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Behavioural Assessment of the A2a/NR2B Combination in the Unilateral 6-OHDA-Lesioned Rat Model: A New Method to Examine the Therapeutic Potential of Non-Dopaminergic Drugs.

Michel A, Downey P, Van Damme X, De Wolf C, Schwarting R, Scheller D - PLoS ONE (2015)

Bottom Line: The results show that A2A or NR2B receptor antagonists given alone or in combination did not produce enhanced turning as observed with an active dose of L-Dopa/benserazide.Our data suggest that the A2A/NR2B antagonist combination may be able to stimulate motor activity to a similar level as that achieved by L-Dopa but in the absence of the side-effects that are associated with dopaminergic hyperstimulation.If these results translate into the clinic, this combination could represent an alternative symptomatic treatment option for PD.

View Article: PubMed Central - PubMed

Affiliation: UCB Biopharma SPRL, Neurosciences TA Biology, Braine l'Alleud, Belgium.

ABSTRACT
In Parkinson's disease (PD), dopaminergic therapies are often associated with the development of motor complications. Attention has therefore been focused on the use of non-dopaminergic drugs. This study developed a new behavioural method capable of demonstrating the added value of combining adenosinergic and glutamatergic receptor antagonists in unilateral 6-OHDA lesioned rats. Rats were dosed orally with Tozadenant, a selective A2A receptor antagonist, and three different doses of Radiprodil, an NR2B-selective NMDA receptor antagonist. The drugs were given alone or in combination and rats were placed in an open-field for behavioural monitoring. Video recordings were automatically analysed. Five different behaviours were scored: distance traveled, ipsi- and contraversive turns, body position, and space occupancy. The results show that A2A or NR2B receptor antagonists given alone or in combination did not produce enhanced turning as observed with an active dose of L-Dopa/benserazide. Instead the treated rats maintained a straight body position, were able to shift from one direction to the other and occupied a significantly larger space in the arena. The highest "Tozadenant/Radiprodil" dose combination significantly increased all five behavioural parameters recorded compared to rats treated with vehicle or the same doses of the drugs alone. Our data suggest that the A2A/NR2B antagonist combination may be able to stimulate motor activity to a similar level as that achieved by L-Dopa but in the absence of the side-effects that are associated with dopaminergic hyperstimulation. If these results translate into the clinic, this combination could represent an alternative symptomatic treatment option for PD.

No MeSH data available.


Related in: MedlinePlus

Distance traveled (Ethovision, Noldus) in an open-field of 6-OHDA lesioned rats.Comparison of the effect of three different doses of Radiprodil (1, 2 or 3 mg/kg) given in combination with a fixed dose of Tozadenant (30 mg/kg). For comparison, a dose of L-Dopa 14 mg/kg plus benserazide 3.5 mg/kg and a dose of L-Dopa 25 mg/kg (without benserazide) were also tested. RAD3/TOZ is significantly higher than TOZ and RAD3 (**, p<0.01, ***, p<0.001). VEH is significanly lower than RAD2, RAD3 and TOZ (***,p<0.001). L-Dopa/Benserazide is significantly higher than L-Dopa 25 mg/kg (##, p<0.01).
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pone.0135949.g001: Distance traveled (Ethovision, Noldus) in an open-field of 6-OHDA lesioned rats.Comparison of the effect of three different doses of Radiprodil (1, 2 or 3 mg/kg) given in combination with a fixed dose of Tozadenant (30 mg/kg). For comparison, a dose of L-Dopa 14 mg/kg plus benserazide 3.5 mg/kg and a dose of L-Dopa 25 mg/kg (without benserazide) were also tested. RAD3/TOZ is significantly higher than TOZ and RAD3 (**, p<0.01, ***, p<0.001). VEH is significanly lower than RAD2, RAD3 and TOZ (***,p<0.001). L-Dopa/Benserazide is significantly higher than L-Dopa 25 mg/kg (##, p<0.01).

Mentions: Using the Ethovision software, we reproduced the effect we had already observed with automated photobeam activity chambers: an increase in the distance traveled in 6-OHDA rats receiving the combination of A2A/NR2B antagonist drug in comparison to rats having received either drug alone. This effect was observed with the combination of Radiprodil 3 mg/kg and Tozadenant 30 mg/kg (RAD3/TOZ) but not when lower doses of Radiprodil were combined with Tozadenant (Fig 1). These observations were supported by two-way ANOVA which showed a significant effect of Tozadenant [F(1,87) = 55.91, p<0.001], a significant effect of Radiprodil [F(3,87) = 19.56, p<0.001], and a significant Tozadenant x Radiprodil interaction [F(3,87) = 2.75, p<0.05]. Additional post hoc tests showed that the group treated with RAD3/TOZ demonstrated significantly higher levels of distance traveled than the group treated with Tozadenant or with Radiprodil 3 mg/kg alone (p<0.01, p<0.001). These results strongly suggest the presence of a synergistic effect between Radiprodil and Tozadenant for the parameter “distance traveled”. The post hoc analysis also demonstrated that rats treated with Tozadenant 30 mg/kg, Radiprodil 2 or 3 mg/kg had significantly higher levels of distance traveled than the vehicle-treated rats (p<0.001).


Behavioural Assessment of the A2a/NR2B Combination in the Unilateral 6-OHDA-Lesioned Rat Model: A New Method to Examine the Therapeutic Potential of Non-Dopaminergic Drugs.

Michel A, Downey P, Van Damme X, De Wolf C, Schwarting R, Scheller D - PLoS ONE (2015)

Distance traveled (Ethovision, Noldus) in an open-field of 6-OHDA lesioned rats.Comparison of the effect of three different doses of Radiprodil (1, 2 or 3 mg/kg) given in combination with a fixed dose of Tozadenant (30 mg/kg). For comparison, a dose of L-Dopa 14 mg/kg plus benserazide 3.5 mg/kg and a dose of L-Dopa 25 mg/kg (without benserazide) were also tested. RAD3/TOZ is significantly higher than TOZ and RAD3 (**, p<0.01, ***, p<0.001). VEH is significanly lower than RAD2, RAD3 and TOZ (***,p<0.001). L-Dopa/Benserazide is significantly higher than L-Dopa 25 mg/kg (##, p<0.01).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4555651&req=5

pone.0135949.g001: Distance traveled (Ethovision, Noldus) in an open-field of 6-OHDA lesioned rats.Comparison of the effect of three different doses of Radiprodil (1, 2 or 3 mg/kg) given in combination with a fixed dose of Tozadenant (30 mg/kg). For comparison, a dose of L-Dopa 14 mg/kg plus benserazide 3.5 mg/kg and a dose of L-Dopa 25 mg/kg (without benserazide) were also tested. RAD3/TOZ is significantly higher than TOZ and RAD3 (**, p<0.01, ***, p<0.001). VEH is significanly lower than RAD2, RAD3 and TOZ (***,p<0.001). L-Dopa/Benserazide is significantly higher than L-Dopa 25 mg/kg (##, p<0.01).
Mentions: Using the Ethovision software, we reproduced the effect we had already observed with automated photobeam activity chambers: an increase in the distance traveled in 6-OHDA rats receiving the combination of A2A/NR2B antagonist drug in comparison to rats having received either drug alone. This effect was observed with the combination of Radiprodil 3 mg/kg and Tozadenant 30 mg/kg (RAD3/TOZ) but not when lower doses of Radiprodil were combined with Tozadenant (Fig 1). These observations were supported by two-way ANOVA which showed a significant effect of Tozadenant [F(1,87) = 55.91, p<0.001], a significant effect of Radiprodil [F(3,87) = 19.56, p<0.001], and a significant Tozadenant x Radiprodil interaction [F(3,87) = 2.75, p<0.05]. Additional post hoc tests showed that the group treated with RAD3/TOZ demonstrated significantly higher levels of distance traveled than the group treated with Tozadenant or with Radiprodil 3 mg/kg alone (p<0.01, p<0.001). These results strongly suggest the presence of a synergistic effect between Radiprodil and Tozadenant for the parameter “distance traveled”. The post hoc analysis also demonstrated that rats treated with Tozadenant 30 mg/kg, Radiprodil 2 or 3 mg/kg had significantly higher levels of distance traveled than the vehicle-treated rats (p<0.001).

Bottom Line: The results show that A2A or NR2B receptor antagonists given alone or in combination did not produce enhanced turning as observed with an active dose of L-Dopa/benserazide.Our data suggest that the A2A/NR2B antagonist combination may be able to stimulate motor activity to a similar level as that achieved by L-Dopa but in the absence of the side-effects that are associated with dopaminergic hyperstimulation.If these results translate into the clinic, this combination could represent an alternative symptomatic treatment option for PD.

View Article: PubMed Central - PubMed

Affiliation: UCB Biopharma SPRL, Neurosciences TA Biology, Braine l'Alleud, Belgium.

ABSTRACT
In Parkinson's disease (PD), dopaminergic therapies are often associated with the development of motor complications. Attention has therefore been focused on the use of non-dopaminergic drugs. This study developed a new behavioural method capable of demonstrating the added value of combining adenosinergic and glutamatergic receptor antagonists in unilateral 6-OHDA lesioned rats. Rats were dosed orally with Tozadenant, a selective A2A receptor antagonist, and three different doses of Radiprodil, an NR2B-selective NMDA receptor antagonist. The drugs were given alone or in combination and rats were placed in an open-field for behavioural monitoring. Video recordings were automatically analysed. Five different behaviours were scored: distance traveled, ipsi- and contraversive turns, body position, and space occupancy. The results show that A2A or NR2B receptor antagonists given alone or in combination did not produce enhanced turning as observed with an active dose of L-Dopa/benserazide. Instead the treated rats maintained a straight body position, were able to shift from one direction to the other and occupied a significantly larger space in the arena. The highest "Tozadenant/Radiprodil" dose combination significantly increased all five behavioural parameters recorded compared to rats treated with vehicle or the same doses of the drugs alone. Our data suggest that the A2A/NR2B antagonist combination may be able to stimulate motor activity to a similar level as that achieved by L-Dopa but in the absence of the side-effects that are associated with dopaminergic hyperstimulation. If these results translate into the clinic, this combination could represent an alternative symptomatic treatment option for PD.

No MeSH data available.


Related in: MedlinePlus