A dopamine transporter–radioligand binding study demonstrated a dopaminergic innervation around t... more A dopamine transporter–radioligand binding study demonstrated a dopaminergic innervation around the pallidal complex in the normal monkey (n=5), i.e. where a subpopulation of pallidal neurons known as “border cells” is classically identified. Surprisingly, this peripallidal binding persists in monkeys rendered parkinsonian (n=5) with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. The border cell electrophysiological activity was then analysed in normal and parkinsonian monkeys (n=2), either in the untreated state or following administration of levodopa. Pallidal border cell firing frequency was significantly decreased after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment (8.9±0.7 vs 31.4±1.6Hz, P<0.05). This decrease was partly corrected by levodopa administration (19.2±1.0Hz, P<0.05 vs both normal and parkinsonian situations).The peripallidal dopaminergic innervation suggests that pallidal border cells are under a direct dopaminergic control, arising from the ...
(E)-N-(3-iodoprop-2-enyl)-2-carbomethoxy-3-(4-methyl- phenyl) nortropane (PE2I), a cocaine analog... more (E)-N-(3-iodoprop-2-enyl)-2-carbomethoxy-3-(4-methyl- phenyl) nortropane (PE2I), a cocaine analog, is a new, highly specific tracer for imaging dopamine transporter labeled with 123I for in vivo SPECT. Its reversible binding on dopamine trans- porter and its rapid kinetics allow quantification of its binding potential according to a 3-compartment model. For quantifica- tion of distribution volume of reversible tracer, Logan developed a noninvasive and
The concept of a threshold of dopamine (DA) depletion for onset of Parkinson's disease sympt... more The concept of a threshold of dopamine (DA) depletion for onset of Parkinson's disease symptoms, although widely accepted, has, to date, not been determined experimentally in nonhuman primates in which a more rigorous definition of the ...
Several important advances have been made in our understanding of the pathways that lead to cell ... more Several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease and Huntington's disease. These advances have been informed by both direct analysis of the post-mortem brain and by study of the biological consequences of the genetic causes of these diseases. Some of the pathways that have been implicated so far include mitochondrial dysfunction, oxidative stress, kinase pathways, calcium dysregulation, inflammation, protein handling, and prion-like processes. Intriguingly, these pathways seem to be important in the pathogenesis of both diseases and have led to the identification of molecular targets for candidate interventions designed to slow or reverse their course. We review some recent advances that underlie putative therapies for neuroprotection in Parkinson's disease and Huntington's disease, and potential targets that might be exploited in the future. Although we will need to overcome...
Adeno-associated virus (AAV)-mediated gene delivery has emerged as an effective and safe tool for... more Adeno-associated virus (AAV)-mediated gene delivery has emerged as an effective and safe tool for both preclinical and clinical studies of neurological disorders. The recent discovery that several serotypes are able to cross the blood-brain barrier when administered systemically has been a real breakthrough in the field of neurodegenerative diseases. Widespread transgene expression after systemic injection could spark interest as a therapeutic approach. Such strategy will avoid invasive brain surgery and allow non-focal gene therapy promising for CNS diseases affecting large portion of the brain. Here, we will review the recent results achieved through different systemic routes of injection generated in the last decade using systemic AAV-mediated delivery and propose a brief assessment of their values. In particular, we emphasize how the methods used for virus engineering could improve brain transduction after peripheral delivery.
To unravel the causes of major depressive disorder (MDD), the third leading cause of disease burd... more To unravel the causes of major depressive disorder (MDD), the third leading cause of disease burden around the world, ethological animal models have recently been proposed. Our previous studies highlighted a depressive-like profile among single- and socially-housed farm-bred cynomolgus macaques. Although phylogenetically close, cynomolgus and rhesus macaques, the two most commonly used macaque species in biomedical research, differ on several levels such as patterns of aggression, reconciliation, temperament, or dominance styles. The question of whether one captive macaque species was more vulnerable than another in the development of a pathological profile reminiscent of MDD symptoms was explored. Behavioral data (including body postures, orientations, gaze directions, inter-individual distances, and locations in the cage) were collected in farming conditions. Using an unbiased validated ethological scan-sampling method, followed by multiple correspondence and hierarchical clusteri...
Movement disorders : official journal of the Movement Disorder Society, 2014
Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodo... more Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold-standard LID macaque model. Dipraglurant (3, 10, and 30 mg/kg, by mouth) was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8). Dipraglurant inhibited dyskinesias in the LID macaque model, with best effect reached at 30 mg/kg dose with no alteration of levodopa efficacy. Acute challenges of dipraglurant were efficacious on choreic and dystonic LID in the MPTP-macaque model. Dipraglurant pharmacokinetic variables were similar to those of levodopa, suggesting that both drugs can be co-administered simultaneously in further studies.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 3, 2003
We investigated, in mice, the influence of life experience on the vulnerability to 1-methyl-4-phe... more We investigated, in mice, the influence of life experience on the vulnerability to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a major neurotoxin that induces a Parkinson's disease-like syndrome in humans, and to cocaine, a potent psychostimulant that promotes drug addiction. Our findings show that adult C57BL/6 mice raised in an enriched environment (EE) for only 2 months are significantly more resistant to both drugs compared with mice raised in a standard environment (SE). Indeed, EE mice showed decreased locomotor activity in response to cocaine (10 and 20 mg/kg) as well as a different pattern of c-fos expression in the striatum compared with SE mice. After MPTP treatment, SE mice showed a 75% loss of dopamine neurons, whereas EE mice showed only a 40% loss. The dopamine transporter plays a key role in mediating the effects of both drugs. We thus investigated the regulation of its expression. EE mice showed less dopamine transporter binding in the striatum and less ...
ΔFosB is a surrogate marker of L-dopa-induced dyskinesia (LID), the unavoidable disabling consequ... more ΔFosB is a surrogate marker of L-dopa-induced dyskinesia (LID), the unavoidable disabling consequence of Parkinson's disease L-dopa long-term treatment. However, the relationship between the electrical activity of FosB/ΔFosB-expressing neurons and LID manifestation is unknown. We used the Daun02 prodrug-inactivation method associated with lentiviral expression of ß-galactosidase under the control of the FosB promoter to investigate a causal link between the activity of FosB/ΔFosB-expressing neurons and dyskinesia severity in both rat and monkey models of Parkinson's disease and LID. Whole-cell recordings of medium spiny neurons (MSNs) were performed to assess the effects of Daun02 and daunorubicin on neuronal excitability. We first show that daunorubicin, the active product of Daun02 metabolism by ß-galactosidase, decreases the activity of MSNs in rat brain slices and that Daun02 strongly decreases the excitability of rat MSN primary cultures expressing ß-galactosidase upon ...
A dopamine transporter–radioligand binding study demonstrated a dopaminergic innervation around t... more A dopamine transporter–radioligand binding study demonstrated a dopaminergic innervation around the pallidal complex in the normal monkey (n=5), i.e. where a subpopulation of pallidal neurons known as “border cells” is classically identified. Surprisingly, this peripallidal binding persists in monkeys rendered parkinsonian (n=5) with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment. The border cell electrophysiological activity was then analysed in normal and parkinsonian monkeys (n=2), either in the untreated state or following administration of levodopa. Pallidal border cell firing frequency was significantly decreased after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment (8.9±0.7 vs 31.4±1.6Hz, P<0.05). This decrease was partly corrected by levodopa administration (19.2±1.0Hz, P<0.05 vs both normal and parkinsonian situations).The peripallidal dopaminergic innervation suggests that pallidal border cells are under a direct dopaminergic control, arising from the ...
(E)-N-(3-iodoprop-2-enyl)-2-carbomethoxy-3-(4-methyl- phenyl) nortropane (PE2I), a cocaine analog... more (E)-N-(3-iodoprop-2-enyl)-2-carbomethoxy-3-(4-methyl- phenyl) nortropane (PE2I), a cocaine analog, is a new, highly specific tracer for imaging dopamine transporter labeled with 123I for in vivo SPECT. Its reversible binding on dopamine trans- porter and its rapid kinetics allow quantification of its binding potential according to a 3-compartment model. For quantifica- tion of distribution volume of reversible tracer, Logan developed a noninvasive and
The concept of a threshold of dopamine (DA) depletion for onset of Parkinson's disease sympt... more The concept of a threshold of dopamine (DA) depletion for onset of Parkinson's disease symptoms, although widely accepted, has, to date, not been determined experimentally in nonhuman primates in which a more rigorous definition of the ...
Several important advances have been made in our understanding of the pathways that lead to cell ... more Several important advances have been made in our understanding of the pathways that lead to cell dysfunction and death in Parkinson's disease and Huntington's disease. These advances have been informed by both direct analysis of the post-mortem brain and by study of the biological consequences of the genetic causes of these diseases. Some of the pathways that have been implicated so far include mitochondrial dysfunction, oxidative stress, kinase pathways, calcium dysregulation, inflammation, protein handling, and prion-like processes. Intriguingly, these pathways seem to be important in the pathogenesis of both diseases and have led to the identification of molecular targets for candidate interventions designed to slow or reverse their course. We review some recent advances that underlie putative therapies for neuroprotection in Parkinson's disease and Huntington's disease, and potential targets that might be exploited in the future. Although we will need to overcome...
Adeno-associated virus (AAV)-mediated gene delivery has emerged as an effective and safe tool for... more Adeno-associated virus (AAV)-mediated gene delivery has emerged as an effective and safe tool for both preclinical and clinical studies of neurological disorders. The recent discovery that several serotypes are able to cross the blood-brain barrier when administered systemically has been a real breakthrough in the field of neurodegenerative diseases. Widespread transgene expression after systemic injection could spark interest as a therapeutic approach. Such strategy will avoid invasive brain surgery and allow non-focal gene therapy promising for CNS diseases affecting large portion of the brain. Here, we will review the recent results achieved through different systemic routes of injection generated in the last decade using systemic AAV-mediated delivery and propose a brief assessment of their values. In particular, we emphasize how the methods used for virus engineering could improve brain transduction after peripheral delivery.
To unravel the causes of major depressive disorder (MDD), the third leading cause of disease burd... more To unravel the causes of major depressive disorder (MDD), the third leading cause of disease burden around the world, ethological animal models have recently been proposed. Our previous studies highlighted a depressive-like profile among single- and socially-housed farm-bred cynomolgus macaques. Although phylogenetically close, cynomolgus and rhesus macaques, the two most commonly used macaque species in biomedical research, differ on several levels such as patterns of aggression, reconciliation, temperament, or dominance styles. The question of whether one captive macaque species was more vulnerable than another in the development of a pathological profile reminiscent of MDD symptoms was explored. Behavioral data (including body postures, orientations, gaze directions, inter-individual distances, and locations in the cage) were collected in farming conditions. Using an unbiased validated ethological scan-sampling method, followed by multiple correspondence and hierarchical clusteri...
Movement disorders : official journal of the Movement Disorder Society, 2014
Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodo... more Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold-standard LID macaque model. Dipraglurant (3, 10, and 30 mg/kg, by mouth) was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8). Dipraglurant inhibited dyskinesias in the LID macaque model, with best effect reached at 30 mg/kg dose with no alteration of levodopa efficacy. Acute challenges of dipraglurant were efficacious on choreic and dystonic LID in the MPTP-macaque model. Dipraglurant pharmacokinetic variables were similar to those of levodopa, suggesting that both drugs can be co-administered simultaneously in further studies.
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 3, 2003
We investigated, in mice, the influence of life experience on the vulnerability to 1-methyl-4-phe... more We investigated, in mice, the influence of life experience on the vulnerability to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a major neurotoxin that induces a Parkinson's disease-like syndrome in humans, and to cocaine, a potent psychostimulant that promotes drug addiction. Our findings show that adult C57BL/6 mice raised in an enriched environment (EE) for only 2 months are significantly more resistant to both drugs compared with mice raised in a standard environment (SE). Indeed, EE mice showed decreased locomotor activity in response to cocaine (10 and 20 mg/kg) as well as a different pattern of c-fos expression in the striatum compared with SE mice. After MPTP treatment, SE mice showed a 75% loss of dopamine neurons, whereas EE mice showed only a 40% loss. The dopamine transporter plays a key role in mediating the effects of both drugs. We thus investigated the regulation of its expression. EE mice showed less dopamine transporter binding in the striatum and less ...
ΔFosB is a surrogate marker of L-dopa-induced dyskinesia (LID), the unavoidable disabling consequ... more ΔFosB is a surrogate marker of L-dopa-induced dyskinesia (LID), the unavoidable disabling consequence of Parkinson's disease L-dopa long-term treatment. However, the relationship between the electrical activity of FosB/ΔFosB-expressing neurons and LID manifestation is unknown. We used the Daun02 prodrug-inactivation method associated with lentiviral expression of ß-galactosidase under the control of the FosB promoter to investigate a causal link between the activity of FosB/ΔFosB-expressing neurons and dyskinesia severity in both rat and monkey models of Parkinson's disease and LID. Whole-cell recordings of medium spiny neurons (MSNs) were performed to assess the effects of Daun02 and daunorubicin on neuronal excitability. We first show that daunorubicin, the active product of Daun02 metabolism by ß-galactosidase, decreases the activity of MSNs in rat brain slices and that Daun02 strongly decreases the excitability of rat MSN primary cultures expressing ß-galactosidase upon ...
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Papers by Erwan Bezard