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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

Ipsi- and contra turning bias (Ethovision, Noldus) in open-field of 6-OHDA 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. Ipsi turns: RAD3/TOZ is significantly higher than RAD3 (*, p<0.05). VEH significantly lower than TOZ, RAD2 and RAD3 (**, p<0.01); L-Dopa 25 mg/kg is significantly higher than L-Dopa/Benserazide (##, p<0.01). Contra turns: RAD3/TOZ is significantly higher than TOZ (*, p<0.05) and RAD3 (***,p<0.001). VEH is significantly lower than TOZ, RAD2 and RAD3 (**, p<0.01). L-Dopa/benzerazide is significantly higher than L-Dopa 25 mg/kg (###, p<0.001).
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pone.0135949.g002: Ipsi- and contra turning bias (Ethovision, Noldus) in open-field of 6-OHDA 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. Ipsi turns: RAD3/TOZ is significantly higher than RAD3 (*, p<0.05). VEH significantly lower than TOZ, RAD2 and RAD3 (**, p<0.01); L-Dopa 25 mg/kg is significantly higher than L-Dopa/Benserazide (##, p<0.01). Contra turns: RAD3/TOZ is significantly higher than TOZ (*, p<0.05) and RAD3 (***,p<0.001). VEH is significantly lower than TOZ, RAD2 and RAD3 (**, p<0.01). L-Dopa/benzerazide is significantly higher than L-Dopa 25 mg/kg (###, p<0.001).

Mentions: Typically, rats treated with L-Dopa and benserazide showed profound turning towards the contralateral side. This group of rats showed significantly higher levels of contraversive turns (p<0.001, Student’s t-test) in comparison to rats treated with L-Dopa alone (25 mg/kg). This increase in the L-Dopa/benserazide group was at the expense of the level of ipsi turns. Accordingly, rats treated with L-Dopa 25 mg/kg showed significantly superior levels of ipsilateral turns than those treated L-Dopa/benserazide (p<0.01) (Fig 2).


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)

Ipsi- and contra turning bias (Ethovision, Noldus) in open-field of 6-OHDA 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. Ipsi turns: RAD3/TOZ is significantly higher than RAD3 (*, p<0.05). VEH significantly lower than TOZ, RAD2 and RAD3 (**, p<0.01); L-Dopa 25 mg/kg is significantly higher than L-Dopa/Benserazide (##, p<0.01). Contra turns: RAD3/TOZ is significantly higher than TOZ (*, p<0.05) and RAD3 (***,p<0.001). VEH is significantly lower than TOZ, RAD2 and RAD3 (**, p<0.01). L-Dopa/benzerazide is significantly higher than L-Dopa 25 mg/kg (###, p<0.001).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0135949.g002: Ipsi- and contra turning bias (Ethovision, Noldus) in open-field of 6-OHDA 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. Ipsi turns: RAD3/TOZ is significantly higher than RAD3 (*, p<0.05). VEH significantly lower than TOZ, RAD2 and RAD3 (**, p<0.01); L-Dopa 25 mg/kg is significantly higher than L-Dopa/Benserazide (##, p<0.01). Contra turns: RAD3/TOZ is significantly higher than TOZ (*, p<0.05) and RAD3 (***,p<0.001). VEH is significantly lower than TOZ, RAD2 and RAD3 (**, p<0.01). L-Dopa/benzerazide is significantly higher than L-Dopa 25 mg/kg (###, p<0.001).
Mentions: Typically, rats treated with L-Dopa and benserazide showed profound turning towards the contralateral side. This group of rats showed significantly higher levels of contraversive turns (p<0.001, Student’s t-test) in comparison to rats treated with L-Dopa alone (25 mg/kg). This increase in the L-Dopa/benserazide group was at the expense of the level of ipsi turns. Accordingly, rats treated with L-Dopa 25 mg/kg showed significantly superior levels of ipsilateral turns than those treated L-Dopa/benserazide (p<0.01) (Fig 2).

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