Rho-inhibition and neuroprotective effect on rotenone-treated dopaminergic neurons in vitro

Mattii, Letizia; Pardini, Carla; Ippolito, Chiara; Bianchi, Francesco; Sabbatini, Antonietta Raffaella Maria; Vaglini, Francesca

doi:10.1016/j.neuro.2019.02.006

Cited by 8 publications

(7 citation statements)

References 32 publications

(38 reference statements)

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“…Furthermore, in previous studies, a potent mitochondrial complex I inhibitor upregulated Cx43 expression in astrocytes of a Parkinson's disease animal model and dopaminergic neurons [63,64]. However, inhibition of RhoA using C3 inhibited Cx43 upregulation by mitochondrial complex inhibitors [63], suggesting that RhoA activity affects Cx43 expression and hemichannel function in neurodegenerative diseases. Interestingly, our study also found that the interaction between RhoA and Cx43 was increased in models of prion disease (Figures 4 and 5).…”

Section: Discussionmentioning

confidence: 89%

“…In addition, various Cx43-interacting proteins are responsible for the development of several human diseases, among which RhoA has been previously reported to differ between healthy and osteoarthritis samples [35]. Furthermore, in previous studies, a potent mitochondrial complex I inhibitor upregulated Cx43 expression in astrocytes of a Parkinson's disease animal model and dopaminergic neurons [63,64]. However, inhibition of RhoA using C3 inhibited Cx43 upregulation by mitochondrial complex inhibitors [63], suggesting that RhoA activity affects Cx43 expression and hemichannel function in neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 93%

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RhoA/ROCK Regulates Prion Pathogenesis by Controlling Connexin 43 Activity

Kim

Mostafa

et al. 2020

IJMS

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Scrapie infection, which converts cellular prion protein (PrPC) into the pathological and infectious isoform (PrPSc), leads to neuronal cell death, glial cell activation and PrPSc accumulation. Previous studies reported that PrPC regulates RhoA/Rho-associated kinase (ROCK) signaling and that connexin 43 (Cx43) expression is upregulated in in vitro and in vivo prion-infected models. However, whether there is a link between RhoA/ROCK and Cx43 in prion disease pathogenesis is uncertain. Here, we investigated the role of RhoA/ROCK signaling and Cx43 in prion diseases using in vitro and in vivo models. Scrapie infection induced RhoA activation, accompanied by increased phosphorylation of LIM kinase 1/2 (LIMK1/2) at Thr508/Thr505 and cofilin at Ser3 and reduced phosphorylation of RhoA at Ser188 in hippocampal neuronal cells and brains of mice. Scrapie infection-induced RhoA activation also resulted in PrPSc accumulation followed by a reduction in the interaction between RhoA and p190RhoGAP (a GTPase-activating protein). Interestingly, scrapie infection significantly enhanced the interaction between RhoA and Cx43. Moreover, RhoA and Cx43 colocalization was more visible in both the membrane and cytoplasm of scrapie-infected hippocampal neuronal cells than in controls. Finally, RhoA and ROCK inhibition reduced PrPSc accumulation and the RhoA/Cx43 interaction, leading to decreased Cx43 hemichannel activity in scrapie-infected hippocampal neuronal cells. These findings suggest that RhoA/ROCK regulates Cx43 activity, which may have an important role in the pathogenesis of prion disease.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 93%

RhoA/ROCK Regulates Prion Pathogenesis by Controlling Connexin 43 Activity

Kim

Mostafa

et al. 2020

IJMS

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“…Rotenone is a very potent toxin in the low nanomolar range for several neuronal cell lines, such as SH-SY5Y and PC-12 and for primary mesencephalic dopaminergic neurons [ 38 , 39 ]. In other studies, rotenone was used on β-cells as an inhibitor of mitochondrial activity; however, its toxicity was not analyzed systematically and the IC 50 for viability was not determined [ 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

β-Cells Different Vulnerability to the Parkinsonian Neurotoxins Rotenone, 1-Methyl-4-phenylpyridinium (MPP+) and 6-Hydroxydopamine (6-OHDA)

et al. 2021

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Neurotoxins such as rotenone, 1-methyl-4-phenylpyridinium (MPP+) and 6-hydroxydopamine (6-OHDA) are well known for their high toxicity on dopaminergic neurons and are associated with Parkinson’s disease (PD) in murine models and humans. In addition, PD patients often have glucose intolerance and may develop type 2 diabetes (T2D), whereas T2D patients have higher risk of PD compared to general population. Based on these premises, we evaluated the toxicity of these three toxins on pancreatic β-cell lines (INS-1 832/13 and MIN6) and we showed that rotenone is the most potent for reducing β-cells viability and altering mitochondrial structure and bioenergetics in the low nanomolar range, similar to that found in dopaminergic cell lines. MPP+ and 6-OHDA show similar effects but at higher concentration. Importantly, rotenone-induced toxicity was counteracted by α-tocopherol and partially by metformin, which are endowed with strong antioxidative and cytoprotective properties. These data show similarities between dopaminergic neurons and β-cells in terms of vulnerability to toxins and pharmacological agents capable to protect both cell types.

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“…Statins are inhibitors of HMG-CoA reductase -the ratelimiting enzyme in cholesterol biosynthesis -but they have also exhibited neuroprotective properties, particularly in terms of the CNS-penetrant statin, simvastatin (Tong et al, 2018;Yan et al, 2018;Mattii et al, 2019;Simchovitz et al, 2019;Hanan et al, 2020;reviewed in Carroll and Wyse, 2017). It was also recently suggested that simvastatin treatment can reduce the risk of developing progressive supranuclear palsy and potentially delaying onset of symptoms (Bayram et al, 2020).…”

Section: Simvastatinmentioning

confidence: 99%

Drug Repurposing for Parkinson’s Disease: The International Linked Clinical Trials experience

2021

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The international Linked Clinical Trials (iLCT) program for Parkinson’s to date represents one of the most comprehensive drug repurposing programs focused on one disease. Since initial planning in 2010, it has rapidly grown – giving rise to seven completed, and 15 ongoing, clinical trials of 16 agents each aimed at delivering disease modification in Parkinson’s disease (PD). In this review, we will provide an overview of the history, structure, process, and progress of the program. We will also present some examples of agents that have been selected and prioritized by the program and subsequently evaluated in clinical trials. Our goal with this review is to provide a template that can be considered across other therapeutic areas.

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Rho-inhibition and neuroprotective effect on rotenone-treated dopaminergic neurons in vitro

Cited by 8 publications

References 32 publications

RhoA/ROCK Regulates Prion Pathogenesis by Controlling Connexin 43 Activity

RhoA/ROCK Regulates Prion Pathogenesis by Controlling Connexin 43 Activity

β-Cells Different Vulnerability to the Parkinsonian Neurotoxins Rotenone, 1-Methyl-4-phenylpyridinium (MPP+) and 6-Hydroxydopamine (6-OHDA)

Drug Repurposing for Parkinson’s Disease: The International Linked Clinical Trials experience

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