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.
The effects of a deletion for the brain derived neurotrophic factor (BDNF) allele (± BDNF) upon age-related changes in nigrostriatal dopaminergic (NSDA) function were assessed. Behavioral (beam ...crossing and spontaneous activity) and neurochemical (potassium-stimulated dopamine release from superfused striatum) measures were compared among Young (4–5 month), Middle (11–13 month) and Aged (19–21 month) ± BDNF and their wild type littermate control (+/+ BDNF) mice. No statistically significant differences were obtained between +/+ and ± BDNF mice at the Young age sampling period for any of the behavioral or neurochemical measures. Behavioral and neurochemical responses indices of NSDA function begin to diverge between +/+ and ± Middle age BDNF mice and maximal differences were observed at the Aged period. For both movement and stereotypy times, scores obtained from +/+ mice were significantly decreased compared with ± BDNF mice at the Aged period and center time scores of +/+ mice were decreased at both the Middle and Aged periods compared with ± BDNF mice. Neurochemically, potassium-stimulated DA release of +/+ mice was significantly greater than ± BDNF mice with maximal differences obtained at the Aged period. These results demonstrate marked differences in age-related changes of NSDA function between +/+ and ± BDNF mice and suggest that the deletion of one allele for BDNF may make these mice more susceptible to age-related declines in NSDA function.
Depletion of dopamine (DA) reduces D sub(3) receptor number, but D sub(3) receptor expression is also regulated by brain-derived neurotrophic factor (BDNF). We took advantage of transgenic ...heterozygous BDNF mutant mice (+/-) to determine if reduced BDNF and loss of da fibers produced by methamphetamine were additive in their impact on D sub(3) receptor number. We assessed selective markers of the dopaminergic system including caudate-putamen da concentrations and quantitative autoradiographic measurement of tyrosine hydroxylase (TH) levels, da transporter (DAT), and da D sub(3) receptor binding between vehicle and methamphetamine-treated BDNF +/- and their wildtype (WT) littermate control mice. Caudate-putamen da concentrations, TH and DAT levels were significantly reduced following methamphetamine treatment in both WT and BDNF +/- mice. The extent of methamphetamine-induced reduction in TH and DAT was greater for the WT than BDNF +/- mice and DAT levels were also decreased to a greater extent in nucleus accumbens of WT as compared to BDNF +/- mice. Lower D sub(3) receptor existed in caudate-putamen and nucleus accumbens in BDNF +/- mice and these differences were not affected by methamphetamine treatment. Taken together, these results not only substantiate the importance of BDNF in controlling D sub(3) receptor expression, but also indicate that a methamphetamine-induced depletion of da fibers fails to produce an additive effect with lowered BDNF for control of D sub(3) receptor expression. In addition, the reduction of D sub(3) receptor expression is associated with a decreased neurotoxic response to methamphetamine in BDNF +/- mice.
High-resolution dipolar n.m.r. spectra in solids Griffin, R. G.; Bodenhausen, G.; Haberkorn, R. A. ...
Philosophical transactions of the Royal Society of London. Series A: Mathematical and physical sciences,
03/1981, Letnik:
299, Številka:
1452
Journal Article
Recenzirano
Recent advances in solid state n.m.r. spectroscopy permit obervation of high-resolution dipolar spectra, and thus renewed consideration can be given to solid state n.m.r. as a tool for determining ...molecular structure. This is illustrated with 13C and 14N single-crystal spectra obtained with both one- and two-dimensional n.m.r. techniques. The successful observation of these spectra is due to the fact that many dipolar interactions are inhomogeneous, and for this reason it is also possible to obtain high-resolution dipolar spectra from powder samples. Methods that accomplish this goal are described and illustrated with 13C -1H dipolar spectra.
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