Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson's Disease

Francardo, Veronica; Geva, Michal; Bez, Francesco; Denis, Quentin; Steiner, Lilach; Hayden, Michael R.; Cenci, M. Angela

doi:10.1007/s13311-018-00699-9

Cited by 48 publications

(56 citation statements)

References 65 publications

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“…Neuroprotective properties of pridopidine via S1Ractivation have been demonstrated previously in numerous preclinical models of NDD including HD, PD, and ALS [1,[13][14][15][16][17]. These effects of pridopidine are S1R-mediated, because genetic knock-down or pharmacological inhibition of S1Rs abolishes the pridopidine effects [14][15][16]. Pridopidine shows a S1R-dependent neuroprotective effect against mutant Huntingtin (mHtt)-induced cell death in vitro and in vivo in cortical and striatal neurons in experimental HD mice [39].…”

Section: Discussionmentioning

confidence: 81%

“…Pridopidine shows in vivo high S1R occupancy vs. low D2/D3R occupancy at behaviorally effective doses in rat brains using [ 11 C]SA4503 and [ 11 C] Raclopride PET [8]. Neuroprotective properties of pridopidine via S1Ractivation have been demonstrated previously in numerous preclinical models of NDD including HD, PD, and ALS [1,[13][14][15][16][17]. These effects of pridopidine are S1R-mediated, because genetic knock-down or pharmacological inhibition of S1Rs abolishes the pridopidine effects [14][15][16].…”

Section: Discussionmentioning

confidence: 95%

“…Importantly, S1R activation, e.g., by pridopidine, enhances neuroprotective effects in preclinical models of neurodegeneration, including HD and ALS, acting to stimulate brain repair and plasticity. Pridopidine augments brain-derived neurotrophic growth factor (BDNF) secretion and rescues dendritic spine loss and restores the aberrant calcium signaling via the S1R shown in experimental HD, Parkinson disease (PD), and ALS [13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

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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

Grachev

Meyer

Becker

et al. 2020

Eur J Nucl Med Mol Imaging

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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.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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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

Grachev

Meyer

Becker

et al. 2020

Eur J Nucl Med Mol Imaging

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“…Originally, pridopidine was investigated for the symptomatic treatment of Huntington’s disease (HD), but two phase-3 trials sponsored by Teva did not show efficacy in improving voluntary motor function in HD patients. Later, it was found to display high binding affinity for human sigma-1 receptor (S1R) with a reported K i value of 81.7 nM [ 58 , 59 ]. Pridopidine was shown to improve functional neurorestoration, probably by acting on S1R, in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of PD in mice [ 59 ].…”

Section: Updates On the Clinical Progress Of Dopaminergic Pd Treatmenmentioning

confidence: 99%

Recent advances in dopaminergic strategies for the treatment of Parkinson’s disease

et al. 2020

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s Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease worldwide. However, there is no available therapy reversing the neurodegenerative process of PD. Based on the loss of dopamine or dopaminergic dysfunction in PD patients, most of the current therapies focus on symptomatic relief to improve patient quality of life. As dopamine replacement treatment remains the most effective symptomatic pharmacotherapy for PD, herein we provide an overview of the current pharmacotherapies, summarize the clinical development status of novel dopaminergic agents, and highlight the challenge and opportunity of emerging preclinical dopaminergic approaches aimed at managing the features and progression of PD.

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“…One of the promising targets for PD treatment is chaperone Sigma1R [ 20 , 21 , 22 ]. Sigma1Rs are widely spread in the brain and nigrostriatal pathway in particular [ 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Deferred Administration of Afobazole Induces Sigma1R-Dependent Restoration of Striatal Dopamine Content in a Mouse Model of Parkinson’s Disease

Kadnikov

Verbovaya

Воронков

et al. 2020

IJMS

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Previously, we demonstrated that the immediate administration of multitarget anxiolytic afobazole slows down the progression of neuronal damage in a 6-hydroxidodamine (6-OHDA) model of Parkinson’s disease due to the activation of chaperone Sigma1R. The aim of the present study is to evaluate the therapeutic potential of deferred afobazole administration in this model. Male ICR mice received a unilateral 6-OHDA lesion of the striatum. Fourteen days after the surgery, mice were treated with afobazole, selective Sigma1R agonist PRE-084, selective Sigma1R antagonist BD-1047, and a combination of BD-1047 with afobazole or PRE-084 for another 14 days. The deferred administration of afobazole restored the intrastriatal dopamine content in the 6-OHDA-lesioned striatum and facilitated motor behavior in rotarod tests. The action of afobazole accorded with the effect of Sigma1R selective agonist PRE-084 and was blocked by Sigma1R selective antagonist BD-1047. The present study illustrates the Sigma1R-dependent effects of afobazole in a 6-OHDA model of Parkinson’s disease and reveals the therapeutic potential of Sigma1R agonists in treatment of the condition.

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Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson's Disease

Cited by 48 publications

References 65 publications

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

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

Recent advances in dopaminergic strategies for the treatment of Parkinson’s disease

Deferred Administration of Afobazole Induces Sigma1R-Dependent Restoration of Striatal Dopamine Content in a Mouse Model of Parkinson’s Disease

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