Centrally acting drug moxonidine decreases reactive oxygen species via inactivation of the phosphoinositide-3 kinase signaling in the rostral ventrolateral medulla in hypertensive rats

Wang, Yang-Kai; Yu, Qiang; Tan, Xing; Wu, Zhao-Tang; Zhang, Ruwen; Yang, Yi; Wang, Yuan; Hu, Qikuan; Wang, Weizhong

doi:10.1097/hjh.0000000000000887

Cited by 17 publications

(19 citation statements)

References 56 publications

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“…It is reported that the activity of the PI3K/AKT pathway is enhanced in the RVLM of SHR, and the phosphorylation of AKT in the PVN of hypertensive rats is also increased . Recently, we also confirmed that an inactivation of PI3K signaling in the RVLM is involved in antioxidative stress induced by central antihypertensive mechanism . However, the present data does not address the question how ACE2 reduces the production of proinflammatory cytokines via an inactivation of PI3K signaling.…”

Section: Discussioncontrasting

confidence: 70%

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The phosphoinositide‐3 kinase signaling is involved in neuroinflammation in hypertensive rats

et al. 2017

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Section: Discussioncontrasting

confidence: 70%

“…It has been demonstrated that the PI3K signaling in the RVLM is upregulated in hypertension, and its inactivation leads to reduction in reactive oxygen species (ROS) production and cardiovascular function . Moreover, we recently report that gene knockdown of the PI3K subunit p110δ in the RVLM exerts the centrally antihypertensive action .…”

Section: Introductionmentioning

confidence: 96%

The phosphoinositide‐3 kinase signaling is involved in neuroinflammation in hypertensive rats

et al. 2017

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“…This further suggested the relevance of the simultaneous activation of I 1 /I 2 -IRs to dampen neurotoxic signalling induced by KA in mice (especially in the hippocampus). However, and contrary to the observed effect of efaroxan preventing the hypothermic response of moxonidine, the acute inhibitory effects of LSL61122 and moxonidine on hippocampal p35/p25 cleavage were not antagonised by idazoxan (against LSL61122) or by efaroxan (against moxonidine), as it was expected for these commonly used I 2 -or I 1 -IR antagonists (see Cambridge and Robinson, 2005;Edwards and Ernsberger, 2003;Garau et al, 2013;Sánchez-Blázquez et al, 2000;Wang et al, 2016). In fact, idazoxan has previously been shown to inhibit calpaindependent cleavage of spectrin α upon glutamate treatment through reversible blockade of NMDAR-mediated Ca 2+ influx in vitro (Jiang et al, 2010), to induce hypothermia and neuroprotection in an ischemia model in rats (present study; Craven and Conway, 1997) and to modulate immunoreactive IR proteins in the mouse brain (Keller and García-Sevilla, 2015a).…”

Section: Discussionmentioning

confidence: 66%

Inhibitory effects of imidazoline receptor ligands on basal and kainic acid-induced neurotoxic signalling in mice

Keller

Garcı́a-Sevilla

2016

J Psychopharmacol

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This in vivo study assessed the potential of the imidazoline receptor (IR) ligands moxonidine (selective I1-IR), BU224 (selective I2-IR) and LSL61122 (mixed I1/I2-IR) to dampen excitotoxic signalling induced by kainic acid (KA; 45 mg/kg) in the mouse brain (hippocampus and cerebral cortex). KA triggered a strong behavioural syndrome (seizures; maximal at 60-90 minutes) and sustained stimulation (at 72 hours with otherwise normal mouse behaviour) of pro-apoptotic c-Jun-N-terminal kinases (JNK) and calpain with increased cleavage of p35 into neurotoxic p25 (cyclin-dependent kinase 5 [Cdk5] activators) in mouse hippocampus. Pretreatment (five days) with LSL61122 (10 mg/kg), but not moxonidine (1 mg/kg) or BU224 (20 mg/kg), attenuated the KA-induced behavioural syndrome, and all three IR ligands inhibited JNK and calpain activation, as well as p35/p25 cleavage after KA in the hippocampus (effects also observed after acute IR drug treatments). Efaroxan (I1-IR, 10 mg/kg) and idazoxan (I2-IR, 10 mg/kg), postulated IR antagonists, did not antagonise the effects of moxonidine and LSL61122 on KA targets (these IR ligands showed agonistic properties inhibiting pro-apoptotic JNK). Brain subcellular preparations revealed reduced synaptosomal postsynaptic density-95 protein contents (a mediator of JNK activation) and indicated increased p35/Cdk5 complexes (with pro-survival functions) after treatment with moxonidine, BU224 and LSL61122. These results showed that I1- and I2-IR ligands (moxonidine and BU224), and especially the mixed I1/I2-IR ligand LSL61122, are partly neuroprotective against KA-induced excitotoxic signalling. These findings suggest a therapeutic potential of IR drugs in disorders associated with glutamate-mediated neurodegeneration.

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“…Superoxide generation was determined by fluorescent-labelled dihydroethidium (DHE, Molecular Probes) staining as previously described [22,28]. Protein immunofluorescence staining was performed as previously described [21,29].…”

Section: Immunohistochemistry and Immunofluorescence Studiesmentioning

confidence: 99%

“…Measurement of RVLM protein was performed as previously described [28,30]. Briefly, protein extracted from the RVLM was used for measurements of TNF-α, the 67-kDa isoform of glutamate decarboxylase (GAD67), atrial natriuretic peptide (ANP), beta-myosin heavy chain (β-MHC), NAD(P)H oxidase subunit NOX 2 (gp91 phox ) and NOX 4 (Santa Cruz Biotechnology Inc, Santa Cruz, California) expressions by western blot.…”

Section: Western Blottingmentioning

confidence: 99%

Exercise Training Attenuates Proinflammatory Cytokines, Oxidative Stress and Modulates Neurotransmitters in the Rostral Ventrolateral Medulla of Salt-Induced Hypertensive Rats

Huo

et al. 2018

Cell Physiol Biochem

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Background/Aims: Exercise training (ExT) was associated with cardiovascular diseases including hypertension. The rostral ventrolateral medulla (RVLM) is a key region for central control of blood pressure and sympathetic nerve activity. Therefore, this study aimed to investigate the mechanisms within RVLM that can influence exercise training induced effects in salt-induced hypertension. Methods: Male Wistar rats were fed with a normal salt (0.3%) (NS) or a high salt (8%) (HS) diet for 12 weeks to induce hypertension. Then these rats were given moderate-intensity ExT for a period of 12 weeks. RVLM was used to determine glutamate and gamma-aminobutyric acid (HPLC), phosphorylated IKKβ, Fra-LI, 67-kDa isoform of glutamate decarboxylase (GAD67), proinflammatory cytokines (PIC) and NADPH-oxidase (NOX) subunits expression (Immunohistochemistry and Immunofluorescence, Western blotting). PIC and NF-κB p65 activity in the plasma were evaluated by ELISA studies. Renal sympathetic nerve activity (RSNA) was recorded and analyzed using the PowerLab system. Results: High salt diet resulted in increased mean arterial pressure and cardiac hypertrophy. These high salt diet rats had higher RVLM levels of glutamate, PIC, phosphorylated IKKβ, NF-κB p65 activity, Fra-LI, superoxide, NOX-2 (gp91^phox) and 4, and lower RVLM levels of gamma-aminobutyric acid and GAD67, and higher plasma levels of PIC, norepinephrine, and higher RSNA. ExT attenuated these changes in salt-induced hypertensive rats. Conclusions: These findings suggest that high salt diet increases the activity of NF-κB and the levels of PIC and oxidative stress, and induces an imbalance between excitatory and inhibitory neurotransmitters in the RVLM. ExT attenuates hypertension and cardiac hypertrophy partially mediated by attenuating oxidative stress and modulating neurotransmitters in the RVLM.

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Centrally acting drug moxonidine decreases reactive oxygen species via inactivation of the phosphoinositide-3 kinase signaling in the rostral ventrolateral medulla in hypertensive rats

Abstract: The centrally antihypertensive drug moxonidine decreases ROS production in the RVLM through inactivation of the PI3K/Akt signaling pathway in hypertension.

Cited by 17 publications

References 56 publications

The phosphoinositide‐3 kinase signaling is involved in neuroinflammation in hypertensive rats

The phosphoinositide‐3 kinase signaling is involved in neuroinflammation in hypertensive rats

Inhibitory effects of imidazoline receptor ligands on basal and kainic acid-induced neurotoxic signalling in mice

Exercise Training Attenuates Proinflammatory Cytokines, Oxidative Stress and Modulates Neurotransmitters in the Rostral Ventrolateral Medulla of Salt-Induced Hypertensive Rats

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