oxepins and Parkinsonian-Disorders

The propargylamine derivative CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine) has previously been found to exhibit neurorescuing and antiapoptotic properties in several in vitro and in vivo paradigms. After showing that this compound does not inhibit monoamine oxidase B and only marginally inhibits monoamine oxidase A at concentrations or doses far above those relevant for its reported neuroprotective effects, we investigated it in models considered relevant for Parkinson's disease. CGP 3466 or its hydrogen maleate salt, CGP 3466B, at concentrations between 10(-11) M and 10(-7) M, protected rat embryonic mesencephalic dopaminergic neurons in free-floating or dispersed cell culture from death inflicted by treatment with 1-methyl-4-phenyl pyridinium ion (MPP+) as measured by different readouts such as dopamine uptake, tyrosine hydroxylase activity, and counts of tyrosine hydroxylase-positive cells. Treatment of mice lesioned with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 2x30 mg/kg s.c. at a 72-h interval) with CGP 3466 (0.1 mg/kg s.c.) or CGP 3466B (0.014 mg/kg and 0.14 mg/kg p.o.) b.i.d. for 18 days partially prevented the loss of tyrosine hydroxylase-positive cells in the substantia nigra; a lower dose of CGP 3466B (0.0014 mg/kg p.o.) showed a marginal effect, whereas a high dose, i.e. 1.4 mg/kg p.o., was ineffective, suggesting a bell-shaped dose-response relationship which has also been observed in other paradigms. The effect of CGP 3466 on motor function was evaluated in rats that received intrastriatal injections of 6-OHDA unilaterally, according to a four-site injection protocol, and that were subsequently treated b.i.d. with 0.014 mg/kg i.p. CGP 3466B for 3 weeks. After another 3 weeks without treatment, skilled paw use was assessed by means of the staircase test. The results indicated a significant improvement of skilled motor performance as measured by means of the number of eaten pellets. Since due to the long wash-out period a symptomatic effect of CGP 3466B can be ruled out, it is likely that this improvement was related to interference with the course of the degeneration of the dopaminergic neurons. In conclusion, our results indicate that CGP 3466 is able to prevent death of dopaminergic cells in in vitro and in vivo models of Parkinson's disease. In addition, treatment with CGP 3466 resulted in improved skilled motor performance in 6-OHDA-lesioned rats.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Antiparkinson Agents; Brain; Cell Culture Techniques; Cell Death; Disease Models, Animal; Dopamine; Female; Liver; Mesencephalon; Mice; Mice, Inbred C57BL; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Neurons; Oxepins; Oxidopamine; Parkinsonian Disorders; Pregnancy; Rats; Selegiline; Substantia Nigra; Tritium; Tyrosine 3-Monooxygenase

The propargylamine CGP 3466B prevents dopamine cell death both in vitro and in rodent models of Parkinson's disease. The present study investigates the efficacy of this compound to prevent the behavioral consequences of dopaminergic cell death in the best animal model of Parkinson's disease, the bilaterally MPTP-treated monkey. Rhesus monkeys were bilaterally treated with MPTP, using a two-step procedure: 2.50 mg MPTP was infused into the left carotid artery followed by a second bolus of 1.25 mg into the right carotid artery, 8 weeks later. Subcutaneous injection of either 0.014 mg/kg CGP 3466B (n = 4) or its solvent (distilled water; n = 4), twice daily for fourteen days, started two hours after the second MPTP infusion. A Parkinson rating scale was assessed for the evaluation of the effects. After the first MPTP treatment, the monkeys developed mild to moderate parkinsonian symptoms. The second MPTP treatment strongly increased the severity of Parkinson scores in all control monkeys, as assessed on day 3, 7, 14, 21, 28 and 35 after the second MPTP treatment. In contrast, CGP 3466B nearly completely prevented the increase of parkinsonian symptoms after the second MPTP treatment. The therapeutic effects of CGP 3466B were still present after a washout period of 3 weeks, implying that the effects were not symptomatic. These data are the first to show that the systemic administration of CGP 3466B is able to prevent the development of MPTP-induced motor symptoms in primates. This compound may have great value for inhibiting the progression of the neurodegenerative process in patients with Parkinson's disease.

Topics: Animals; Brain; Disease Models, Animal; Dose-Response Relationship, Drug; Macaca mulatta; Male; Neurons; Neuroprotective Agents; Oxepins; Pargyline; Parkinsonian Disorders; Propylamines