Lack of Rhes Increases MDMA-Induced Neuroinflammation and Dopamine Neuron Degeneration: Role of Gender and Age

Costa, Giulia; Porceddu, Pier Francesca; Serra, Marcello; Casu, Maria Antonietta; Schiano, Valentina; Napolitano, Francesco; Pinna, Annalisa; Usiello, Alessandro; Morelli, Micaela

doi:10.3390/ijms20071556

Cited by 20 publications

(23 citation statements)

References 62 publications

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“…In agreement with this evidence, recent studies reported that lack of Rhes in mice enhanced the motor stimulation associated to amphetamine 17 , phencyclidine 17 , MDMA 25 administration, suggesting a primary role of this protein in modulating psychostimulants responses.…”

Section: Introductionsupporting

confidence: 73%

The striatal-enriched protein Rhes is a critical modulator of cocaine-induced molecular and behavioral responses

Napolitano

Rosa

Russo

et al. 2019

Sci Rep

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Previous evidence pointed out a role for the striatal-enriched protein Rhes in modulating dopaminergic transmission. Based on the knowledge that cocaine induces both addiction and motor stimulation, through its ability to enhance dopaminergic signaling in the corpus striatum, we have now explored the involvement of Rhes in the effects associated with this psychostimulant. Our behavioral data showed that a lack of Rhes in knockout animals caused profound alterations in motor stimulation following cocaine exposure, eliciting a significant leftward shift in the dose-response curve and triggering a dramatic hyperactivity. We also found that Rhes modulated either short- or long-term motor sensitization induced by cocaine, since lack of this protein prevents both of them in mutants. Consistent with this in vivo observation, we found that lack of Rhes in mice caused a greater increase in striatal cocaine-dependent D1R/cAMP/PKA signaling, along with considerable enhancement of Arc, zif268, and Homer1 mRNA expression. We also documented that lack of Rhes in mice produced cocaine-related striatal alterations in proteomic profiling, with a differential expression of proteins clustering in calcium homeostasis and cytoskeletal protein binding categories. Despite dramatic striatal alterations associated to cocaine exposure, our data did not reveal any significant changes in midbrain dopaminergic neurons as a lack of Rhes did not affect: (i) DAT activity; (ii) D2R-dependent regulation of GIRK; and (iii) D2R-dependent regulation of dopamine release. Collectively, our results strengthen the view that Rhes acts as a pivotal physiological “molecular brake” for striatal dopaminergic system overactivation induced by psychostimulants, thus making this protein of interest in regulating the molecular mechanism underpinning cocaine-dependent motor stimulatory effects.

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Section: Introductionsupporting

confidence: 73%

The striatal-enriched protein Rhes is a critical modulator of cocaine-induced molecular and behavioral responses

Napolitano

Rosa

Russo

et al. 2019

Sci Rep

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“…Accordingly, reserpine-treated female rats did not show any reduction of tyrosine hydroxylase immunoreactivity in the SNc and dorsal striatum compared to males [90]. The lack of Ras homolog enriched in striatum (Rhes), a protein that exert pleiotropic effects on cell function, in KO mice induced a decrease in tyrosine hydroxylase expression in males only, while KO females showed resistance to DA neuron degeneration, which tended to decrease only with aging [91,92]. Interestingly, neuronal loss in male SNc is accompanied by a significant reduction in total ganglioside content, especially neuronal-or synaptic-enriched gangliosides GD1a and GT1b.…”

Section: Dopaminergic Neurodegenerationmentioning

confidence: 93%

Parkinson’s Disease in Women and Men: What’s the Difference?

Cerri¹,

Mus²,

Blandini³

2019

JPD

438

309

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Increasing evidence points to biological sex as an important factor in the development and phenotypical expression of Parkinson's disease (PD). Risk of developing PD is twice as high in men than women, but women have a higher mortality rate and faster progression of the disease. Moreover, motor and nonmotor symptoms, response to treatments and disease risk factors differ between women and men. Altogether, sex-related differences in PD support the idea that disease development might involve distinct pathogenic mechanisms (or the same mechanism but in a different way) in male and female patients. This review summarizes the most recent knowledge concerning differences between women and men in PD clinical features, risk factors, response to treatments and mechanisms underlying the disease pathophysiology. Unraveling how the pathology differently affect the two sexes might allow the development of tailored interventions and the design of innovative programs that meet the distinct needs of men and women, improving patient care.

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“…Cells were sampled with a 40× objective through a defined depth with a guard zone of 2 µm. Coefficients of error ranged from 0.05 to 0.1 (Costa et al, 2017(Costa et al, , 2019a.…”

Section: Stereological Counting Of Th-immunoreactive Neurons In the Sncmentioning

confidence: 99%

Gender Differences in Neurodegeneration, Neuroinflammation and Na+-Ca2+ Exchangers in the Female A53T Transgenic Mouse Model of Parkinson’s Disease

Costa

Sisalli

Simola

et al. 2020

Front. Aging Neurosci.

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Twelve-month-old male mice expressing the human A53T variant of α-synuclein (A53T) develop dopamine neuron degeneration, neuroinflammation, and motor deficits, along with dysfunctions of the mitochondrial Na +-Ca 2+ exchanger (NCX) isoforms 1 (NCX1) and 3 (NCX3) in the nigrostriatal system. Since gender is thought to play a role in the etiology of Parkinson's disease (PD), we characterized neurochemical and behavioral alterations in 12-month-old female A53T transgenic mice. We investigated the presence of dopaminergic degeneration, astrogliosis and microgliosis using immunohistochemistry for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP) and ionized calciumbinding adaptor molecule-1 (IBA-1) in both the substantia nigra pars compacta (SNc) and striatum. In the same regions, we also evaluated the co-localization of NCX1 in cells positive for IBA-1 and the co-localization of NCX3 in TH-positive neurons and fibers. Furthermore, in both male and female mice, we performed motor (beam walking and pole tests) and memory [novel object recognition (NOR) and spontaneous alternation] tasks, together with tests to evaluate peripheral deficits (olfactory and stool collection tests). Female A53T transgenic mice displayed degeneration of nigral dopaminergic neurons, but neither microgliosis nor astrogliosis in the SNc and striatum. Moreover, female A53T transgenic mice displayed co-localization between NCX1 and IBA-1 positive cells in the striatum but not SNc, whereas NCX3 did not co-localize with either TH-positive terminals or neuronal bodies in the nigrostriatal system. Furthermore, female A53T

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Lack of Rhes Increases MDMA-Induced Neuroinflammation and Dopamine Neuron Degeneration: Role of Gender and Age

Cited by 20 publications

References 62 publications

The striatal-enriched protein Rhes is a critical modulator of cocaine-induced molecular and behavioral responses

The striatal-enriched protein Rhes is a critical modulator of cocaine-induced molecular and behavioral responses

Parkinson’s Disease in Women and Men: What’s the Difference?

Gender Differences in Neurodegeneration, Neuroinflammation and Na+-Ca2+ Exchangers in the Female A53T Transgenic Mouse Model of Parkinson’s Disease

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