Neurotoxicity of MPTP and uptake of MPPT into dopamine and norepinephrine neurons in mice.
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1-Methyl-4-phenylpyridinium↗
Biomedical subjects
K T Lu
Publications and source records attributed to K T Lu.
Differential interactive effects of gliotoxin and MPTP in the substantia nigra and the locus coeruleus in BALB/c mice.
We have previously demonstrated that chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) infusion to the substantia nigra (SN) and the locus coeruleus (LC) both produce a long-lasting neurotoxicity on dopamine (DA) and norepinephrine (NE) neurons in these two areas, respectively. In the present study, we further examined the toxicity of MPTP in these two areas by using the immunohistochemical method. We have also assessed the role of glia cells in the SN and LC in mediating the toxicity of MPTP. Immunohistochemical results have confirmed the direct toxicity of MPTP in the SN, as revealed by significant decreases of tyrosine hydroxylase (TH)-positive cells in the SN and TH-positive fibers in the striatum. The specific gliotoxin alpha-aminoadipic acid (alpha-AA), when administered to the SN at 48 h interval, partially antagonized DA depletions and behavioral deficits produced by chronic MPTP treatment. When alpha-AA was administered to the SN every 24 h, it completely abolished the toxicity of MPTP. On the other hand, chronic MPTP infusions to the LC significantly decreased DA-beta-hydroxylase-positive cells in this area. When alpha-AA was injected into the LC at 48 h intervals, it did not prevent depletions of NE in the LC and the hippocampus caused by chronic MPTP infusions. It did not protect against the behavioral deficits produced by MPTP, either. When alpha-AA was injected into the LC every 24 h, it only partially prevented the toxicity of MPTP on NE in the LC. It also partially prevented the motor-impairing effect of MPTP; however, it barely protected against MPTP's toxicity on NE in the hippocampus and it did not antagonize the stereotypy deficit produced by chronic MPTP, either. Phasic tremor and rigidity were observed following MPTP infusions to the SN and the LC every day, but these symptoms were less frequently observed during the later experimental stage. Serotonin measures were not significantly altered by these treatments throughout these experiments. Immunoblotting results of glial fibrillary acidic protein (GFAP), a marker protein of astrocytes, have confirmed proper lesions of astrocytes by alpha-AA. These results together suggest that chronic MPTP treatment exerts a direct and long-lasting toxicity on DA neurons along the nigrostriatal pathway and NE neurons along the coeruleus-hippocampal pathway. The neurotoxicity of MPTP is probably mediated through astrocytes in the SN, and may be partly mediated through astrocytes in the LC also. These results imply a role for dendritic uptake of DA and NE in these cell body regions. However, these findings also suggest the possibility of differential mechanisms of MPTP's toxicity in these two areas.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
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↗
Involvement of mitogen-activated protein kinase in hippocampal long-term potentiation.
Mitogen-activated protein kinase (MAPK) cascade classically is thought to be involved in cellular transformation, including proliferation and differentiation. Recent behavioral studies suggest that MAPK may also have a role in learning and memory. Long-term potentiation (LTP), a candidate mechanism for learning and memory, has at least two distinct temporal phases: an early phase (E-LTP) which lasts for 1-2 h and a late phase (L-LTP) which can persist >/=3 h. Here, we report that PD 098059, a selective inhibitor of MAPK cascade, attenuates L-LTP induced by bath application of forskolin without affecting basal synaptic transmission. This effect was mimicked by direct injection of animals with MAPK antisense oligonucleotide into the hippocampal CA1 region. MAPK activity measured by using a synthetic peptide corresponding to the sequence surrounding the major site of phosphorylation of the myelin-basic protein by MAPK was enhanced by forskolin. The same antisense treatment also completely inhibited the increased MAPK activity. These results demonstrate an involvement of MAPK in the induction of L-LTP in the hippocampal CA1 neurons.
Animals↗
Protein synthesis in the hippocampus associated with memory facilitation by corticotropin-releasing factor in rats.
The present study used pharmacological, biochemical, and behavioral methods to examine the role of protein synthesis in the hippocampus in memory processes of a passive avoidance learning in rats. Results indicated that corticotropin-releasing factor (CRF) significantly improved memory retention in rats. Both cycloheximide (CHX) and actinomycin-D (ACT-D) impaired memory at high doses. At doses of CHX and ACT-D that did not affect memory alone, they both antagonized the memory-enhancing effect of CRF. Biochemically, there were specific increases in the optical density of three protein bands in the cytosolic fraction of hippocampal cells in rats showing good memory. There were also marked increases in the optical density of two protein bands in the nucleus fraction of the same animals. Similar results were observed in animals injected with CRF. However, no significant protein alteration was observed in animals receiving stress. These results together suggest that there are new protein syntheses in the hippocampus that are specifically associated with passive avoidance learning in rats.
Animals↗