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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

Comparison of the behavioural profile (space occupancy and body position) of 6-OHDA-lesioned rats after acute administration of (A) L-Dopa 14 mg/kg/benserazide 3.5 mg/kg; (B) L-Dopa 25 mg/kg and, (C) RAD3/TOZ combination.Fig 3A: Typically, lesioned rats even after the first administration of L-Dopa/benserazide showed a bent body position with some loss of floor contact with forepaw(s) during rotational activity. The contraversive rotations are characterized by a small diameter of the circle drawn when the nose turns around the center of gravity. The trajectory refers to a sum of circles express in various locations of the surface arena; Fig 3B: Rats treated with a weak dose of L-Dopa (25 mg/kg) expressed a mix of contralateral rotations and straight movement during exploration of the floor. The body position is straight and all the paws are in contact with the floor during the rotations; Fig 3C Rats treated with RAD3/TOZ combination showed a straight body position with all paws in contact with the floor while explorating. The trajectories are straight and space occupancy is large; there are some alterance during exploration of the walls and the center of the arena.
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pone.0135949.g003: Comparison of the behavioural profile (space occupancy and body position) of 6-OHDA-lesioned rats after acute administration of (A) L-Dopa 14 mg/kg/benserazide 3.5 mg/kg; (B) L-Dopa 25 mg/kg and, (C) RAD3/TOZ combination.Fig 3A: Typically, lesioned rats even after the first administration of L-Dopa/benserazide showed a bent body position with some loss of floor contact with forepaw(s) during rotational activity. The contraversive rotations are characterized by a small diameter of the circle drawn when the nose turns around the center of gravity. The trajectory refers to a sum of circles express in various locations of the surface arena; Fig 3B: Rats treated with a weak dose of L-Dopa (25 mg/kg) expressed a mix of contralateral rotations and straight movement during exploration of the floor. The body position is straight and all the paws are in contact with the floor during the rotations; Fig 3C Rats treated with RAD3/TOZ combination showed a straight body position with all paws in contact with the floor while explorating. The trajectories are straight and space occupancy is large; there are some alterance during exploration of the walls and the center of the arena.

Mentions: Typically, when 6-OHDA-lesioned rats are administered with a fully active dose of dopaminergic drugs, they exhibit a bent body position during their rotational activity together with some loss of contact with the floor with one or both forelimbs. These behavioural effects were observed after the acute L-Dopa/benserazide administration (Fig 3A). By contrast, rats receiving the lower dose of L-Dopa showed a straighter position of the trunk during rotational activity with adequate and full contact of the four paws on the floor (Fig 3B). Statistical analysis showed that rats treated with L-dopa 25 mg/kg spent larger amounts of time on their four paws without any bent position of the trunk in comparison to rats treated with L-Dopa and benserazide (Student’s t-test, p<0.01) (Fig 4). Typically, the non-dopaminergic drugs did not induce any trunk torsion in unilateral 6-OHDA-lesioned rats and showed very good restoration of the body position in comparison to vehicle-treated rats (Fig 3C). This observation was supported by statistical analysis which showed significant effects of Radiprodil [F(3,87) = 17.45, p<0.001], Tozadenant [F(1,87) = 26.30, p<0.001], and a “Tozadenant x Radiprodil” interaction [F(3,87) = 3.36, p<0.05]. In addition, the rats treated with the RAD3/TOZ combination spent more time in this position than rats treated with vehicle or with Tozadenant alone but not Radiprodil (Tukey post hoc test, p<0.01). Tozadenant, Radiprodil 2 and Radiprodil 3 mg/kg also restored the quality of the body position of hemiparkinsonian rats. Post hoc comparisons showed that these groups of rats spent significantly more time in the quadrupedal and non-bent body position than the vehicle-treated rats (Tukey post hoc test, 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)

Comparison of the behavioural profile (space occupancy and body position) of 6-OHDA-lesioned rats after acute administration of (A) L-Dopa 14 mg/kg/benserazide 3.5 mg/kg; (B) L-Dopa 25 mg/kg and, (C) RAD3/TOZ combination.Fig 3A: Typically, lesioned rats even after the first administration of L-Dopa/benserazide showed a bent body position with some loss of floor contact with forepaw(s) during rotational activity. The contraversive rotations are characterized by a small diameter of the circle drawn when the nose turns around the center of gravity. The trajectory refers to a sum of circles express in various locations of the surface arena; Fig 3B: Rats treated with a weak dose of L-Dopa (25 mg/kg) expressed a mix of contralateral rotations and straight movement during exploration of the floor. The body position is straight and all the paws are in contact with the floor during the rotations; Fig 3C Rats treated with RAD3/TOZ combination showed a straight body position with all paws in contact with the floor while explorating. The trajectories are straight and space occupancy is large; there are some alterance during exploration of the walls and the center of the arena.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0135949.g003: Comparison of the behavioural profile (space occupancy and body position) of 6-OHDA-lesioned rats after acute administration of (A) L-Dopa 14 mg/kg/benserazide 3.5 mg/kg; (B) L-Dopa 25 mg/kg and, (C) RAD3/TOZ combination.Fig 3A: Typically, lesioned rats even after the first administration of L-Dopa/benserazide showed a bent body position with some loss of floor contact with forepaw(s) during rotational activity. The contraversive rotations are characterized by a small diameter of the circle drawn when the nose turns around the center of gravity. The trajectory refers to a sum of circles express in various locations of the surface arena; Fig 3B: Rats treated with a weak dose of L-Dopa (25 mg/kg) expressed a mix of contralateral rotations and straight movement during exploration of the floor. The body position is straight and all the paws are in contact with the floor during the rotations; Fig 3C Rats treated with RAD3/TOZ combination showed a straight body position with all paws in contact with the floor while explorating. The trajectories are straight and space occupancy is large; there are some alterance during exploration of the walls and the center of the arena.
Mentions: Typically, when 6-OHDA-lesioned rats are administered with a fully active dose of dopaminergic drugs, they exhibit a bent body position during their rotational activity together with some loss of contact with the floor with one or both forelimbs. These behavioural effects were observed after the acute L-Dopa/benserazide administration (Fig 3A). By contrast, rats receiving the lower dose of L-Dopa showed a straighter position of the trunk during rotational activity with adequate and full contact of the four paws on the floor (Fig 3B). Statistical analysis showed that rats treated with L-dopa 25 mg/kg spent larger amounts of time on their four paws without any bent position of the trunk in comparison to rats treated with L-Dopa and benserazide (Student’s t-test, p<0.01) (Fig 4). Typically, the non-dopaminergic drugs did not induce any trunk torsion in unilateral 6-OHDA-lesioned rats and showed very good restoration of the body position in comparison to vehicle-treated rats (Fig 3C). This observation was supported by statistical analysis which showed significant effects of Radiprodil [F(3,87) = 17.45, p<0.001], Tozadenant [F(1,87) = 26.30, p<0.001], and a “Tozadenant x Radiprodil” interaction [F(3,87) = 3.36, p<0.05]. In addition, the rats treated with the RAD3/TOZ combination spent more time in this position than rats treated with vehicle or with Tozadenant alone but not Radiprodil (Tukey post hoc test, p<0.01). Tozadenant, Radiprodil 2 and Radiprodil 3 mg/kg also restored the quality of the body position of hemiparkinsonian rats. Post hoc comparisons showed that these groups of rats spent significantly more time in the quadrupedal and non-bent body position than the vehicle-treated rats (Tukey post hoc test, 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