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High fat diet feeding exacerbates the toxic effects of 6-hydroxydopamine in rats: Possible involvement of histone acetylation
Abstracts / Parkinsonism and Related Disorders 22 (2016) e149ee192
e181
P 6.023. HIGH FAT DIET FEEDING EXACERBATES THE TOXIC EFFECTS OF 6HYDROXYDOPAMINE IN RATS: POSSIBLE INVOLVEMENT OF HISTONE ACETYLATION
P 6.027. SYMPTOMATIC AND BIOCHEMICAL ASSESSMENTS USING MICRODIALYSIS METHOD OF AN ANTIDYSKINETIC COMPOUND IN A LDOPA INDUCED DYSKINESIAS RAT MODEL
Sorabh Sharma, Rajeev Taliyan. Neuropharmacology Division, Department of Pharmacy, BITS-Pilani, Pilani, India
Sandra Robelet 1, Vincent Girod 1, Delphine Revy 2, Audrey 3, Bouzereau Adeline 2. 1 Syncrosome, Marseille, 2 Syncrosome, Marseille, France; 3 Syncrosome, Marseille, France
Objectives: Clinical evidence has shown a correlation between Parkinson's disease (PD) and type 2 diabetes, as abnormal glucose tolerance has been reported in >50% of PD patients. Recently, insulin resistance was found to be present in 62% of PD patients with dementia, of whom 30% were glucose intolerant [1]. However, the underlying pathways are still elusive. Therefore, the present study was designed to explore the effect of insulin resistance on striatal dopaminergic neurons in an animal model of PD. Methods: High fat feeding in rodents is an established model of insulin resistance. We subjected rats to a normal pellet diet (NPD) or high-fat diet (HFD) for 8 weeks before infusing low dose of 6-hydroxydopamine (6OHDA) into the medial forebrain bundle. The animals were divided into four groups: 1) NPD 2) HFD 3) NPD + 6-OHDA 4) HFD + 6-OHDA. To delineate the molecular mechanisms, we study the changes in histone acetylation in striatum region. Results: The rats subjected to HFD exhibited characteristic features of insulin resistance. The animals treated with low dose 6-OHDA+ HFD feeding showed significant motor deficits as compared to HFD alone, NPD alone or NPD+ 6-OHDA treated animals. Moreover, these animals also exhibited greater dopamine depletion and significant reduction in histone acetylation as compared to other groups. Conclusions: The present study suggests that insulin resistance may lower the threshold for developing PD possibly via altering the epigenetic pathways such as histone acetylation. References: 1. Bosco D, et al. Journal of the Neurological Sciences 2012;315:39e43. P 6.024. UNPRECEDENTED THERAPEUTIC POTENTIAL WITH A COMBINATION OF A2A/NR2B RECEPTOR ANTAGONISTS AS OBSERVED IN THE 6-OHDA LESIONED RAT MODEL OF PARKINSON'S DISEASE Anne Michel 1, Patrick Downey 1, Jean-marie Nicolas 2, Dieter Scheller 1. 1 Neurosciences TA Biology, UCB Biopharma SPRL, Braine L'Alleud, Belgium; 2 Non-Clinical Development, UCB Biopharma SPRL, Braine L'Alleud, Belgium Objectives: This study evaluates the effects of various NR2B and A2A receptor antagonists when given alone or in combination to unilaterally 6-OHDA-lesioned rats. These drug combinations were either given as monotherapy or as add-on therapy with the co-administration of LDopa. Methods: Rats given monotherapy were assessed on distance travelled 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 over time and to determine whether any interaction between two drugs was additive or synergistic. Post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Results: Motor activity improved significantly and was sustained for longer when the NR2B and A2A antagonists 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 rotations in comparison to the single drugs. Interestingly, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. Conclusions: The combined administration of A2A/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.
Bourdet France;
Objectives: Parkinson's disease is characterized by the loss of dopaminergic neurons and is associated to motor symptoms: akinesia, rigidity and tremor and postural abnormality. L-DOPA remains the most effective therapy in the management of motor symptoms of PD. However a longterm treatment leads to abnormal involuntary movements (AIM) named dyskinesias. Given that L-DOPA is still a necessity in the treatment of advanced PD, reducing or avoiding L-DOPA induced dyskinesias (LID) is a key objective in the management of PD motor symptoms. The aim of this project was to develop a suitable model of LID model in which a reference compound (amantadine : weak NMDA antagonist) was able to reduce dyskinesias. Additionally to the symptomatic assessment we studied the glutamatergic activity in our LID model using microdialysis Methods: Dyskinesias were induced by a chronic treatment with L-DOPA in a unilateral 6-OHDA rat model. Symptomatic evaluation of dyskinesias was assessed using a scoring of AIM. Glutamate levels were evaluated by HPLC using the brain microdialysis technique in SNr and striatum performed in the same animal in awaken conditions. Results: Results showed that the administration of amantadine reduced LID. Moreover, thanks to the microdialysis allowing the monitoring of the neurotransmitters activity in freely moving animals, our study showed that in Parkinsonian rats, the chronic L-DOPA treatment increased basal glutamate extracellular levels in the striatum and in the SNr. Conclusions: To conclude the LID rat model is a suitable preclinical model to study antidyskinetic properties of a candidate compound on both symptoms and dysfunctional neurotransmitters activity. P 6.028. INCREASED SEROTONIN INNERVATION OF THE SENSORIMOTOR STRIATUM IN A PRIMATE MODEL OF PARKINSON'S DISEASE re se Di Paolo 2, Martin Parent 1. 1 Department of Dave Gagnon 1, The Psychiatry and Neuroscience, Laval University, Quebec City, Canada; 2 Faculty of Pharmacy, Quebec City, Canada Objectives: Chronic use of L-Dopa to treat Parkinson's disease often produces adverse side effects, such as L-Dopa-induced dyskinesia. Unregulated release of dopamine by serotonin (5-HT) axons following L-Dopa administration is a major presynaptic determinant of dyskinesia. Our study was designed to characterize the reorganization of 5-HT striatal afferent projections following dopaminergic denervation in a primate model of Parkinson's disease. Methods: Eight cynomolgus monkeys were used. Four received MPTP and four served as controls. The state of striatal 5-HT and dopamine innervation was evaluated by unbiased stereological approach using immunohistochemistry. Results: Our investigation revealed a 34% increase in the number of 5-HT axon varicosities in the dorsolateral putamen of MPTP monkeys compared to controls. This increase was particularly obvious in the sensorimotor territory of the striatum, where the dopamine denervation was the most severe. Electron microscopic examination of the dorsolateral putamen showed that the SERT+ axon varicosities established about twice as many synaptic contacts in MPTP monkeys than in controls. No significant difference in the density of TpH+ cell bodies between MPTP and control monkeys was observed. Conclusions: Our findings demonstrate the highly plastic nature of 5-HT striatal afferent projections, a feature that becomes obvious in the absence of dopamine. Although the number of dorsal raphe neurons remains constant in parkinsonian monkeys, their ascending axonal projections undergo marked proliferative and synaptic adaptive changes that might play a significant role in the expression of L-Dopa-induced dyskinesi
e181
P 6.023. HIGH FAT DIET FEEDING EXACERBATES THE TOXIC EFFECTS OF 6HYDROXYDOPAMINE IN RATS: POSSIBLE INVOLVEMENT OF HISTONE ACETYLATION
P 6.027. SYMPTOMATIC AND BIOCHEMICAL ASSESSMENTS USING MICRODIALYSIS METHOD OF AN ANTIDYSKINETIC COMPOUND IN A LDOPA INDUCED DYSKINESIAS RAT MODEL
Sorabh Sharma, Rajeev Taliyan. Neuropharmacology Division, Department of Pharmacy, BITS-Pilani, Pilani, India
Sandra Robelet 1, Vincent Girod 1, Delphine Revy 2, Audrey 3, Bouzereau Adeline 2. 1 Syncrosome, Marseille, 2 Syncrosome, Marseille, France; 3 Syncrosome, Marseille, France
Objectives: Clinical evidence has shown a correlation between Parkinson's disease (PD) and type 2 diabetes, as abnormal glucose tolerance has been reported in >50% of PD patients. Recently, insulin resistance was found to be present in 62% of PD patients with dementia, of whom 30% were glucose intolerant [1]. However, the underlying pathways are still elusive. Therefore, the present study was designed to explore the effect of insulin resistance on striatal dopaminergic neurons in an animal model of PD. Methods: High fat feeding in rodents is an established model of insulin resistance. We subjected rats to a normal pellet diet (NPD) or high-fat diet (HFD) for 8 weeks before infusing low dose of 6-hydroxydopamine (6OHDA) into the medial forebrain bundle. The animals were divided into four groups: 1) NPD 2) HFD 3) NPD + 6-OHDA 4) HFD + 6-OHDA. To delineate the molecular mechanisms, we study the changes in histone acetylation in striatum region. Results: The rats subjected to HFD exhibited characteristic features of insulin resistance. The animals treated with low dose 6-OHDA+ HFD feeding showed significant motor deficits as compared to HFD alone, NPD alone or NPD+ 6-OHDA treated animals. Moreover, these animals also exhibited greater dopamine depletion and significant reduction in histone acetylation as compared to other groups. Conclusions: The present study suggests that insulin resistance may lower the threshold for developing PD possibly via altering the epigenetic pathways such as histone acetylation. References: 1. Bosco D, et al. Journal of the Neurological Sciences 2012;315:39e43. P 6.024. UNPRECEDENTED THERAPEUTIC POTENTIAL WITH A COMBINATION OF A2A/NR2B RECEPTOR ANTAGONISTS AS OBSERVED IN THE 6-OHDA LESIONED RAT MODEL OF PARKINSON'S DISEASE Anne Michel 1, Patrick Downey 1, Jean-marie Nicolas 2, Dieter Scheller 1. 1 Neurosciences TA Biology, UCB Biopharma SPRL, Braine L'Alleud, Belgium; 2 Non-Clinical Development, UCB Biopharma SPRL, Braine L'Alleud, Belgium Objectives: This study evaluates the effects of various NR2B and A2A receptor antagonists when given alone or in combination to unilaterally 6-OHDA-lesioned rats. These drug combinations were either given as monotherapy or as add-on therapy with the co-administration of LDopa. Methods: Rats given monotherapy were assessed on distance travelled 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 over time and to determine whether any interaction between two drugs was additive or synergistic. Post hoc analyses were conducted to compare the effect of the combination with the effect of the drugs alone. Results: Motor activity improved significantly and was sustained for longer when the NR2B and A2A antagonists 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 rotations in comparison to the single drugs. Interestingly, the activity observed with some combinations could not be described by a simplistic additive effect and involved more subtle synergistic pharmacological interactions. Conclusions: The combined administration of A2A/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.
Bourdet France;
Objectives: Parkinson's disease is characterized by the loss of dopaminergic neurons and is associated to motor symptoms: akinesia, rigidity and tremor and postural abnormality. L-DOPA remains the most effective therapy in the management of motor symptoms of PD. However a longterm treatment leads to abnormal involuntary movements (AIM) named dyskinesias. Given that L-DOPA is still a necessity in the treatment of advanced PD, reducing or avoiding L-DOPA induced dyskinesias (LID) is a key objective in the management of PD motor symptoms. The aim of this project was to develop a suitable model of LID model in which a reference compound (amantadine : weak NMDA antagonist) was able to reduce dyskinesias. Additionally to the symptomatic assessment we studied the glutamatergic activity in our LID model using microdialysis Methods: Dyskinesias were induced by a chronic treatment with L-DOPA in a unilateral 6-OHDA rat model. Symptomatic evaluation of dyskinesias was assessed using a scoring of AIM. Glutamate levels were evaluated by HPLC using the brain microdialysis technique in SNr and striatum performed in the same animal in awaken conditions. Results: Results showed that the administration of amantadine reduced LID. Moreover, thanks to the microdialysis allowing the monitoring of the neurotransmitters activity in freely moving animals, our study showed that in Parkinsonian rats, the chronic L-DOPA treatment increased basal glutamate extracellular levels in the striatum and in the SNr. Conclusions: To conclude the LID rat model is a suitable preclinical model to study antidyskinetic properties of a candidate compound on both symptoms and dysfunctional neurotransmitters activity. P 6.028. INCREASED SEROTONIN INNERVATION OF THE SENSORIMOTOR STRIATUM IN A PRIMATE MODEL OF PARKINSON'S DISEASE re se Di Paolo 2, Martin Parent 1. 1 Department of Dave Gagnon 1, The Psychiatry and Neuroscience, Laval University, Quebec City, Canada; 2 Faculty of Pharmacy, Quebec City, Canada Objectives: Chronic use of L-Dopa to treat Parkinson's disease often produces adverse side effects, such as L-Dopa-induced dyskinesia. Unregulated release of dopamine by serotonin (5-HT) axons following L-Dopa administration is a major presynaptic determinant of dyskinesia. Our study was designed to characterize the reorganization of 5-HT striatal afferent projections following dopaminergic denervation in a primate model of Parkinson's disease. Methods: Eight cynomolgus monkeys were used. Four received MPTP and four served as controls. The state of striatal 5-HT and dopamine innervation was evaluated by unbiased stereological approach using immunohistochemistry. Results: Our investigation revealed a 34% increase in the number of 5-HT axon varicosities in the dorsolateral putamen of MPTP monkeys compared to controls. This increase was particularly obvious in the sensorimotor territory of the striatum, where the dopamine denervation was the most severe. Electron microscopic examination of the dorsolateral putamen showed that the SERT+ axon varicosities established about twice as many synaptic contacts in MPTP monkeys than in controls. No significant difference in the density of TpH+ cell bodies between MPTP and control monkeys was observed. Conclusions: Our findings demonstrate the highly plastic nature of 5-HT striatal afferent projections, a feature that becomes obvious in the absence of dopamine. Although the number of dorsal raphe neurons remains constant in parkinsonian monkeys, their ascending axonal projections undergo marked proliferative and synaptic adaptive changes that might play a significant role in the expression of L-Dopa-induced dyskinesi