Age-related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson's disease

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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AAV-Mediated Expression of Dominant-Negative ULK1 Increases Neuronal Survival and Enhances Motor Performance in the MPTP Mouse Model of Parkinson’s Disease

Molecular Neurobiology ◽

10.1007/s12035-019-01744-0 ◽

2019 ◽

Vol 57 (2) ◽

pp. 685-697 ◽

Cited By ~ 4

Author(s):

Dirk Balke ◽

Lars Tatenhorst ◽

Vivian Dambeck ◽

Vinicius Toledo Ribas ◽

Björn F. Vahsen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Motor Performance ◽

Neuronal Survival ◽

Dominant Negative

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Gastric Helicobacter suis Infection Partially Protects against Neurotoxicity in A 6-OHDA Parkinson’s Disease Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms222111328 ◽

2021 ◽

Vol 22 (21) ◽

pp. 11328

Author(s):

Helena Berlamont ◽

Arnout Bruggeman ◽

Eva Bauwens ◽

Charysse Vandendriessche ◽

Elien Clarebout ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mouse Model ◽

Neuroprotective Effect ◽

Cell Loss ◽

Antioxidant Genes ◽

Exact Etiology ◽

Gastric Biopsies ◽

6 Hydroxydopamine

The exact etiology of Parkinson’s disease (PD) remains largely unknown, but more and more research suggests the involvement of the gut microbiota. Interestingly, idiopathic PD patients were shown to have at least a 10 times higher prevalence of Helicobacter suis (H. suis) DNA in gastric biopsies compared to control patients. H. suis is a zoonotic Helicobacter species that naturally colonizes the stomach of pigs and non-human primates but can be transmitted to humans. Here, we investigated the influence of a gastric H. suis infection on PD disease progression through a 6-hydroxydopamine (6-OHDA) mouse model. Therefore, mice with either a short- or long-term H. suis infection were stereotactically injected with 6-OHDA in the left striatum and sampled one week later. Remarkably, a reduced loss of dopaminergic neurons was seen in the H. suis/6-OHDA groups compared to the control/6-OHDA groups. Correspondingly, motor function of the H. suis-infected 6-OHDA mice was superior to that in the non-infected 6-OHDA mice. Interestingly, we also observed higher expression levels of antioxidant genes in brain tissue from H. suis-infected 6-OHDA mice, as a potential explanation for the reduced 6-OHDA-induced cell loss. Our data support an unexpected neuroprotective effect of gastric H. suis on PD pathology, mediated through changes in oxidative stress.

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Influence of Striatal Dopamine, Cerebral Small Vessel Disease, and Other Risk Factors on Age-Related Parkinsonian Motor Signs

The Journals of Gerontology Series A ◽

10.1093/gerona/glz161 ◽

2019 ◽

Vol 75 (4) ◽

pp. 696-701

Author(s):

Caterina Rosano ◽

Andrea L Metti ◽

Andrea L Rosso ◽

Stephanie Studenski ◽

Nicolaas I Bohnen

Keyword(s):

Risk Factors ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Small Vessel Disease ◽

Cerebral Small Vessel Disease ◽

Older Age ◽

Striatal Dopamine ◽

Small Vessel ◽

Vessel Disease ◽

Age Related

Abstract Objective Parkinsonian motor signs are common and disabling in older adults without Parkinson’s disease (PD), but its risk factors are not completely understood. We assessed the influence of striatal dopamine levels, cerebral small vessel disease, and other factors on age-related parkinsonian motor signs in non-PD adults. Methods Striatal dopamine transporter (DAT) binding was quantified via [11C]-CFT positron emission tomography in 87 neurologically intact adults (20–85 years, 57.47% female) with concurrent data on: Unified Parkinson’s Disease Rating Scale motor (UPDRSm), white matter hyperintensities (WMH), and other risk factors (grip strength, vibratory sensitivity, cardio- and cerebro-vascular comorbidities). Sex-adjusted nonparametric models first estimated the associations of age, DAT, WMH, and other factors with UPDRSm; next, interactions of age by DAT, WMH, or other factors were tested. To quantify the influence of DAT, WMH, and other risk factors on the main association of age with UPDRSm, multivariable mediation models with bootstrapped confidence intervals (CI) were used. Results Older age, lower DAT, higher WMH, and worse risk factors significantly predicted worse UPDRSm (sex-adjusted p < .04 for all). DAT, but not WMH or other factors, positively and significantly interacted with age (p = .02). DAT significantly reduced the age-UPDRSm association by 30% (results of fully adjusted mediation model: indirect effect: 0.027; bootstrapped 95% CI: 0.0007, 0.074). Conclusions Striatal dopamine appears to influence to some extent the relationship between age and parkinsonian signs. However, much of the variance of parkinsonian signs appears unexplained. Longitudinal studies to elucidate the multifactorial causes of this common condition of older age are warranted.

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Chaperone Sigma1R mediates the neuroprotective action of afobazole in the 6-OHDA model of Parkinson’s disease

Scientific Reports ◽

10.1038/s41598-019-53413-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 9

Author(s):

Mikhail V. Voronin ◽

Ilya A. Kadnikov ◽

Dmitry N. Voronkov ◽

Sergey B. Seredenin

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuroprotective Effect ◽

Treatment Options ◽

Striatal Dopamine ◽

Dopamine Content ◽

Sigma 1 ◽

6 Hydroxydopamine ◽

Therapeutic Perspective

AbstractParkinson’s disease (PD) is a progressive neurodegenerative disease with limited treatment options. Therefore, the identification of therapeutic targets is urgently needed. Previous studies have shown that the ligand activation of the sigma-1 chaperone (Sigma1R) promotes neuroprotection. The multitarget drug afobazole (5-ethoxy-2-[2-(morpholino)-ethylthio]benzimidazole dihydrochloride) was shown to interact with Sigma1Rs and prevent decreases in striatal dopamine in the 6-hydroxydopamine (6-OHDA)-induced parkinsonism model. The aim of the present study was to elucidate the role of Sigma1Rs in afobazole pharmacological activity. Using ICR mice we found that administration of afobazole (2.5 mg/kg, i.p.) or selective agonist of Sigma1R PRE-084 (1.0 mg/kg, i.p.) over 14 days normalizes motor disfunction and prevents decreases in dopamine in the 6-OHDA-lesioned striatum. Afobazole administration also prevents the loss of TH + neurons in the substantia nigra. The pre-administration of selective Sigma1R antagonist BD-1047 (3.0 mg/kg, i.p.) abolishes the activity of either afobazole or PRE-084, as determined using the rotarod test and the analysis of striatal dopamine content. The current study demonstrates the contribution of Sigma1Rs in the neuroprotective effect of afobazole in the 6-OHDA model of Parkinson’s disease and defines the therapeutic perspective of Sigma1R agonists in the clinic.

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