Antiparkinsonian effects of the "Radiprodil and Tozadenant" combination in MPTP-treated marmosets

Investigate a combination of two clinically tested drugs, the NR2B antagonist Radiprodil and the A2A antagonist Tozadenant in the MPTP-treated marmoset model of Parkinson's Disease (PD).In PD, there remains a need for the development of non-dopaminergic drugs to effectively treat the motor symptoms without the induction of L-Dopa-induced motor complications.Clinically relevant doses of Radiprodil and Tozadenant were given both alone and in combination without the addition of L-Dopa, and the antiparkinsonian efficacy of the treatments was assessed in a primate model of PD.When compared to the drugs tested alone, the drug combination led to a significant increase of motor activity and an improvement of motor disability in MPTP-treated marmosets. In addition, the motor restoration brought about by the combination was almost completely devoid of dyskinesia. Interestingly, treated primates were not overstimulated, but were able to move normally when motivated by the exploration of novel objects.We have demonstrated in a primate model that, the "Radiprodil/Tozadenant" combination significantly improves motor activity, extending previous results obtained in unilaterally lesioned 6-OHDA-rats. The strength of the preclinical data accumulated so far suggests that the use of such an A2A and NR2B antagonist combination could bring significant motor improvement to PD patients, without inducing the motor complications induced by L-Dopa therapy. Although encouraging, these preclinical data need to be confirmed in the clinic

Annotated provisional agenda. Fifty-sixth meeting of the Presiding Officers of the Regional Conference on Women in Latin America and the Caribbean

<p>Data are individual scores. Left graph: dyskinesia score in MPTP-treated marmosets having received Radiprodil (2 mg/kg) and Tozadenant (150 mg/kg) treatment alone or in combination over the 10-hour of behavioural recording. Right graph: dyskinesia scores recorded over 5 hours after L-Dopa treatment (8 mg/kg; **, p<0.05, Mann-Withney test).</p

Comparison of the effects of the “Radiprodil and Tozadenant” combination with the effects of L-Dopa on the level of locomotor activity in MPTP-treated marmosets.

<p><i>Left graph</i>: Lomotor activity (mean value ± SEM) measured over 10 hours following Radiprodil (2 mg/kg) and Tozadenant (150 mg/kg) treatment given alone or in combination in MPTP-treated marmosets (n = 12). Five hours after the first drug administration, a second administration was given and, at the same time, novel objects were introduced in the testing cage. * <i>versus</i> Radiprodil group (one-way ANOVA, p<0.01, followed by planned contrasts). <i>Right graph</i>: Locomotor activity measured over 5 hours follwing L-Dopa (8 mg/kg). p<0.001 L-Dopa <i>v</i>s Vehicle (Student test on total score).</p

Statistical analysis of the “Radiprodil and Tozandenant” combination in MPTP-treated marmosets for the disability score.

<p>Sum of the number of observation sequences (means ± SEM) wherein the primates’ behaviour was assessed as ‘on-time’ activity (motor disability scoring<8). The behaviour was scored over 10 hours after Radiprodil (2 mg/kg) and Tozadenant (150 mg/kg) treatment given alone or in combination in MPTP-treated marmosets (n = 12/group). Period 1 corresponds to the effect observed when the animals are in the usual testing cage. Period 2 indicates the effect associated with the second drug administration and the introduction of a novel object in the testing environment (Two-way mixed ANOVA followed by planned contrasts with *, p<0.05 and **, p<0.01).</p

Effects of N7-methylation, N7-platination, and C8-hydroxylation of guanine on H-bond formation with cytosine: platinum coordination strengthens the Watson-Crick pair.

The hydrogen bonding properties of 1-methylcytosine (1-MeC) with the following guanine base derivatives have been studied in DMSO-d6, applying concentration-dependent 1H NMR spectroscopy: 9-ethylguanine, 7,9-dimethylguanine (7,9-DimeGH+), and 7,8-dihydro-8-oxo-9-methylguanine (8-O-9-MeGH), as well as three 9-ethylguanine complexes carrying different Pt(II) moieties at the N7 position. The association constants K for the Watson-Crick pairing schemes are by a factor 2-3 higher in the cases of platinated guanine complexes compared to the Watson-Crick pair between 9-ethylguanine and 1-methylcytosine (K = 6.9 +/- 1.3 M(-1)). Similar enhanced stabilities are observed for the pairs formed between 1-MeC and 7,9-DimeGH+ or 8-O-9-MeGH. The increase in N1H acidity of the guanine derivative upon modification at the N7 or C8 positions can be correlated with the association constants K; the result is a bell-shaped curve meaning that acidification initially stabilizes hydrogen bond formation up to a certain maximum; further acidification then leads to a destabilization. For two of the examples studied in solution, hydrogen bonding according to Watson-Crick between N7-platinated 9-ethylguanine and 1-methylcytosine has also been established by X-ray crystallography