CGP 3466 protects dopaminergic neurons in lesion models of Parkinson's disease

The propargylamine derivative CGP 3466 (dibenzo[b,f]oxepin-10-ylmethyl-meth yl-prop-2-ynyl-amine) has previously been found to exhibit neurorescuing an d antiapoptotic properties in several in vitro and in vivo paradigms. After showing that this compound does not inhibit monoamine oxidase B and only m arginally inhibits monoamine oxidase A at concentrations or doses far above those relevant for its reported neuroprotective effects, we investigated i t in models considered relevant for Parkinson's disease. CGP 3466 or its hy drogen maleate salt, CGP 3466B, at concentrations between 10(-11) M and 10( -7) M, protected rat embryonic mesencephalic dopaminergic neurons in free-f loating or dispersed cell culture from death inflicted by treatment with 1- methyl-4-phenyl pyridinium ion (MPP+) as measured by different readouts suc h as dopamine uptake, tyrosine hydroxylase activity, and counts of tyrosine hydroxylase-positive cells. Treatment of mice lesioned with 1-methyl-4-phe nyl-1,2,3,6-tetrahydropyridine (MPTP; 2x30 mg/kg s.c. at a 72-h interval) w ith 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-p ositive 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 whi ch has also been observed in other paradigms. The effect of CGP 3466 on motor function was evaluated in rats that receive d intrastriatal injections of 6-OHDA unilaterally, according to a four-site injection protocol, and that were subsequently treated b.i.d. with 0.014 m g/kg i.p. CGP 3466B for 3 weeks. After another 3 weeks without treatment, s killed paw use was assessed by means of the staircase test. The results ind icated a significant improvement of skilled motor performance as measured b y means of the number of eaten pellets. Since due to the long washout perio d a symptomatic effect of CGP 3466B can be ruled out, it is likely that thi s improvement was related to interference with the course of the degenerati on of the dopaminergic neurons. In conclusion, our results indicate that CGP 3466 is able to prevent death of dopaminergic cells in vitro and in vivo models of Parkinson's disease. I n addition, treatment with CGP 3466 resulted in improved skilled motor perf ormance in 6-OHDA-lesioned rats.