The Experts below are selected from a list of 117 Experts worldwide ranked by ideXlab platform
Franziska Zientek - One of the best experts on this subject based on the ideXlab platform.
-
sigma 1 and dopamine d2 d3 receptor occupancy of Pridopidine in healthy volunteers and patients with huntington disease a 18 f fluspidine and 18 f fallypride pet study
European Journal of Nuclear Medicine and Molecular Imaging, 2021Co-Authors: Igor D Grachev, Gina Pastino, Philipp M Meyer, Georg Becker, Marcus Bronzel, Doug Marsteller, Ole Voges, Laura Rabinovich, Helena Knebel, Franziska ZientekAbstract:Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, Pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of Pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD. Using [18F] fluspidine PET (300 MBq, 0–90 min), 11 male HVs (Pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (Pridopidine 90 mg) were investigated twice, without and 2 h after single dose of Pridopidine. Using [18F] fallypride PET (200 MBq, 0–210 min), four male HVs were studied without and 2 h following Pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot. S1R occupancy as function of Pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at Pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg Pridopidine. In contrast, at 90 mg Pridopidine, the D2/D3R occupancy was only minimal (~ 3%). Our PET findings indicate that at clinically relevant single dose of 90 mg, Pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of Pridopidine to the S1R. Our findings provide significant clarification about Pridopidine’s mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.
-
sigma 1 and dopamine d2 d3 receptor occupancy of Pridopidine in healthy volunteers and patients with huntington disease a 18f fluspidine and 18f fallypride pet study
European Journal of Nuclear Medicine and Molecular Imaging, 2020Co-Authors: Igor D Grachev, Gina Pastino, Philipp M Meyer, Georg Becker, Marcus Bronzel, Doug Marsteller, Ole Voges, Laura Rabinovich, Helena Knebel, Franziska ZientekAbstract:Purpose Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, Pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of Pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD. Methods Using [18F] fluspidine PET (300 MBq, 0-90 min), 11 male HVs (Pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (Pridopidine 90 mg) were investigated twice, without and 2 h after single dose of Pridopidine. Using [18F] fallypride PET (200 MBq, 0-210 min), four male HVs were studied without and 2 h following Pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot. Results S1R occupancy as function of Pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at Pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg Pridopidine. In contrast, at 90 mg Pridopidine, the D2/D3R occupancy was only minimal (~ 3%). Conclusions Our PET findings indicate that at clinically relevant single dose of 90 mg, Pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of Pridopidine to the S1R. Our findings provide significant clarification about Pridopidine's mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.
Michal Geva - One of the best experts on this subject based on the ideXlab platform.
-
Pridopidine protects neurons from mutant huntingtin toxicity via the sigma 1 receptor
Neurobiology of Disease, 2019Co-Authors: Chelsy R Eddings, Michal Geva, Michael R Hayden, Nicolas Arbez, Sergey S Akimov, Christopher A RossAbstract:Huntington's disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin gene (HTT), translated into a Huntingtin protein with a polyglutamine expansion. There is preferential loss of medium spiny neurons within the striatum and cortical pyramidal neurons. Pridopidine is a small molecule showing therapeutic potential in HD preclinical and clinical studies. Pridopidine has nanomolar affinity to the sigma-1 receptor (sigma-1R), which is located predominantly at the endoplasmic reticulum (ER) and mitochondrial associated ER membrane, and activates neuroprotective pathways. Here we evaluate the neuroprotective effects of Pridopidine against mutant Huntingtin toxicity in mouse and human derived in vitro cell models. We also investigate the involvement of the sigma-1 receptor in the mechanism of Pridopidine. Pridopidine protects mutant Huntingtin transfected mouse primary striatal and cortical neurons, with an EC50 in the mid nanomolar range, as well as HD patient-derived induced pluripotent stem cells (iPSCs). This protection by Pridopidine is blocked by NE-100, a purported sigma-1 receptor antagonist, and not blocked by ANA-12, a reported TrkB receptor antagonist. 3PPP, a documented sigma-1 receptor agonist, shows similar neuroprotective effects. Genetic knock out of the sigma-1 receptor dramatically decreases protection from Pridopidine and 3PPP, but not protection via brain derived neurotrophic factor (BDNF). The neuroprotection afforded by Pridopidine in our HD cell models is robust and sigma-1 receptor dependent. These studies support the further development of Pridopidine, and other sigma-1 receptor agonists as neuroprotective agents for HD and perhaps for other disorders.
-
Pridopidine a clinic ready compound reduces 3 4 dihydroxyphenylalanine induced dyskinesia in parkinsonian macaques
Movement Disorders, 2019Co-Authors: Tom H Johnston, Michal Geva, Lilach Steiner, Aric Orbach, Spyros Papapetropoulos, Juhamatti Savola, Ian J Reynolds, Paula Ravenscroft, Michael P Hill, Susan H FoxAbstract:BACKGROUND Pridopidine, in development for Huntington's disease, may modulate aberrant l-dopa-induced effects including l-dopa-induced dyskinesia (LID). OBJECTIVE This study investigated whether Pridopidine could reduce LID in the MPTP macaque model of Parkinson's disease and characterized the observed behavioral effects in terms of receptor occupancy. METHODS The pharmacokinetic profile and effects of Pridopidine (15-30 mg/kg) on parkinsonism, dyskinesia, and quality of on-time, in combination with l-dopa, were assessed in MPTP macaques with LID. Pridopidine receptor occupancy was estimated using known in vitro binding affinities to σ1 and dopamine D2 receptors, in vivo PET imaging, and pharmacokinetic profiling across different species. RESULTS Pridopidine produced a dose-dependent reduction in dyskinesia (up to 71%, 30 mg/kg) and decreased the duration of on-time with disabling dyskinesia evoked by l-dopa by 37% (20 mg/kg) and 60% (30 mg/kg). Pridopidine did not compromise the anti-parkinsonian benefit of l-dopa. Plasma exposures following the ineffective dose (15 mg/kg) were associated with full σ1 occupancy (>80%), suggesting that σ1 engagement alone is unlikely to account for the antidyskinetic benefits of Pridopidine. Exposures following effective doses (20-30 mg/kg), while providing full σ1 occupancy, provide only modest dopamine D2 occupancy (<40%). However, effective Pridopidine doses clearly engage a range of receptors (including adrenergic-α2C , dopamine-D3 , and serotoninergic-5-HT1A sites) to a higher degree than D2 and might contribute to the antidyskinetic actions. CONCLUSIONS In MPTP macaques, Pridopidine produced a significant decrease in LID without compromising the antiparkinsonian benefit of l-dopa. Although the actions of Pridopidine were associated with full σ1 occupancy, effective exposures are more likely associated with occupancy of additional, non-sigma receptors. This complex pharmacology may underlie the effectiveness of Pridopidine against LID. © 2018 International Parkinson and Movement Disorder Society.
-
targeting the sigma 1 receptor via Pridopidine ameliorates central features of als pathology in a sod1g93a model
Cell Death and Disease, 2019Co-Authors: Ariel Ionescu, Michal Geva, Michael R Hayden, Tal Gradus, Topaz Altman, Roy Maimon, Noi Saraf Avraham, Eran PerlsonAbstract:Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting both the upper and lower motor neurons (MNs), with no effective treatment currently available. Early pathological events in ALS include perturbations in axonal transport (AT), formation of toxic protein aggregates and Neuromuscular Junction (NMJ) disruption, which all lead to axonal degeneration and motor neuron death. Pridopidine is a small molecule that has been clinically developed for Huntington disease. Here we tested the efficacy of Pridopidine for ALS using in vitro and in vivo models. Pridopidine beneficially modulates AT deficits and diminishes NMJ disruption, as well as motor neuron death in SOD1G93A MNs and in neuromuscular co-cultures. Furthermore, we demonstrate that Pridopidine activates the ERK pathway and mediates its beneficial effects through the sigma-1 receptor (S1R). Strikingly, in vivo evaluation of Pridopidine in SOD1G93A mice reveals a profound reduction in mutant SOD1 aggregation in the spinal cord, and attenuation of NMJ disruption, as well as subsequent muscle wasting. Taken together, we demonstrate for the first time that Pridopidine improves several cellular and histological hallmark pathologies of ALS through the S1R.
-
Pridopidine induces functional neurorestoration via the sigma 1 receptor in a mouse model of parkinson s disease
Neurotherapeutics, 2019Co-Authors: Veronica Francardo, Michal Geva, Francesco Bez, Quentin Denis, Lilach Steiner, Michael R Hayden, Angela M CenciAbstract:Pridopidine is a small molecule in clinical development for the treatment of Huntington’s disease. It was recently found to have high binding affinity to the sigma-1 receptor, a chaperone protein involved in cellular defense mechanisms and neuroplasticity. Here, we have evaluated the neuroprotective and neurorestorative effects of Pridopidine in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of parkinsonism in mice. By 5 weeks of daily administration, a low dose of Pridopidine (0.3 mg/kg) had significantly improved deficits in forelimb use (cylinder test, stepping test) and abolished the ipsilateral rotational bias typical of hemiparkinsonian animals. A higher dose of Pridopidine (1 mg/kg) significantly improved only the rotational bias, with a trend towards improvement in forelimb use. The behavioral recovery induced by Pridopidine 0.3 mg/kg was accompanied by a significant protection of nigral dopamine cell bodies, an increased dopaminergic fiber density in the striatum, and striatal upregulation of GDNF, BDNF, and phosphorylated ERK1/2. The beneficial effects of Pridopidine 0.3 mg/kg were absent in 6-OHDA-lesioned mice lacking the sigma-1 receptor. Pharmacokinetic data confirmed that the effective dose of Pridopidine reached brain concentrations sufficient to bind S1R. Our results are the first to show that Pridopidine promotes functional neurorestoration in the damaged nigrostriatal system acting via the sigma-1 receptor.
-
Image_4_Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical Neurons From a Mouse Model of Huntington Disease.TIF
2019Co-Authors: Amy I. Smith-dijak, Michal Geva, Michael R Hayden, Wissam B. Nassrallah, Lily Y. J. Zhang, Lynn A. RaymondAbstract:Huntington disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the huntingtin gene. The onset of symptoms is preceded by synaptic dysfunction. Homeostatic synaptic plasticity (HSP) refers to processes that maintain the stability of networks of neurons, thought to be required to enable new learning and cognitive flexibility. One type of HSP is synaptic scaling, in which the strength of all of the synapses onto a cell increases or decreases following changes in the cell’s level of activity. Several pathways implicated in synaptic scaling are dysregulated in HD, including brain-derived neurotrophic factor (BDNF) and calcium signaling. Here, we investigated whether HSP is disrupted in cortical neurons from an HD mouse model. We treated cultured cortical neurons from wild-type (WT) FVB/N or YAC128 HD mice with tetrodotoxin (TTX) for 48 h to silence action potentials and then recorded miniature excitatory postsynaptic currents. In WT cultures, these increased in both amplitude and frequency after TTX treatment, and further experiments showed that this was a result of insertion of AMPA receptors and formation of new synapses, respectively. Manipulation of BDNF concentration in the culture medium revealed that BDNF signaling contributed to these changes. In contrast to WT cortical neurons, YAC128 cultures showed no response to action potential silencing. Strikingly, we were able to restore the TTX-induced changes in YAC128 cultures by treating them with Pridopidine, a drug which enhances BDNF signaling through stimulation of the sigma-1 receptor (S1R), and with the S1R agonist 3-PPP. These data provide evidence for disruption of HSP in cortical neurons from an HD mouse model that is restored by stimulation of S1R. Our results suggest a potential new direction for developing therapy to mitigate cognitive deficits in HD.
Michael R Hayden - One of the best experts on this subject based on the ideXlab platform.
-
Pridopidine protects neurons from mutant huntingtin toxicity via the sigma 1 receptor
Neurobiology of Disease, 2019Co-Authors: Chelsy R Eddings, Michal Geva, Michael R Hayden, Nicolas Arbez, Sergey S Akimov, Christopher A RossAbstract:Huntington's disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin gene (HTT), translated into a Huntingtin protein with a polyglutamine expansion. There is preferential loss of medium spiny neurons within the striatum and cortical pyramidal neurons. Pridopidine is a small molecule showing therapeutic potential in HD preclinical and clinical studies. Pridopidine has nanomolar affinity to the sigma-1 receptor (sigma-1R), which is located predominantly at the endoplasmic reticulum (ER) and mitochondrial associated ER membrane, and activates neuroprotective pathways. Here we evaluate the neuroprotective effects of Pridopidine against mutant Huntingtin toxicity in mouse and human derived in vitro cell models. We also investigate the involvement of the sigma-1 receptor in the mechanism of Pridopidine. Pridopidine protects mutant Huntingtin transfected mouse primary striatal and cortical neurons, with an EC50 in the mid nanomolar range, as well as HD patient-derived induced pluripotent stem cells (iPSCs). This protection by Pridopidine is blocked by NE-100, a purported sigma-1 receptor antagonist, and not blocked by ANA-12, a reported TrkB receptor antagonist. 3PPP, a documented sigma-1 receptor agonist, shows similar neuroprotective effects. Genetic knock out of the sigma-1 receptor dramatically decreases protection from Pridopidine and 3PPP, but not protection via brain derived neurotrophic factor (BDNF). The neuroprotection afforded by Pridopidine in our HD cell models is robust and sigma-1 receptor dependent. These studies support the further development of Pridopidine, and other sigma-1 receptor agonists as neuroprotective agents for HD and perhaps for other disorders.
-
targeting the sigma 1 receptor via Pridopidine ameliorates central features of als pathology in a sod1g93a model
Cell Death and Disease, 2019Co-Authors: Ariel Ionescu, Michal Geva, Michael R Hayden, Tal Gradus, Topaz Altman, Roy Maimon, Noi Saraf Avraham, Eran PerlsonAbstract:Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting both the upper and lower motor neurons (MNs), with no effective treatment currently available. Early pathological events in ALS include perturbations in axonal transport (AT), formation of toxic protein aggregates and Neuromuscular Junction (NMJ) disruption, which all lead to axonal degeneration and motor neuron death. Pridopidine is a small molecule that has been clinically developed for Huntington disease. Here we tested the efficacy of Pridopidine for ALS using in vitro and in vivo models. Pridopidine beneficially modulates AT deficits and diminishes NMJ disruption, as well as motor neuron death in SOD1G93A MNs and in neuromuscular co-cultures. Furthermore, we demonstrate that Pridopidine activates the ERK pathway and mediates its beneficial effects through the sigma-1 receptor (S1R). Strikingly, in vivo evaluation of Pridopidine in SOD1G93A mice reveals a profound reduction in mutant SOD1 aggregation in the spinal cord, and attenuation of NMJ disruption, as well as subsequent muscle wasting. Taken together, we demonstrate for the first time that Pridopidine improves several cellular and histological hallmark pathologies of ALS through the S1R.
-
Pridopidine induces functional neurorestoration via the sigma 1 receptor in a mouse model of parkinson s disease
Neurotherapeutics, 2019Co-Authors: Veronica Francardo, Michal Geva, Francesco Bez, Quentin Denis, Lilach Steiner, Michael R Hayden, Angela M CenciAbstract:Pridopidine is a small molecule in clinical development for the treatment of Huntington’s disease. It was recently found to have high binding affinity to the sigma-1 receptor, a chaperone protein involved in cellular defense mechanisms and neuroplasticity. Here, we have evaluated the neuroprotective and neurorestorative effects of Pridopidine in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of parkinsonism in mice. By 5 weeks of daily administration, a low dose of Pridopidine (0.3 mg/kg) had significantly improved deficits in forelimb use (cylinder test, stepping test) and abolished the ipsilateral rotational bias typical of hemiparkinsonian animals. A higher dose of Pridopidine (1 mg/kg) significantly improved only the rotational bias, with a trend towards improvement in forelimb use. The behavioral recovery induced by Pridopidine 0.3 mg/kg was accompanied by a significant protection of nigral dopamine cell bodies, an increased dopaminergic fiber density in the striatum, and striatal upregulation of GDNF, BDNF, and phosphorylated ERK1/2. The beneficial effects of Pridopidine 0.3 mg/kg were absent in 6-OHDA-lesioned mice lacking the sigma-1 receptor. Pharmacokinetic data confirmed that the effective dose of Pridopidine reached brain concentrations sufficient to bind S1R. Our results are the first to show that Pridopidine promotes functional neurorestoration in the damaged nigrostriatal system acting via the sigma-1 receptor.
-
Image_4_Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical Neurons From a Mouse Model of Huntington Disease.TIF
2019Co-Authors: Amy I. Smith-dijak, Michal Geva, Michael R Hayden, Wissam B. Nassrallah, Lily Y. J. Zhang, Lynn A. RaymondAbstract:Huntington disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the huntingtin gene. The onset of symptoms is preceded by synaptic dysfunction. Homeostatic synaptic plasticity (HSP) refers to processes that maintain the stability of networks of neurons, thought to be required to enable new learning and cognitive flexibility. One type of HSP is synaptic scaling, in which the strength of all of the synapses onto a cell increases or decreases following changes in the cell’s level of activity. Several pathways implicated in synaptic scaling are dysregulated in HD, including brain-derived neurotrophic factor (BDNF) and calcium signaling. Here, we investigated whether HSP is disrupted in cortical neurons from an HD mouse model. We treated cultured cortical neurons from wild-type (WT) FVB/N or YAC128 HD mice with tetrodotoxin (TTX) for 48 h to silence action potentials and then recorded miniature excitatory postsynaptic currents. In WT cultures, these increased in both amplitude and frequency after TTX treatment, and further experiments showed that this was a result of insertion of AMPA receptors and formation of new synapses, respectively. Manipulation of BDNF concentration in the culture medium revealed that BDNF signaling contributed to these changes. In contrast to WT cortical neurons, YAC128 cultures showed no response to action potential silencing. Strikingly, we were able to restore the TTX-induced changes in YAC128 cultures by treating them with Pridopidine, a drug which enhances BDNF signaling through stimulation of the sigma-1 receptor (S1R), and with the S1R agonist 3-PPP. These data provide evidence for disruption of HSP in cortical neurons from an HD mouse model that is restored by stimulation of S1R. Our results suggest a potential new direction for developing therapy to mitigate cognitive deficits in HD.
-
Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical Neurons From a Mouse Model of Huntington Disease
Frontiers Media S.A., 2019Co-Authors: Michal Geva, Michael R Hayden, Amy I. Smith-dijak, Wissam B. Nassrallah, Lily Y. J. Zhang, Lynn A. RaymondAbstract:Huntington disease (HD) is an inherited neurodegenerative disorder caused by a mutation in the huntingtin gene. The onset of symptoms is preceded by synaptic dysfunction. Homeostatic synaptic plasticity (HSP) refers to processes that maintain the stability of networks of neurons, thought to be required to enable new learning and cognitive flexibility. One type of HSP is synaptic scaling, in which the strength of all of the synapses onto a cell increases or decreases following changes in the cell’s level of activity. Several pathways implicated in synaptic scaling are dysregulated in HD, including brain-derived neurotrophic factor (BDNF) and calcium signaling. Here, we investigated whether HSP is disrupted in cortical neurons from an HD mouse model. We treated cultured cortical neurons from wild-type (WT) FVB/N or YAC128 HD mice with tetrodotoxin (TTX) for 48 h to silence action potentials and then recorded miniature excitatory postsynaptic currents. In WT cultures, these increased in both amplitude and frequency after TTX treatment, and further experiments showed that this was a result of insertion of AMPA receptors and formation of new synapses, respectively. Manipulation of BDNF concentration in the culture medium revealed that BDNF signaling contributed to these changes. In contrast to WT cortical neurons, YAC128 cultures showed no response to action potential silencing. Strikingly, we were able to restore the TTX-induced changes in YAC128 cultures by treating them with Pridopidine, a drug which enhances BDNF signaling through stimulation of the sigma-1 receptor (S1R), and with the S1R agonist 3-PPP. These data provide evidence for disruption of HSP in cortical neurons from an HD mouse model that is restored by stimulation of S1R. Our results suggest a potential new direction for developing therapy to mitigate cognitive deficits in HD
Rebecca Kusko - One of the best experts on this subject based on the ideXlab platform.
-
Large-scale transcriptomic analysis reveals that Pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse
'Springer Science and Business Media LLC', 2018Co-Authors: Rebecca Kusko, Jennifer Dreymann, Jermaine Ross, Yoonjeong Cha, Renan Escalante-chong, Marta Garcia-miralles, Liang Juin Tan, Michael E. Burczynski, Ben Zeskind, Daphna LaifenfeldAbstract:Abstract Background Huntington Disease (HD) is an incurable autosomal dominant neurodegenerative disorder driven by an expansion repeat giving rise to the mutant huntingtin protein (mHtt), which is known to disrupt a multitude of transcriptional pathways. Pridopidine, a small molecule in development for treatment of HD, has been shown to improve motor symptoms in HD patients. In HD animal models, Pridopidine exerts neuroprotective effects and improves behavioral and motor functions. Pridopidine binds primarily to the sigma-1 receptor, (IC50 ~ 100 nM), which mediates its neuroprotective properties, such as rescue of spine density and aberrant calcium signaling in HD neuronal cultures. Pridopidine enhances brain-derived neurotrophic factor (BDNF) secretion, which is blocked by putative sigma-1 receptor antagonist NE-100, and was shown to upregulate transcription of genes in the BDNF, glucocorticoid receptor (GR), and dopamine D1 receptor (D1R) pathways in the rat striatum. The impact of different doses of Pridopidine on gene expression and transcript splicing in HD across relevant brain regions was explored, utilizing the YAC128 HD mouse model, which carries the entire human mHtt gene containing 128 CAG repeats. Methods RNAseq was analyzed from striatum, cortex, and hippocampus of wild-type and YAC128 mice treated with vehicle, 10 mg/kg or 30 mg/kg Pridopidine from the presymptomatic stage (1.5 months of age) until 11.5 months of age in which mice exhibit progressive disease phenotypes. Results The most pronounced transcriptional effect of Pridopidine at both doses was observed in the striatum with minimal effects in other regions. In addition, for the first time Pridopidine was found to have a dose-dependent impact on alternative exon and junction usage, a regulatory mechanism known to be impaired in HD. In the striatum of YAC128 HD mice, Pridopidine treatment initiation prior to symptomatic manifestation rescues the impaired expression of the BDNF, GR, D1R and cAMP pathways. Conclusions Pridopidine has broad effects on restoring transcriptomic disturbances in the striatum, particularly involving synaptic transmission and activating neuroprotective pathways that are disturbed in HD. Benefits of treatment initiation at early disease stages track with trends observed in the clinic
-
Additional file 6: of Large-scale transcriptomic analysis reveals that Pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse
2018Co-Authors: Rebecca Kusko, Jennifer Dreymann, Jermaine Ross, Yoonjeong Cha, Renan Escalante-chong, Marta Garcia-miralles, Michael E. Burczynski, Ben Zeskind, Liang Tan, Daphna LaifenfeldAbstract:Figure S1. Pridopidine reverses downregulation of G Protein-Coupled Receptor 3 (Gpr3) gene expression in the striatum of YAC128 mice. Shown are RNAseq results for Gpr3 in the YAC128 striatum after Pridopidine treatment. “**” and “##” represent significant (Adj. p-val
-
Additional file 5: of Large-scale transcriptomic analysis reveals that Pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse
2018Co-Authors: Rebecca Kusko, Jennifer Dreymann, Jermaine Ross, Yoonjeong Cha, Renan Escalante-chong, Marta Garcia-miralles, Michael E. Burczynski, Ben Zeskind, Liang Tan, Daphna LaifenfeldAbstract:Table S5. Pathway analysis of alternatively spliced genes identified after high dose treatment with Pridopidine. (XLSX 31 kb
-
the sigma 1 receptor mediates the beneficial effects of Pridopidine in a mouse model of huntington disease
Neurobiology of Disease, 2017Co-Authors: Daniel A Ryskamp, Michal Geva, Michael R Hayden, Jun Wu, Rebecca Kusko, Iris Grossman, Ilya BezprozvannyAbstract:The tri-nucleotide repeat expansion underlying Huntington disease (HD) results in corticostriatal synaptic dysfunction and subsequent neurodegeneration of striatal medium spiny neurons (MSNs). HD is a devastating autosomal dominant disease with no disease-modifying treatments. Pridopidine, a postulated “dopamine stabilizer”, has been shown to improve motor symptoms in clinical trials of HD. However, the target(s) and mechanism of action of Pridopidine remain to be fully elucidated. As binding studies identified sigma-1 receptor (S1R) as a high-affinity receptor for Pridopidine, we evaluated the relevance of S1R as a therapeutic target of Pridopidine in HD. S1R is an endoplasmic reticulum - (ER) resident transmembrane protein and is regulated by ER calcium homeostasis, which is perturbed in HD. Consistent with ER calcium dysregulation, we observed striatal upregulation of S1R in aged YAC128 transgenic HD mice and HD patients. We previously demonstrated that dendritic MSN spines are lost in aged corticostriatal co-cultures from YAC128 mice. We report here that Pridopidine and the chemically similar S1R agonist 3-PPP prevent MSN spine loss in aging YAC128 co-cultures. Spine protection was blocked by neuronal deletion of S1R. Pridopidine treatment suppressed supranormal ER Ca2 + release, restored ER calcium levels and reduced excessive store-operated calcium (SOC) entry in spines, which may account for its synaptoprotective effects. Normalization of ER Ca2 + levels by Pridopidine was prevented by S1R deletion. To evaluate long-term effects of Pridopidine, we analyzed expression profiles of calcium signaling genes. Pridopidine elevated striatal expression of calbindin and homer1a, whereas their striatal expression was reduced in aged Q175KI and YAC128 HD mouse models compared to WT. Pridopidine and 3-PPP are proposed to prevent calcium dysregulation and synaptic loss in a YAC128 corticostriatal co-culture model of HD. The actions of Pridopidine were mediated by S1R and led to normalization of ER Ca2 + release, ER Ca2 + levels and spine SOC entry in YAC128 MSNs. This is a new potential mechanism of action for Pridopidine, highlighting S1R as a potential target for HD therapy. Upregulation of striatal proteins that regulate calcium, including calbindin and homer1a, upon chronic therapy with Pridopidine, may further contribute to long-term beneficial effects of Pridopidine in HD.
-
the sigma 1 receptor mediates the beneficial effects of Pridopidine in a mouse model of huntington disease
Neurobiology of Disease, 2017Co-Authors: Daniel A Ryskamp, Michal Geva, Michael R Hayden, Rebecca Kusko, Iris Grossman, Ilya BezprozvannyAbstract:The tri-nucleotide repeat expansion underlying Huntington disease (HD) results in corticostriatal synaptic dysfunction and subsequent neurodegeneration of striatal medium spiny neurons (MSNs). HD is a devastating autosomal dominant disease with no disease-modifying treatments. Pridopidine, a postulated "dopamine stabilizer", has been shown to improve motor symptoms in clinical trials of HD. However, the target(s) and mechanism of action of Pridopidine remain to be fully elucidated. As binding studies identified sigma-1 receptor (S1R) as a high-affinity receptor for Pridopidine, we evaluated the relevance of S1R as a therapeutic target of Pridopidine in HD. S1R is an endoplasmic reticulum - (ER) resident transmembrane protein and is regulated by ER calcium homeostasis, which is perturbed in HD. Consistent with ER calcium dysregulation, we observed striatal upregulation of S1R in aged YAC128 transgenic HD mice and HD patients. We previously demonstrated that dendritic MSN spines are lost in aged corticostriatal co-cultures from YAC128 mice. We report here that Pridopidine and the chemically similar S1R agonist 3-PPP prevent MSN spine loss in aging YAC128 co-cultures. Spine protection was blocked by neuronal deletion of S1R. Pridopidine treatment suppressed supranormal ER Ca2+ release, restored ER calcium levels and reduced excessive store-operated calcium (SOC) entry in spines, which may account for its synaptoprotective effects. Normalization of ER Ca2+ levels by Pridopidine was prevented by S1R deletion. To evaluate long-term effects of Pridopidine, we analyzed expression profiles of calcium signaling genes. Pridopidine elevated striatal expression of calbindin and homer1a, whereas their striatal expression was reduced in aged Q175KI and YAC128 HD mouse models compared to WT. Pridopidine and 3-PPP are proposed to prevent calcium dysregulation and synaptic loss in a YAC128 corticostriatal co-culture model of HD. The actions of Pridopidine were mediated by S1R and led to normalization of ER Ca2+ release, ER Ca2+ levels and spine SOC entry in YAC128 MSNs. This is a new potential mechanism of action for Pridopidine, highlighting S1R as a potential target for HD therapy. Upregulation of striatal proteins that regulate calcium, including calbindin and homer1a, upon chronic therapy with Pridopidine, may further contribute to long-term beneficial effects of Pridopidine in HD.
Igor D Grachev - One of the best experts on this subject based on the ideXlab platform.
-
sigma 1 and dopamine d2 d3 receptor occupancy of Pridopidine in healthy volunteers and patients with huntington disease a 18 f fluspidine and 18 f fallypride pet study
European Journal of Nuclear Medicine and Molecular Imaging, 2021Co-Authors: Igor D Grachev, Gina Pastino, Philipp M Meyer, Georg Becker, Marcus Bronzel, Doug Marsteller, Ole Voges, Laura Rabinovich, Helena Knebel, Franziska ZientekAbstract:Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, Pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of Pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD. Using [18F] fluspidine PET (300 MBq, 0–90 min), 11 male HVs (Pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (Pridopidine 90 mg) were investigated twice, without and 2 h after single dose of Pridopidine. Using [18F] fallypride PET (200 MBq, 0–210 min), four male HVs were studied without and 2 h following Pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot. S1R occupancy as function of Pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at Pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg Pridopidine. In contrast, at 90 mg Pridopidine, the D2/D3R occupancy was only minimal (~ 3%). Our PET findings indicate that at clinically relevant single dose of 90 mg, Pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of Pridopidine to the S1R. Our findings provide significant clarification about Pridopidine’s mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.
-
sigma 1 and dopamine d2 d3 receptor occupancy of Pridopidine in healthy volunteers and patients with huntington disease a 18f fluspidine and 18f fallypride pet study
European Journal of Nuclear Medicine and Molecular Imaging, 2020Co-Authors: Igor D Grachev, Gina Pastino, Philipp M Meyer, Georg Becker, Marcus Bronzel, Doug Marsteller, Ole Voges, Laura Rabinovich, Helena Knebel, Franziska ZientekAbstract:Purpose Pridopidine is an investigational drug for Huntington disease (HD). Pridopidine was originally thought to act as a dopamine stabilizer. However, Pridopidine shows highest affinity to the sigma-1 receptor (S1R) and enhances neuroprotection via the S1R in preclinical studies. Using [18F] fluspidine and [18F] fallypride PET, the purpose of this study was to assess in vivo target engagement/receptor occupancy of Pridopidine to the S1R and dopamine D2/D3 receptor (D2/D3R) at clinical relevant doses in healthy volunteers (HVs) and as proof-of-concept in a small number of patients with HD. Methods Using [18F] fluspidine PET (300 MBq, 0-90 min), 11 male HVs (Pridopidine 0.5 to 90 mg; six dose groups) and three male patients with HD (Pridopidine 90 mg) were investigated twice, without and 2 h after single dose of Pridopidine. Using [18F] fallypride PET (200 MBq, 0-210 min), four male HVs were studied without and 2 h following Pridopidine administration (90 mg). Receptor occupancy was analyzed by the Lassen plot. Results S1R occupancy as function of Pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at Pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg Pridopidine. In contrast, at 90 mg Pridopidine, the D2/D3R occupancy was only minimal (~ 3%). Conclusions Our PET findings indicate that at clinically relevant single dose of 90 mg, Pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of Pridopidine to the S1R. Our findings provide significant clarification about Pridopidine's mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.