Unprecedented therapeutic potential with a combination of A2A/NR2B receptor antagonists as observed in the 6-OHDA lesioned rat model of Parkinson’s disease

Abstract

In Parkinson's disease, the long-term use of dopamine replacing agents is associated with the development of motor complications; therefore, there is a need for non-dopaminergic drugs. This study evaluated the potential therapeutic impact of six different NR2B and A 2A receptor antagonists given either alone or in combination in unilateral 6-OHDA-lesioned rats without (monotherapy) or with (addon therapy) the co-administration of L-Dopa: Sch-58261+ Merck 22; Sch58261+Co-101244; Preladenant + Merck 22; Preladenant + Radiprodil; Tozadenant + Radiprodil; Istradefylline + Co-101244. Animals given monotherapy were assessed on distance traveled and rearing, whereas those given add-on therapy were assessed on contralateral rotations. Three-way mixed ANOVA were conducted to assess the main effect of each drug separately and to determine whether any interaction between two drugs was additive or synergistic. Additional post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Motor activity improved significantly and was sustained for longer when the drugs were given in combination than when administered separately at the same dose. Similarly, when tested as add-on treatment to L-Dopa, the combinations resulted in higher levels of contralateral rotation in comparison to the single drugs. Of special interest, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. The combined administration of A 2A /NR2B-receptor antagonists improved motor behaviour in 6-OHDA rats. Given the proven translatability of this model such a combination may be expected to be effective in improving motor symptoms in patients.

Comparative assessment of 6‐[18F]fluoro‐L‐m‐tyrosine and 6‐[18F]fluoro‐L‐dopa to evaluate dopaminergic presynaptic integrity in a Parkinson's disease rat model

“…6‐OHDA was administered unilaterally and surgical procedure was performed as previously described (Michel et al . ). Briefly, after imipramine administration (to protect noradrenergic neurons) and ketamine/xylazine anaesthesia, 4 μg of 6‐OHDA (2 μg/μL, total of 2 μL per rat), injected in the substantia nigra, and 10 μg of 6‐OHDA (4 μg/μL, total of 2.5 μL per rat), injected in the right ascending medial forebrain bundle, were delivered in the rat brain to induce, respectively, a partial and a full dopaminergic lesion (coordinates relative to the bregma and to the surface of the dura; partial lesion AP = −5.0, ML = −2.10, DV= −8.0; full lesion: AP = −3.5, ML = −1.5, DV = −8.7).…”

Morpholine derivatives as potential agents for neurological manifestations of nervous system diseases

“…Показано, что тозаденант обладает синергизмом с радипродилом -антагонистом NMDA-рецепторов подтипа NR2B [75]. У крыс с 6-ГД-моделью БП комбинация тозаденант + радипродил (30 мг/кг + 1, 2 или 3 мг/кг) увеличивала подвижность, при этом не приводя к развитию дискинезии [76].…”