Involvement of microglial RhoA/Rho-Kinase pathway activation in the dopaminergic neuron death. Role of angiotensin via angiotensin type 1 receptors

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

doi:10.1016/j.nbd.2012.04.010

Cited by 90 publications

(89 citation statements)

References 75 publications

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“…Regardless of the underlying mechanism, neuroprotective effects of ROCK inhibitors from various neuronal injuries have been reported. 38,39 In the present study, ROCK inhibitor downregulated cyclin D1, CDK4 and LIMK2 expression induced by SE via enhanced p27 Kip1 expression. Furthermore, elevated p27 Kip1 expression by DOX prevented SE-induced neuronal death.…”

Section: Discussionsupporting

confidence: 50%

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

et al. 2014

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Although the aberrant activation of cell cycle proteins has a critical role in neuronal death, effectors or mediators of cyclin D1/ cyclin-dependent kinase 4 (CDK4)-mediated death signal are still unknown. Here, we describe a previously unsuspected role of LIM kinase 2 (LIMK2) in programmed necrotic neuronal death. Downregulation of p27 Kip1 expression by Rho kinase (ROCK) activation induced cyclin D1/CDK4 expression levels in neurons vulnerable to status epilepticus (SE). Cyclin D1/CDK4 complex subsequently increased LIMK2 expression independent of caspase-3 and receptor interacting protein kinase 1 activity. In turn, upregulated LIMK2 impaired dynamic-related protein-1 (DRP1)-mediated mitochondrial fission without alterations in cofilin phosphorylation/expression and finally resulted in necrotic neuronal death. Inhibition of LIMK2 expression and rescue of DRP1 function attenuated this programmed necrotic neuronal death induced by SE. Therefore, we suggest that the ROCK-p27 Kip1 -cyclin D1/CDK4-LIMK2-DRP1-mediated programmed necrosis may be new therapeutic targets for neuronal death. The cell cycle is essential for a vital process, including proliferation, differentiation and survival of various cells. Cell cycle progression is regulated by two classes of proteins, the cyclins and the cyclin-dependent kinases (CDKs). Among them, cyclin D1 forms a complex with CDK4 and inactivates retinoblastoma protein (Rb) through phosphorylation resulting in activating E2 promoter-binding factor (E2F) family of transcription factors. Active E2F induces various gene transcriptions involving the cell cycle. 1 In post-mitotic neurons, some pathological conditions upregulate cyclin D1/CDK4 complex expression to induce activation of E2F members that contributes to increased transcription of proapoptotic molecules. 2,3 However, it is unclear whether cyclin D1 expression directly induces neuronal death for a number of following reasons. First, due to a time lag between cyclin D1/CDK4 expression and the onset of DNA fragmentation, most cyclin D1-positive neurons show TUNEL negativity. 4,5 Second, cyclin D1 level is unaltered in cultured embryonic neurons following apoptosis induction. 6 Third, Rb phosphorylation is rarely observed in vivo, 4 although cyclin D1/CDK4 complex phosphorylates Rb protein in apoptotic cultured neurons. 6 Fourth, cyclin D1 induction following ischemia is associated with regeneration and resistance to apoptosis rather than a mediator of apoptosis. 5,7,8 Fifth, effectors or mediators of cyclin D1/CDK4-mediated death signal are still unknown. Finally, neuronal death induced by various insults is morphologically necrotic rather than apoptotic. 9-12 Therefore, it is likely that some essential factors are missing in the cyclin D/CDK4-mediated neuronal death pathway.LIM kinases (LIMK1 and LIMK2) phosphorylate cofilin that is a stimulus-responsive mediator of actin dynamics. [13][14][15] Interestingly, non-phosphorylated cofilin targets mitochondrial membranes in response to apoptotic stimuli for cytochrome c releas...

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Section: Discussionsupporting

confidence: 50%

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

et al. 2014

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“…Interestingly, we also observed a significant increase in AT1 (and decrease in AT2) receptor expression, which may be related to a feedback mechanism for regulating levels of brain angiotensinogen (O'Callaghan et al, 2011) or to induction of further proinflammatory changes in astrocytes (Clark et al, 2008;Lanz et al, 2010). An increase in AII levels has been shown to increase oxidative stress in neurons (Joglar et al, 2009;Zawada et al, 2011) and to enhance the microglial neuroinflammatory response (Rodriguez-Pallares et al, 2008;Villar-Cheda et al, 2012). Furthermore, in the present study, we observed that estrogen, via ER-a, also induces direct neuroprotection of dopaminergic neurons; thus, in cultures of the dopaminergic neuron cell line (i.e., in the absence of glia), the ER-a agonist PPT inhibits the loss of dopaminergic cells induced by MPP þ and MPP þ þ AII, possibly by inhibition of neuronal oxidative stress and apoptosis (Brendel et al, 2013;Wang et al, 2012).…”

Section: Discussionmentioning

confidence: 60%

Critical period for dopaminergic neuroprotection by hormonal replacement in menopausal rats

Rodríguez‐Pérez

Borrajo

Valenzuela

et al. 2015

Neurobiology of Aging

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“…It has been demonstrated that Rho/ROCK signaling pathway plays important roles in various cardio-cerebral vascular diseases through its cell-mediated signal transduction system (Koumura et al 2011;Raad et al 2012;Villar-Cheda et al 2012;Inan and Büyükafşar 2008;Fukata et al 2001;Tcherkezian and Lamarche-vane 2007;Harvey et al 2010;Gao et al 2013;Yan et al 2015). Previous studies had shown that, a number of abnormal activations of the Rho/Rock signaling pathway are present in the endothelium following cerebral ischemia, finally resulting in endothelial dysfunction and microcirculatory disturbance (Gibson et al 2014;Takemoto et al 2002;Yagita et al 2007).…”

Section: Discussionmentioning

confidence: 99%

“…The Rho/Rho-kinase (Rho-associated kinases, ROCK) signaling pathway is one of the most widely studied cell signaling pathways recently that plays important roles in the pathogenesis of several nervous system disorders, such as stroke (Koumura et al 2011), Alzheimer's disease (Raad et al 2012), Parkinson's disease (Villar-Cheda et al 2012), and chronic pain (Inan and Büyükafşar 2008). A wide range of functions have been reported for this pathway, both in the normal nervous system and in brain pathology.…”

Section: Introductionmentioning

confidence: 99%

Tetramethylpyrazine Protects Against Oxygen-Glucose Deprivation-Induced Brain Microvascular Endothelial Cells Injury via Rho/Rho-kinase Signaling Pathway

et al. 2016

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Tetramethylpyrazine (TMP, also known as Ligustrazine), which is isolated from Chinese Herb Medicine Ligustium wollichii Franchat (Chuan Xiong), has been widely used in China for the treatment of ischemic stroke by Chinese herbalists. Brain microvascular endothelial cells (BMECs) are the integral parts of the blood-brain barrier (BBB), protecting BMECs against oxygen-glucose deprivation (OGD) which is important for the treatment of ischemic stroke. Here, we investigated the protective mechanisms of TMP, focusing on OGD-injured BMECs and the Rho/Rho-kinase (Rho-associated kinases, ROCK) signaling pathway. The model of OGD-injured BMECs was established in this study. BMECs were identified by von Willebrand factor III staining and exposed to fasudil, or TMP at different concentrations (14.3, 28.6, 57.3 µM) for 2 h before 24 h of OGD injury. The effect of each treatment was examined by cell viability assays, measurement of intracellular reactive oxygen species (ROS), and transendothelial electric resistance and western blot analysis (caspase-3, endothelial nitric oxide synthase (eNOS), RhoA, Rac1). Our results show that TMP significantly attenuated apoptosis and the permeability of BMECs induced by OGD. In addition, TMP could notably down-regulate the characteristic proteins in Rho/ROCK signaling pathway such as RhoA and Rac1, which triggered abnormal changes of eNOS and ROS, respectively. Altogether, our results show that TMP has a strong protective effect against OGD-induced BMECs injury and suggest that the mechanism might be related to the inhibition of the Rho/ROCK signaling pathway.

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Involvement of microglial RhoA/Rho-Kinase pathway activation in the dopaminergic neuron death. Role of angiotensin via angiotensin type 1 receptors

Cited by 90 publications

References 75 publications

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

Critical period for dopaminergic neuroprotection by hormonal replacement in menopausal rats

Tetramethylpyrazine Protects Against Oxygen-Glucose Deprivation-Induced Brain Microvascular Endothelial Cells Injury via Rho/Rho-kinase Signaling Pathway

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