Antihypertensive and neuroprotective activities of rhynchophylline: The role of rhynchophylline in neurotransmission and ion channel activity

Zhou, Jiyin; Zhou, Shiwen

doi:10.1016/j.jep.2010.08.041

Cited by 127 publications

(80 citation statements)

References 19 publications

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“…S8A), was identified as one of the top three compounds that bind to EphA4 with the lowest docking energies. Rhy is the major alkaloid constituent of Uncaria rhynchophylla (Miq) Jack (UR), a Chinese medicinal herb commonly used in formulas targeting central nervous system diseases (34). Nonetheless, the clinical applications of Rhy in neurodegenerative diseases such as AD have not been investigated.…”

Section: Blockade Of Epha4 Signaling Reverses the Impaired Hippocampalmentioning

confidence: 99%

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

Hung

Huang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

166

180

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Alzheimer's disease (AD), characterized by cognitive decline, has emerged as a disease of synaptic failure. The present study reveals an unanticipated role of erythropoietin-producing hepatocellular A4 (EphA4) in mediating hippocampal synaptic dysfunctions in AD and demonstrates that blockade of the ligand-binding domain of EphA4 reverses synaptic impairment in AD mouse models. Enhanced EphA4 signaling was observed in the hippocampus of amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD, whereas soluble amyloid-β oligomers (Aβ), which contribute to synaptic loss in AD, induced EphA4 activation in rat hippocampal slices. EphA4 depletion in the CA1 region or interference with EphA4 function reversed the suppression of hippocampal long-term potentiation in APP/PS1 transgenic mice, suggesting that the postsynaptic EphA4 is responsible for mediating synaptic plasticity impairment in AD. Importantly, we identified a smallmolecule rhynchophylline as a novel EphA4 inhibitor based on molecular docking studies. Rhynchophylline effectively blocked the EphA4-dependent signaling in hippocampal neurons, and oral administration of rhynchophylline reduced the EphA4 activity effectively in the hippocampus of APP/PS1 transgenic mice. More importantly, rhynchophylline administration restored the impaired long-term potentiation in transgenic mouse models of AD. These findings reveal a previously unidentified role of EphA4 in mediating AD-associated synaptic dysfunctions, suggesting that it is a new therapeutic target for this disease.Abeta | receptor tyrosine kinase | ephrin | drug discovery

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Section: Blockade Of Epha4 Signaling Reverses the Impaired Hippocampalmentioning

confidence: 99%

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

Hung

Huang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

166

180

View full text Add to dashboard Cite

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“…1) is an important active tetracyclic oxindole alkaloid isolated from Uncaria rhynchophylla which is a traditional Chinese medicine and often used to treat central nervous system illnesses such as hypertension, convulsions, tremor, stroke etc. [13,14]. Furthermore, ethanol extract of Uncaria was found to improve the cognitive impairment of AD [15].…”

Section: Introductionmentioning

confidence: 99%

Rhynchophylline Protects Against the Amyloid β-Induced Increase of Spontaneous Discharges in the Hippocampal CA1 Region of Rats

Shao

et al. 2015

Neurochem Res

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Accumulated soluble amyloid β (Aβ)-induced aberrant neuronal network activity has been recognized as a key causative factor leading to cognitive deficits which are the most outstanding characteristic of Alzheimer's disease (AD). As an important structure associated with learning and memory, the hippocampus is one of the brain regions that are impaired very early in AD, and the hippocampal CA1 region is selectively vulnerable to soluble Aβ oligomers. Our recent study showed that soluble Aβ1-42 oligomers induced hyperactivity and perturbed the firing patterns in hippocampal neurons. Rhynchophylline (RIN) is an important active tetracyclic oxindole alkaloid isolated from Uncaria rhynchophylla which is a traditional Chinese medicine and often used to treat central nervous system illnesses such as hypertension, convulsions, tremor, stroke etc. Previous evidence showed that RIN possessed neuroprotective effects of improving the cognitive function of mice with Alzheimer-like symptoms. In the present study, we aimed to investigate the protective effect of RIN against soluble Aβ1-42 oligomers-induced hippocampal hyperactivity. The results showed that (1) the mean frequency of spontaneous discharge was increased by the local application of 3 μM soluble Aβ1-42 oligomers; (2) 30 μM RIN did not exert any obvious effects on basal physiological discharges; and (3) treatment with RIN effectively inhibited the soluble Aβ1-42 oligomers-induced enhancement of spontaneous discharge, in a concentration-dependent manner with an IC50 = 9.0 μM. These in vivo electrophysiological results indicate that RIN can remold the spontaneous discharges disturbed by Aβ and counteract the deleterious effect of Aβ1-42 on neural circuit. The experimental findings provide further evidence to affirm the potential of RIN as a worthy candidate for further development into a therapeutic agent for AD.

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“…Rhynchophylline, an alkaloid constituent of Uncaria species, was supposed to induce an anti-hypertensive effect through mechanisms related to the modulation of calcium and potassium ion channels. 24) Furthermore, the extract of Uncaria prevented learning deficits induced by the transient occlusion of bilateral carotid arteries. 25) In this study, SKT exerted slight suppression of urinary protein as compared with the significant reduction of blood pressure and with the significant protective effect against histological injury.…”

Section: Discussionmentioning

confidence: 95%

Protective Effects of Shichimotsu-koka-To on Irreversible Thy-1 Nephritis

Ono

Kamikado

Morimoto

2013

Biological & Pharmaceutical Bulletin

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Oxidative stress and peritubular capillary (PTC) injury are involved in the progression of chronic kidney disease (CKD). We investigated protective effects of Shichimotsu-koka-To (SKT), a Japanese traditional Kampo prescription, against nephrosclerosis and hypertension on a CKD model due to irreversible nephritis. Six-week-old male Wistar rats were subjected to uninephrectomy, and to injection of rabbit anti-thymocyte serum. SKT treatment was continued for 15 weeks, blood pressure was measured, and then renal specimens were collected. PTC networks were detected by immunostaining for CD-31. And superoxide dismutase (SOD)-like activity in the tissue was evaluated. Blood pressure in the SKT group, as well as sham group, was significantly lower than with the vehicle. SKT markedly ameliorated renal function, which was evaluated with urea nitrogen clearance. Compared with the vehicle, SKT treatment lowered both the glomerular enlargement and hyper-cellularity by 80%, and decreased the extracellular matrix area by 75%. SKT treatment also suppressed tubular injury, and maintained PTC networks. Furthermore, SKT recovered SOD-like activity to the basal levels. These results suggest that SKT may be useful for the treatment of CKD during the progression to nephrosclerosis, through the mechanisms of anti-oxidative activity and maintenance of PTC networks.Key words hypertension; glomerular hypertrophy; peritubular capillary; chronic kidney disease; oxidative stressThe number of patients with end-stage renal failure undergoing dialysis is increasing worldwide. Recently, it has been accepted that patients with chronic kidney disease (CKD) also develop cardiovascular diseases, with increased risks of death, cardiovascular events, and hospitalization. 1) Improvement of the clinical outcomes of CKD patients is therefore important. In Japan, chronic glomerulonephritis and nephrosclerosis are major causes of renal failure after diabetic nephropathy, which is the most common cause.2) Hypertension is an important symptom which influences the outcome of CKD, and angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin II receptor blockers (ARBs) are beneficial to protect against renal injury in CKD.3)The herbal formula Shichimotsu-koka-To (SKT; Table 1) has occasionally been prescribed to treat hypertensive patients. 4)SKT was used for non-obesity hypertensive patients, and those complaining of the sensation of a rush of blood to the head, shoulder stiffness, tinnitus, and dull headache; however, in the last two or three decades, abundant new strong antihypertensive drugs have become available, and SKT has been used less. Recently, reevaluation of SKT treatment in combination with ACE-Is/ARBs drugs in CKD has begun. 5) In basic studies, SKT had an anti-hypertensive effect in Dahl strain rats.6) Enhanced serum NO x levels, and anti-oxidant activity through increasing superoxide dismutase (SOD)-like activity in the kidney by SKT were reported. 7,8) Previously, in a rat model of hypertensive nephrosclerosis induced by 5/6 nephrec...

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Antihypertensive and neuroprotective activities of rhynchophylline: The role of rhynchophylline in neurotransmission and ion channel activity

Cited by 127 publications

References 19 publications

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

Blockade of EphA4 signaling ameliorates hippocampal synaptic dysfunctions in mouse models of Alzheimer’s disease

Rhynchophylline Protects Against the Amyloid β-Induced Increase of Spontaneous Discharges in the Hippocampal CA1 Region of Rats

Protective Effects of Shichimotsu-koka-To on Irreversible Thy-1 Nephritis

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