Simvastatin Inhibits the Activation of p21<sup>ras</sup>and Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson's Disease

Ghosh, Alip; Roy, Avik; Matras, Joanna; Brahmachari, Saurav; Gendelman, Howard Eliot; Pahan, Kalipada

doi:10.1523/jneurosci.4144-09.2009

Cited by 157 publications

(184 citation statements)

References 52 publications

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“…Currently there is considerable confusion about the relationship between cholesterol and synucleinopathies (30)(31)(32). Although some studies suggest that cholesterol-lowering drugs have a protective role, others point to associations between low cholesterol and increased risk of PD.…”

Section: Discussionmentioning

confidence: 99%

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Valastyan¹,

Termine²,

Lindquist³

2014

Proc. Natl. Acad. Sci. U.S.A.

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Synucleinopathies are neurodegenerative diseases associated with toxicity of the lipid-binding protein α-synuclein (α-syn). When expressed in yeast, α-syn associates with membranes at the endoplasmic reticulum and traffics with vesicles out to the plasma membrane. At higher levels it elicits a number of phenotypes, including blocking vesicle trafficking. The expression of α-syn splice isoforms varies with disease, but how these isoforms affect protein function is unknown. We investigated two of the most abundant isoforms, resulting in deletion of exon four (α-synΔ4) or exon six (α-synΔ6). α-SynΔ4, missing part of the lipid-binding domain, had reduced toxicity and membrane binding. α-SynΔ6, missing part of the protein-protein interaction domain, had reduced toxicity but no reduction in membrane binding. To compare the mechanism by which the splice isoforms exert toxicity, equally toxic strains were probed with genetic modifiers of α-syn-induced toxicity. Most modifiers equally altered the toxicity induced by the splice isoforms and full-length α-syn (α-synFL). However, the splice isoform strains responded differently to a sterol-binding protein, leading us to examine the effect of sterols on α-syn-induced toxicity. Upon inhibition of sterol synthesis, α-synFL and α-synΔ6, but not α-synΔ4, showed decreased plasma membrane association, increased vesicular association, and increased cellular toxicity. Thus, higher membrane sterol concentrations favor plasma membrane binding of α-synFL and α-synΔ6 and may be protective of synucleinopathy progression. Given the common use of cholesterol-reducing statins and these potential effects on membrane binding proteins, further investigation of how sterol concentration and α-syn splice isoforms affect vesicular trafficking in synucleinopathies is warranted.

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Section: Discussionmentioning

confidence: 99%

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Valastyan¹,

Termine²,

Lindquist³

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent studies showed that statins exhibited profoundly neuroprotective effects on dopaminergic neurodegeneration (Ghosh et al 2009;Hernández-Romero et al 2008;). To our knowledge, there is very little information regarding the relationship between statins, 6-hydroxydopamine (6-OHDA), and histaminergic H1 receptors.…”

Section: Introductionmentioning

confidence: 99%

Effects of simvastatin and 6-hydroxydopamine on histaminergic H1 receptor binding density in rat brains

Deng

Mackovski

et al. 2010

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Statins have been widely used for the treatment of a variety of medical conditions including psychoneurological disorders beyond their original use in lowering cholesterol. Histamine receptors play an important role in the regulation of neural activity, however, it is unknown whether statins act on histamine receptors, particularly for their neural regulatory effects. This study examined the effects of simvastatin and 6-hydroxydopamine (6-OHDA) lesions on histamine H1 receptors using [3H] pyrilamine binding autoradiography. Compared to the saline group, simvastatin (1 mg/kg/day) significantly decreased H1 receptor bindings in the primary motor cortex (M1), ventromedial hypothalamic nucleus (VMH), caudate putamen (CPu), accumbens core (AcbC) and prefrontal cortex (PfC) (all pb0.05); however 10 mg/kg/day simvastatin increased H1 receptor density only in the medial amygdaloid nucleus (Mep) (pb0.05), but had no significant effect in other regions examined. The 6-OHDA lesion did not alter H1 receptor binding density in most brain areas, except a trend decrease in the hippocampus (p=0.07) and a trend increase in the cingulate cortex (p=0.06). These results suggested that simvastatin has different effects on the H1 receptors in different rat brain regions depending on the doses. Therefore, simvastatin can modulate histaminergic neurotransmission in the brain, and support the role of H1 receptors in psychoneurological disorders.

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“…It has been reported that NF-κB is involved in chronic neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease [38,39] . NF-κB also plays an important role in neurite outgrowth, synaptogenesis and synaptic plasticity [40] .…”

mentioning

confidence: 99%

Pyrrolidine Dithiocarbamate Alleviated Anxiety in Diabetic Mice

Guang-pin¹

2017

ijps

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Chu, et al.: Antianxiety Potential of Pyrrolidine DithiocarbamateDiabetes is often associated with psychological complications such as anxiety. The aim of this study was to evaluate the effects of pyrrolidine dithiocarbamate on anxiety of streptozotocin-induced diabetic mouse using the open field and the elevated plus maze tests. Confirmed diabetic mice (>16.7 mM/l of blood glucose) were treated with pyrrolidine dithiocarbamate or 0.9% saline for 10 w. After pyrrolidine dithiocarbamate treatment, mice showed a higher percent of time retention and entries in open arms than the diabetic group in the elevated plus maze. However, there were no differences between total distance and average speed in both groups in the open field test. In conclusion, pyrrolidine dithiocarbamate treatment in diabetic mice exerted anxiolytic-like effects. The present study might be suggestive of a novel treatment approach to diabetic anxiety.

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Simvastatin Inhibits the Activation of p21^rasand Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson's Disease

Cited by 157 publications

References 52 publications

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Effects of simvastatin and 6-hydroxydopamine on histaminergic H1 receptor binding density in rat brains

Pyrrolidine Dithiocarbamate Alleviated Anxiety in Diabetic Mice

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Simvastatin Inhibits the Activation of p21rasand Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson's Disease

Cited by 157 publications

References 52 publications

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Splice isoform and pharmacological studies reveal that sterol depletion relocalizes α-synuclein and enhances its toxicity

Effects of simvastatin and 6-hydroxydopamine on histaminergic H1 receptor binding density in rat brains

Pyrrolidine Dithiocarbamate Alleviated Anxiety in Diabetic Mice

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Product

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Simvastatin Inhibits the Activation of p21^rasand Prevents the Loss of Dopaminergic Neurons in a Mouse Model of Parkinson's Disease