Rho Kinase and Dopaminergic Degeneration

Labandeira‐Garcia, Jose L.; Rodríguez‐Pérez, Ana I.; Villar-Cheda, Begoña; Borrajo, Ana; Dominguez-Meijide, Antonio; Guerra, María J.

doi:10.1177/1073858414554954

Cited by 39 publications

(35 citation statements)

References 158 publications

(221 reference statements)

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“…Recently, RhoA/ROCK inhibition is suggested as a new neuroprotective strategy for PD. Inhibition of RhoA/ROCK signaling has been reported to activate neuroprotective survival cascades in dopaminergic neurons against Parkinson's toxin (Labandeira-Garcia et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

The novel protective effects of loganin against 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity: Enhancement of neurotrophic signaling, activation of IGF‐1R/GLP‐1R, and inhibition of RhoA/ROCK pathway

Tseng

Lin

Chang

et al. 2018

Phytotherapy Research

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Loganin, a major iridoid glycoside obtained from fruits of Cornus officinalis, possesses anti‐inflammatory, antitumor, antidiabetic, and osteoporosis prevention effects. Loganin has been linked to neuroprotection in several models of neurodegeneration, including Parkinson's disease (PD). However, mechanisms underlying the neuroprotective effects of loganin are still mostly unknown. Here, we demonstrated the protective effects of loganin against PD mimetic toxin 1‐methyl‐4‐phenylpyridinium (MPP+) and the important roles of insulin‐like growth factor 1 receptor (IGF‐1R) and glucagon‐like peptide 1 receptor (GLP‐1R) in the neuroprotective mechanisms of loganin. In primary mesencephalic neuronal cultures treated with or without MPP+, loganin up‐regulated expressions of neurotrophic signals including IGF‐1R, GLP‐1R, p‐Akt, BDNF, and tyrosine hydroxylase. Loganin protected against MPP+‐induced apoptosis by up‐regulating antiapoptotic protein and down‐regulating proapoptotic protein. Moreover, loganin attenuated MPP+‐induced neurite damage via up‐regulation of GAP43 and down‐regulation of membrane‐RhoA/ROCK2/p‐LIMK/p‐cofilin. Loganin also attenuated MPP+‐induced reactive oxygen species (ROS) production. However, both AG1024, an IGF‐1R antagonist, and exendin 9‐39, a GLP‐1R antagonist, attenuated the protective effects of loganin on MPP+‐induced cytotoxicity, apoptosis, neurite length decrease, and ROS production. Our results suggest that loganin attenuates MPP+‐induced apoptotic death, neurite damage, and oxidative stress through enhancement of neurotrophic signaling, activation of IGF‐1R/GLP‐1R, and inhibition of RhoA/ROCK pathway, providing the evidence that loganin possesses novel neuroprotective effects.

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Section: Discussionmentioning

confidence: 99%

The novel protective effects of loganin against 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity: Enhancement of neurotrophic signaling, activation of IGF‐1R/GLP‐1R, and inhibition of RhoA/ROCK pathway

Tseng

Lin

Chang

et al. 2018

Phytotherapy Research

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“…RhoA/ROCK is a major modulator of the actin cytoskeleton, which regulates migration of microglia and other inflammatory cells (Yan et al, 2012; Labandeira-Garcia et al, 2015) into lesioned areas (Greenwood et al, 2003; Honing et al, 2004). RhoA/ROCK induces changes in the actin cytoskeleton necessary for cell motility, process retraction and cell spreading, which characterize activation of inflammatory cells, including microglia (Bernhart et al, 2010).…”

Section: Interactions Between Ras and Other Microglial Polarization Rmentioning

confidence: 99%

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Labandeira‐Garcia

Rodríguez‐Pérez

Garrido‐Gil

et al. 2017

Front. Aging Neurosci.

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192

182

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Microglia can transform into proinflammatory/classically activated (M1) or anti-inflammatory/alternatively activated (M2) phenotypes following environmental signals related to physiological conditions or brain lesions. An adequate transition from the M1 (proinflammatory) to M2 (immunoregulatory) phenotype is necessary to counteract brain damage. Several factors involved in microglial polarization have already been identified. However, the effects of the brain renin-angiotensin system (RAS) on microglial polarization are less known. It is well known that there is a “classical” circulating RAS; however, a second RAS (local or tissue RAS) has been observed in many tissues, including brain. The locally formed angiotensin is involved in local pathological changes of these tissues and modulates immune cells, which are equipped with all the components of the RAS. There are also recent data showing that brain RAS plays a major role in microglial polarization. Level of microglial NADPH-oxidase (Nox) activation is a major regulator of the shift between M1/proinflammatory and M2/immunoregulatory microglial phenotypes so that Nox activation promotes the proinflammatory and inhibits the immunoregulatory phenotype. Angiotensin II (Ang II), via its type 1 receptor (AT1), is a major activator of the NADPH-oxidase complex, leading to pro-oxidative and pro-inflammatory effects. However, these effects are counteracted by a RAS opposite arm constituted by Angiotensin II/AT2 receptor signaling and Angiotensin 1–7/Mas receptor (MasR) signaling. In addition, activation of prorenin-renin receptors may contribute to activation of the proinflammatory phenotype. Aged brains showed upregulation of AT1 and downregulation of AT2 receptor expression, which may contribute to a pro-oxidative pro-inflammatory state and the increase in neuron vulnerability. Several recent studies have shown interactions between the brain RAS and different factors involved in microglial polarization, such as estrogens, Rho kinase (ROCK), insulin-like growth factor-1 (IGF-1), tumor necrosis factor α (TNF)-α, iron, peroxisome proliferator-activated receptor gamma, and toll-like receptors (TLRs). Metabolic reprogramming has recently been involved in the regulation of the neuroinflammatory response. Interestingly, we have recently observed a mitochondrial RAS, which is altered in aged brains. In conclusion, dysregulation of brain RAS plays a major role in aging-related changes and neurodegeneration by exacerbation of oxidative stress (OS) and neuroinflammation, which may be attenuated by pharmacological manipulation of RAS components.

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“…In PD models, several studies using different approaches of ROCK inhibition have been published (reviewed in Labandeira-Garcia et al, 2015). In a medium severe subchronic MPTP mouse model of PD (30 mg/kg body weight for five consecutive days) oral treatment with Fasudil led to protection of nigral dopaminergic neurons and preservation of the nigrostriatal projections, resulting in an improved motor performance (Tönges et al, 2012).…”

Section: Rock Inhibition As a Treatment Option For Pd And Alsmentioning

confidence: 99%

Modulation of Microglial Activity by Rho-Kinase (ROCK) Inhibition as Therapeutic Strategy in Parkinson’s Disease and Amyotrophic Lateral Sclerosis

Roser

Tönges

Lingor

2017

Front. Aging Neurosci.

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Neurodegenerative diseases are characterized by the progressive degeneration of neurons in the central and peripheral nervous system (CNS, PNS), resulting in a reduced innervation of target structures and a loss of function. A shared characteristic of many neurodegenerative diseases is the infiltration of microglial cells into affected brain regions. During early disease stages microglial cells often display a rather neuroprotective phenotype, but switch to a more pro-inflammatory neurotoxic phenotype in later stages of the disease, contributing to the neurodegeneration. Activation of the Rho kinase (ROCK) pathway appears to be instrumental for the modulation of the microglial phenotype: increased ROCK activity in microglia mediates mechanisms of the inflammatory response and is associated with improved motility, increased production of reactive oxygen species (ROS) and release of inflammatory cytokines. Recently, several studies suggested inhibition of ROCK signaling as a promising treatment option for neurodegenerative diseases. In this review article, we discuss the contribution of microglial activity and phenotype switch to the pathophysiology of Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS), two devastating neurodegenerative diseases without disease-modifying treatment options. Furthermore, we describe how ROCK inhibition can influence the microglial phenotype in disease models and explore ROCK inhibition as a future treatment option for PD and ALS.

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Rho Kinase and Dopaminergic Degeneration

Cited by 39 publications

References 158 publications

The novel protective effects of loganin against 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity: Enhancement of neurotrophic signaling, activation of IGF‐1R/GLP‐1R, and inhibition of RhoA/ROCK pathway

The novel protective effects of loganin against 1‐methyl‐4‐phenylpyridinium‐induced neurotoxicity: Enhancement of neurotrophic signaling, activation of IGF‐1R/GLP‐1R, and inhibition of RhoA/ROCK pathway

Brain Renin-Angiotensin System and Microglial Polarization: Implications for Aging and Neurodegeneration

Modulation of Microglial Activity by Rho-Kinase (ROCK) Inhibition as Therapeutic Strategy in Parkinson’s Disease and Amyotrophic Lateral Sclerosis

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