Yan, J., L. Studer, et al. (2001). "Ascorbic acid increases the
yield of dopaminergic neurons derived from basic fibroblast growth factor
expanded mesencephalic precursors." J Neurochem 76(1): 307-11.
CNS precursors derived from E12 rat mesencephalon proliferate in the presence of
basic fibroblast growth factor and differentiate in vitro into functional
dopaminergic neurons, which upon transplantation alleviate behavioral symptoms
in a rat model of Parkinson's disease. Here we show that the efficiency of
dopaminergic differentiation decreases in the mesencephalic precursors that were
proliferated or passaged for extended periods in vitro. Ascorbic acid treatment
restored dopaminergic differentiation in these precursors and led to a greater
than 10-fold increase in dopamine neuron yield compared with untreated cultures.
The effect of ascorbic acid was stereospecific and could not be mimicked by any
other antioxidants. The expression of sodium-dependent vitamin C transporter, a
recently identified stereospecific ascorbic acid transporter, was maintained in
mesencephalic precursors for extended in vitro periods. Pre-treatment of in
vitro expanded mesencephalic precursors with ascorbic acid might facilitate the
large-scale generation of dopaminergic neurons for clinical transplantation.
Yantiri, F., A. Gasparyan, et al. (2001). "Glutamyl cysteine synthetase
catalytic and regulatory subunits localize to dopaminergic nigral neurons as
well as to astrocytes." J Neurosci Res 64(2): 203-6.
Glutathione (GSH) is considered one of the primary antioxidant compounds in the
brain, important for the removal of peroxides from this organ. GSH levels have
been reported to be significantly lower in the substantia nigra (SN) of
Parkinson patients vs. age-matched controls. Curiously, GSH has been proposed to
be present in brain astrocytes rather than in neurons even though these cells
are not lost in Parkinson disease. We report that the catalytic and regulatory
subunit proteins of glutamyl cysteine synthetase (GCS), the primary enzyme
involved in GSH synthesis, are present not only in astrocytes but also in
dopaminergic neurons of the SN. This may have important implications in terms of
GSH loss associated with Parkinson disease. Copyright 2001 Wiley-Liss, Inc.
Yasojima, K., W. W. Tourtellotte, et al. (2001). "Marked increase in
cyclooxygenase-2 in ALS spinal cord: implications for therapy." Neurology
57(6): 952-6.
OBJECTIVE: To evaluate the hypothesis that cyclooxygenase-2 (COX-2) is linked to
the pathology of ALS by determining whether COX-2 mRNA levels are upregulated in
ALS spinal cord. METHODS: Spinal cord from 11 ALS cases and 27 controls
consisting of 15 cases of Alzheimer disease (AD), six cases of Parkinson disease
(PD), three cases of cerebrovascular disease, and three control cases were
analyzed. Total RNA was extracted and reverse transcriptase-PCR analysis
performed for the mRNA of COX-2, COX-1, the microglial marker CD11b, and the
housekeeping gene cyclophilin. RESULTS: In ALS compared with non-ALS spinal
cord, COX-2 mRNA was upregulated 7.09-fold (p < 0.0001), COX-1 1.14-fold (p =
0.05), and CD11b 1.85-fold (p = 0.0012). COX-2 mRNA levels in AD, PD,
cerebrovascular disease, and control cases were each significantly lower than in
ALS and were not significantly different from each other. Western blots of the
protein products were in general accord with the mRNA data, with COX-2 protein
levels being upregulated 3.79-fold compared with non-ALS cases (p = 0.015).
CONCLUSIONS: The strong upregulation of COX-2 mRNA in ALS is in accord with
studies in the superoxide dismutase transgenic mouse model in which COX-2
upregulation occurs. Taken in conjunction with evidence of a neuroprotective
effect of COX-2 inhibitors in certain animal models and in organotypic cultures,
the data are supportive of a possible future role for COX-2 inhibitors in the
treatment of ALS.
Yu, T. S., S. D. Wang, et al. (2001). "Changes in the gene expression of GABA(A)
receptor alpha1 and alpha2 subunits and metabotropic glutamate receptor 5 in the
basal ganglia of the rats with unilateral 6-hydroxydopamine lesion and embryonic
mesencephalic grafts." Exp Neurol 168(2): 231-41.
By using an animal model of parkinsonism, we examined the expression of GABA(A)
receptor (R) and metabotropic glutamate receptor (mGluR) 5 in the basal ganglia
after transplantation with dopamine-rich tissue. The adult rats were
unilaterally lesioned by the injection of 6-hydroxydopamine to their left medial
forebrain bundles. At 5-10 weeks following the dopaminergic denervation, the
levels of GABA(A)R in the left caudate-putamen and globus pallidus were about 20
and 16% lower than that of the right intact (control) sides, as shown by
[3H]flunitrazepam binding autoradiography on the brain sections. However, the
receptor density increased to around 132 and 130% of control levels in the
entopeduncular nucleus and substantia nigra pars reticulata of the lesioned
sides. Furthermore, in situ hybridization analysis exhibited parallel trends of
changes in the levels of the GABA(A)R alpha1 and alpha2 subunit and mGluR5 mRNAs
in the neurons of the brain regions with that of the proteins detected by the
binding assay. A number of the rats 5 weeks postlesion were transplanted with
the ventral mesencephalon of the embryonic rat into their left striata. Five
weeks later, the changes in the [3H]flunitrazepam binding seemed to be recovered
by approximately 50-63% on the grafted sides of the areas. Moreover, the
transplantation appeared to produce a nearly complete reversal of the
lesion-induced alterations in the levels of the mRNAs. Thus, the data indicate
the mechanism of gene regulation for the modified expression of the receptors
and could implicate the participation of the receptors in the pathogenesis of
Parkinson's disease.