rodent models of PD. Further examination of the neuroprotective actions of ginseng and its various elements may provide a potential means of slowing the progress of PD.
 ...
PMID:Neuroprotective actions of the ginseng extract G115 in two rodent models of Parkinson's disease. 1463 21


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>