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

Abstract

ObjectiveInvestigate 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).BackgroundIn 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.MethodsClinically 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.ResultsWhen 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.ConclusionWe 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.

Roles of Glutamate Receptors in Parkinson’s Disease

“…The combination therapy of NR2B-selective antagonists with other drugs was also applied. For example, the combination of the GluN2B-selective antagonist Radiprodil and the A 2A antagonist Tozadenant led to significant motor improvement both in 6-OHDA-lesioned rats and MPTP-lesioned marmosets [74,75]. In addition, a series of photo-switchable antagonists for the modulation of NMDA receptors have been synthesized by researchers.…”

An mGlu4‐Positive Allosteric Modulator Alleviates Parkinsonism in Primates

“…The strong rationale for using mGlu4 as a therapeutic target in PD is further supported by preclinical evidence that shows that positive allosteric modulators (PAM) of mGlu4 reduce motor disability in rodent models of PD . Successful transition to clinical trials in PD requires a safe, brain‐penetrant, target‐specific drug with proven therapeutic efficacy in the MPTP‐lesioned macaque model …”

Adenosin A2A Rezeptorantagonisten als Therapieoption beim idiopathischen Parkinson-Syndrom?

“…Klinische Studien bestätigen, dass A 2A Rezeptorantagonisten, wie Istradefyllin, Tozadenant oder Preladenant, zusammen mit der Einnahme von L-Dopa oder D 2 -Rezeptoragonisten, die therapeutischen Effekte dieser amplifizieren können [27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45].…”