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Morphological and metabolic endpoints were used to evaluate MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) toxicity to SH-SY5Y human neuroblastoma cells. After 8 hours of exposure, MPTP was found to affect cell viability only at a very high concentration (3 x 10(-3) M), but its metabolite MPP+ could decrease viability at 10(-4) M. MPTP, via its metabolite MPP+, inhibited NADH dehydrogenase activity when concentrations exceeded 10(-4) M (for MPP+ 10(-5)M). The Ki were 2.4 x 10(-3) M and 3 x 10(-4)M for MPTP and MPP+, respectively. MPTP at concentrations greater than 10(-4) M altered cell morphology as early as one hour after exposure. These changes included formation of cell surface blebs and attenuated neurites. After 8 hours at 10(-3) M and 24 hrs at 10(-4) M, MPTP caused ultrastructural changes of mitochondria with increased electron-density of the matrix and disorganization of cristae, as well as abnormal aggregation of filamentous material of the cytoskeleton. Because these changes of structure and function took place at concentrations lower than those needed to affect cell viability, they may play a role in MPTP neurotoxicity in SH-SY5Y cell culture.
A double-blinded study was conducted to evaluate the dose response of hemiparkinsonian rhesus monkeys to intracerebroventricular (ICV) injections of recombinant methionine human glial cell line-derived neurotrophic factor (GDNF). Thirty rhesus monkeys with stable hemiparkinsonian features were divided into six treatment groups (vehicle, 10, 30, 100, 300 and 1000 microg GDNF; n = 5/group). Each animal received 4 ICV administrations spaced at four week intervals. In addition, the animals were followed for 4 mo after the last injection. Standardized video taped behavioral tests were used to rate parkinsonian features using a nonhuman primate rating scale and assess side effects from treatment. Significant behavioral improvements were measured in animals receiving 100 to 1000 microg GDNF. One month after the last GDNF administration, parkinsonian features in animals receiving 100 and 1000 microg GDNF began to return to baseline levels. However, 300 microg GDNF recipients continued to display behavioral improvements. Parkinsonian features significantly improved were: bradykinesia, rigidity, posture and balance. The most common side effect was a transient weight loss after GDNF administration. Only one other side effect was observed, one animal receiving 1000 microg GDNF displayed dyskinetic movements. The results provide additional information for evaluating the possible clinical application of GDNF for treating Parkinson's disease.
Norepinephrine (NE) depletion caused by damage to locus ceruleus neurons was shown to worsen experimental Parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in monkeys and in rodents. However, it is not clear whether the lesion to the NE system enhances neurotoxicity in the nigrostriatal dopaminergic (DA) pathway and/or impairs the recovery of DA neurons once the neurotoxic insult is generated. In this study, we provide evidence that the lesion of NE terminals, induced by the selective neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg), must occur before MPTP (30 mg/kg) administration in order to enhance MPTP toxicity. As a second step, we evaluated the acute effects of MPTP on the nigrostriatal DA pathway in NE-lesioned animals compared with intact animals. We observed a more marked acute DA depletion, persisting at 12 h, in DSP-4 + MPTP-treated mice compared with MPTP-injected controls. These findings, combined with the lack of an MPTP enhancement when NE depletion was induced 12 h after MPTP administration, suggest that in NE-depleted animals, a more pronounced acute neuronal sensitivity to MPTP occurs. In line with the hypothesis of an acute protective effect by NE axons, we evaluated whether the enhancement of MPTP toxicity in NE-lesioned animals is achieved through alterations to the kinetics of MPTP and its metabolite. Our findings indicate that despite the pivotal role of NE terminals in taking up and storing 1-methyl-4-phenylpyridinium (MPP+), MPTP enhancement does not depend on modifications in the striatal kinetics of MPTP/MPP+ measured at seven different time intervals after MPTP administration.
Positron emission tomography provides researchers and clinicians with information on cerebral blood flow, metabolic pathways or neurotransmission systems, which may help to understand the physiopathology of movement disorders. Studies of the nigrostriatal dopaminergic pathway and data on cerebral glucose metabolism contribute to discriminate between parkinsonian syndromes. New techniques for image processing and statistical analysis, and brain activation studies better emphasize dysfunction of cortico-subcortical neuronal networks responsible for movement disorders, or functional modification after therapeutic action.
The profile of dopamine receptor subtype activation contributing to the therapeutic efficacy and motor response complications of levodopa (nonselective pro-agonist) in Parkinson's disease remains unclear. Potent, selective, short-acting dopamine D2 receptor subfamily agonists show good antiparkinsonian efficacy but produce dyskinesias comparable to levodopa. Nonetheless, agonists displaying higher affinity for dopamine receptors other than the D2 subtype may have a better therapeutic index. To clarify this issue, we compared the nonselective dopamine D1/D2 receptor subfamilies agonist apomorphine to the dopamine D3 receptor preferring agonist [R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4 , 3-b]-1,4-oxazin-9-ol] (PD 128,907) in 6 levodopa-primed , 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned parkinsonian monkeys with reproducible dyskinesias. Single s.c. dosing with the lowest fully effective dose of apomorphine (averaging 27.9 +/- 4.5 microg/kg) and PD 128,907 (averaging 41.7 +/- 4.4 microg/kg) yielded equivalent antiparkinsonian efficacy on the behavioral scale and portable activity monitoring used. A comparable significant dose-dependent increase in the response magnitude and duration was seen with two higher doses. The severity of dyskinesia was also similar between the two drugs. When the lower dose for each drug was administered six times at a fixed 90-min interval, both drugs remained efficacious with no significant tolerance observed. The D3 receptor preferring antagonist U-99194A significantly reduced the motor effects of both apomorphine and PD 128,907. Thus, increased D3 receptor tone does not acutely ameliorate dyskinesias in levodopa-primed parkinsonian monkeys. Given the reported lack of affinity of PD 128,907 for central D1 receptors, our data support the concept that the pharmacological activation of D1 receptors is not mandatory for relief of parkinsonism and production of dyskinesia.
The effects of the antiparkinsonian agent trihexyphenidyl, a selective M1 muscarinic cholinergic receptor antagonist, were studied in doses of 100, 320 and 1000 micrograms/kg i.m. alone. Trihexyphenidyl was then studied in combination with the selective dopamine receptor D1 agonist SKF-82958 [(+/-)-6-chloro-7-8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro- 1H-benzazepine hydrobromide] and the selective D2 agonist N-0923 [(-)2-(N-propyl-N-2-thienylethyl)amino-5-hydroxytetralin HCl] on rotational behavior in five 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned hemiparkinsonian monkeys. Given alone, trihexyphenidyl had no effect on ipsiversive and slightly enhanced contraversive circling. Contraversive circling produced by 74.8 and 234 micrograms/kg SKF-82958 i.m. was potentiated by increasing doses of trihexyphenidyl. On the other hand, contraversive circling produced by 10 and 32 micrograms/kg N-0923 i.m. was progressively reduced with increasing doses of trihexyphenidyl. The results obtained indicate differential actions on circling behavior between a selective M1 muscarinic cholinergic receptor antagonist and selective D1 and D2 receptor agonists in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkey model of hemiparkinsonism.
In this study, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 10(-3) to 10(-4) M for 2 to 5 days) increased the expression of microtubule-associated tau protein in both the supernatant and pellet fractions of lysed SH-SY5Y human neuroblastoma cells. The western blot using anti-tau-1 antibodies demonstrated that the cells contained at least six isoforms of tau proteins, five with molecular weights from 45 to 62 kD. Reverse transcriptase polymerase chain reaction (RT-PCR) using primers coding whole length tau protein further confirmed the presence of tau in SH-SY5Y cells. The PCR product of tau in SH-SY5Y cells had approximately 1050 base pairs. MPTP caused an increased expression of the PCR product of tau, suggesting that the toxicant caused an increase in mRNA coding the tau protein. The expression of cytoskeletal tau protein may, therefore, provide a marker for MPTP neurotoxicity in SH-SY5Y cells.
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces an experimental model of Parkinson's disease (PD). It replicates most of the clinical features of PD as well as the main biochemical and pathologic hallmarks of the disease. Although the MPTP model departs from PD in several aspects, it is thought that important insights into the neurodegenerative process of PD may be obtained by elucidating the molecular mechanism of MPTP. In this article, we summarize the different steps of the complex metabolic pathway of MPTP and show how they may be implicated in predisposing individuals to PD. We also outline findings pertinent to the mode of action of MPTP including overproduction of free radicals, implication of nitric oxide, nitration of tyrosine, impairment of mitochondrial respiration, and occurrence of apoptosis. All of these factors may participate in the cascade of deleterious events that ultimately lead to the death of dopaminergic neurons after MPTP administration. Because of the similarity between PD and the MPTP model, we are speculating that a similar scenario may underlie the neurodegenerative process in PD.
The effects of dopamine receptor agonists on urinary bladder function were evaluated in normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned parkinsonian cynomolgus monkeys to investigate the therapeutic efficacy in the treatment of urinary symptoms in Parkinson's disease. Under ketamine anesthesia, cystometrograms exhibited significant reduction in the volume threshold for the micturition reflex in MPTP-lesioned parkinsonian monkeys when compared with those of normal monkeys. The selective dopamine D2 receptor agonist bromocriptine significantly reduced the bladder volume threshold for the micturition reflex by 25 to 30% in both normal and MPTP-lesioned animals. The nonselective D1/D2 receptor agonist pergolide significantly reduced the bladder volume threshold by 22% in normal monkeys, but increased the volume threshold by 50% in MPTP-lesioned parkinsonian monkeys. Another D1/D2 agonist (5R,8R,10R)-6-methyl-8-(1,2,4-triazol-1-ylmethyl) ergoline maleate (BAM-1110) also increased the bladder volume threshold (by 80%) in parkinsonian monkeys without significant effects on the micturition reflex in normal monkeys. The reduction in the volume threshold by bromocriptine in both normal and MPTP-treated groups and by pergolide in normal monkeys was suppressed by pretreatment with the selective D2 antagonist sulpiride, whereas the increment in the volume threshold by pergolide and BAM-1110 in parkinsonian monkeys was antagonized by pretreatment with the selective D1 antagonist SCH 23390, but not by sulpiride. These findings suggest that concurrent activation of D1/D2 receptors, rather than selective stimulation of D2 receptors, might be beneficial for treating urinary symptoms caused by detrusor hyperreflexia in Parkinson's disease.
The proto-oncogene Bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that Bcl-2 protects against free radicals and that it increases mitochondrial calcium-buffering capacity. The neurotoxicity of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyride (MPTP) is thought to involve both mitochondrial dysfunction and free radical generation. We therefore investigated MPTP neurotoxicity in both Bcl-2 overexpressing mice and littermate controls. MPTP-induced depletion of dopamine and loss of [3H]mazindol binding were significantly attenuated in Bcl-2 overexpressing mice. Protection was more profound with an acute dosing regimen than with daily MPTP administration over 5 d. 1-Methyl-4-phenylpyridinium (MPP+) levels after MPTP administration were similar in Bcl-2 overexpressing mice and littermates. Bcl-2 blocked MPP+-induced activation of caspases. MPTP-induced increases in free 3-nitrotyrosine levels were blocked in Bcl-2 overexpressing mice. These results indicate that Bcl-2 overexpression protects against MPTP neurotoxicity by mechanisms that may involve both antioxidant activity and inhibition of apoptotic pathways.
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We have identified a bis-ethylthiomethyl analog of K-252a, CEP-1347/KT-7515, that promotes neuronal survival in culture and in vivo. The neuronal survival properties of CEP-1347/KT-7515 may be related to its ability to inhibit the activation of c-jun N-terminal kinase, a key kinase in some forms of stress-induced neuronal death and perhaps apoptosis. There is evidence that the selective nigrostriatal dopaminergic neurotoxin, MPTP, produces neuronal apoptosis in culture and in adult mice. Thus, our studies were designed to determine if CEP-1347/KT-7515 could protect dopaminergic neurons from MPTP-mediated neurotoxicity. CEP-1347/KT-7515 was assessed for neuroprotective activity in a low dose MPTP model (20 mg/kg) where there was a 50% loss of striatal dopaminergic terminals in the absence of substantia nigra neuronal loss, and a high dose (40 mg/kg) MPTP model where there was a complete loss of dopaminergic terminals and 80% loss of dopaminergic cell bodies. In the low dose MPTP model, CEP-1347/KT-7515 (0.3 mg/kg/day) attenuated the MPTP-mediated loss of striatal dopaminergic terminals by 50%. In the high dose model, CEP-1347/KT-7515 ameliorated the loss of dopaminergic cell bodies by 50% and partially preserved striatal dopaminergic terminals. CEP-1347/KT-7515 did not inhibit monoamine oxidase B or the dopamine transporter, suggesting that the neuroprotective effects of CEP-1347/KT-7515 occur downstream of the metabolic conversion of MPTP to MPP+ and accumulation of MPP+ into dopaminergic neurons. These data implicate a c-jun N-terminal kinase signaling system in MPTP-mediated dopaminergic degeneration and suggest that CEP-1347/KT-7515 may have potential as a treatment for Parkinson's disease.
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Striking similarities between poisoning by the protoxin MPTP and Parkinson's disease have always been clear (Williams, 1984). Predictions that this could lead to the discovery of the cause of Parkinson's disease have not yet materialized, but the trail has not gone cold.