Development of telmisartan in the therapy of spinal cord injury: pre-clinical study in rats

Lin, Chien-Min; Tsai, Jui Chen; Chang, Che-Jung; Lin, Jia‐Wei

doi:10.2147/dddt.s86616

Cited by 7 publications

(6 citation statements)

References 52 publications

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“…Telmisartan showed to increase level of ~40 kDa PPAR-β/δ expression after spinal cord injury, which was associated with beneficial effects manifested by improved motor function and pain responses. 45 Consistent with this finding, increased level of nuclear ~40 kDa PPAR-β/δ in our study was accompanied by improved performance in rotarod test assessing motor function. This protective mechanism in SCI may be mediated through phosphorylation of 5' AMP-activated protein kinase (AMPK).…”

Section: Discussionsupporting

confidence: 91%

“…This protective mechanism in SCI may be mediated through phosphorylation of 5' AMP-activated protein kinase (AMPK). 45 The action of telmisartan was inhibited by a blockade of the receptor with GSK0660, which resulted in decrease of PPAR-β/δ expression level. Those results suggest, that the restoration of ~40 kDa PPAR-β/δ expression was responsible for therapeutic potential of telmisartan in rats with SCI.…”

Section: Discussionmentioning

confidence: 99%

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Role of PPAR-β/δ/miR-17/TXNIP pathway in neuronal apoptosis after neonatal hypoxic-ischemic injury in rats

et al. 2018

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Activation of peroxisome proliferator-activated receptor beta/delta (PPAR-β/δ), a nuclear receptor acting as a transcription factor, was shown to be protective in various models of neurological diseases. However, there is no information about the role of PPAR-β/δ as well as its molecular mechanisms in neonatal hypoxia-ischemia (HI). In the present study, we hypothesized that PPAR-β/δ agonist GW0742 can activate miR-17-5p, consequently inhibiting TXNIP and ASK1/p38 pathway leading to attenuation of apoptosis. Ten-day-old rat pups were subjected to right common carotid artery ligation followed by 2.5 h hypoxia. GW0742 was administered intranasally 1 and 24 h post HI. PPAR-β/δ receptor antagonist GSK3787 was administered intranasally 1 h before and 24 h after HI, antimir-17-5p and TXNIP CRISPR activation plasmid were administered intracerebroventricularly 24 and 48 h before HI, respectively. Brain infarct area measurement, neurological function tests, western blot, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Fluoro-Jade C and immunofluorescence staining were conducted. GW0742 reduced brain infarct area, brain atrophy, apoptosis, and improved neurological function at 72 h and 4 weeks post HI. Furthermore, GW0742 treatment increased PPAR-β/δ nuclear expression and miR-17-5p level and reduced TXNIP in ipsilateral hemisphere after HI, resulting in inhibition of ASK1/p38 pathway and attenuation of apoptosis. Inhibition of PPAR-β/δ receptor and miR-17-5p and activation of TXNIP reversed the protective effects. For the first time, we provide evidence that intranasal administration of PPAR-β/δ agonist GW0742 attenuated neuronal apoptosis at least in part via PPAR-β/δ/miR-17/TXNIP pathway. GW0742 could represent a therapeutic target for treatment of neonatal hypoxic ischemic encephalopathy (HIE).

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Role of PPAR-β/δ/miR-17/TXNIP pathway in neuronal apoptosis after neonatal hypoxic-ischemic injury in rats

et al. 2018

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“…In addition, TEL-induced stimulation of I Na was not accounted for by either binding to AT1 receptors or activation of PPAR-γ (Mogi et al, 2008). In this scenario, it is therefore possible that TEL confers protection against ischemic or traumatic brain damage possibly as a result of its activation of Na V channels, independent of its agonistic effects on PPAR-γ activity (Mogi et al, 2008;Wang et al, 2014;Kono et al, 2015;Lin et al, 2015;Villapol et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…It has been observed that TEL ameliorates impaired cognitive functions (Mogi et al, 2008;Du et al, 2014;Haruyama et al, 2014) and is beneficial for traumatic or ischemic brain injuries (Łukawski et al, 2014;Wang et al, 2014;Kono et al, 2015;Lin et al, 2015;Villapol et al, 2015) although the underlying mechanism has not been fully elucidated. To what extent this compound perturbs ion-channel activity and neuronal excitability in hippocampal neurons remains largely unclear.…”

Section: Introductionmentioning

confidence: 99%

Telmisartan, an Antagonist of Angiotensin II Receptors, Accentuates Voltage-Gated Na+ Currents and Hippocampal Neuronal Excitability

Lai

Huang

2020

Front. Neurosci.

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Telmisartan (TEL), a non-peptide blocker of the angiotensin II type 1 receptor, is a widely used antihypertensive agent. Nevertheless, its neuronal ionic effects and how they potentially affect neuronal network excitability remain largely unclear. With the aid of patch-clamp technology, the effects of TEL on membrane ion currents present in hippocampal neurons (mHippoE-14 cells) were investigated. For additional characterization of the effects of TEL on hippocampal neuronal excitability, we undertook in vivo studies on Sprague Dawley (SD) rats using pilocarpine-induced seizure modeling, a hippocampal histopathological analysis, and inhibitory avoidance testing. In these hippocampal neurons, TEL increased the peak amplitude of I Na , with a concomitant decline in the current inactivation rate. The TEL concentration dependently enhanced the peak amplitude of depolarization-elicited I Na and lessened the inactivation rate of I Na. By comparison, TEL was more efficacious in stimulating the peak I Na and in prolonging the inactivation time course of this current than tefluthrin or (-)-epicatechin-3-gallate. In the continued presence of pioglitazone, the TEL-perturbed stimulation of I Na remained effective. In addition, cell exposure to TEL shifted the steady-state inactivation I Na curve to fewer negative potentials with no perturbations of the slope factor. Unlike chlorotoxin, either ranolazine, eugenol, or KMUP-1 reversed TEL-mediated increases in the strength of non-inactivating I Na. In the cell-attached voltage-clamp recordings, TEL shortened the latency in the generation of action currents. Meanwhile, TEL increased the peak I Na , with a concurrent decrease in current inactivation in HEKT293T cells expressing SCN5A. Furthermore, although TEL did not aggravate pilocarpine-induced chronic seizures and tended to preserve cognitive performance, it significantly accentuated hippocampal mossy fiber sprouting. Collectively, TEL stimulation of peak I Na in combination with an apparent retardation in current inactivation could be an important mechanism through which hippocampal neuronal excitability is increased, and hippocampal network excitability is accentuated following status epilepticus, suggesting further attention to this finding.

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“…The analgesic and anti-inflammatory effects of telmisartan have been evaluated in preclinical studies of different types of neuropathic pain [65][66][67][68]. The main mechanism underlying these effects is partial activation of PPAR-γ receptors [65,66,68], but according to one study, telmisartan reduced thermal and mechanical hypersensitivity by inhibiting CYP2J2 [67].…”

Section: Discussionmentioning

confidence: 99%

In Silico Drug Repurposing Framework Predicts Repaglinide, Agomelatine and Protokylol as TRPV1 Modulators with Analgesic Activity

et al. 2022

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Pain is one of the most common symptoms experienced by patients. The use of current analgesics is limited by low efficacy and important side effects. Transient receptor potential vanilloid-1 (TRPV1) is a non-selective cation channel, activated by capsaicin, heat, low pH or pro-inflammatory agents. Since TRPV1 is a potential target for the development of novel analgesics due to its distribution and function, we aimed to develop an in silico drug repositioning framework to predict potential TRPV1 ligands among approved drugs as candidates for treating various types of pain. Structures of known TRPV1 agonists and antagonists were retrieved from ChEMBL databases and three datasets were established: agonists, antagonists and inactive molecules (pIC50 or pEC50 < 5 M). Structures of candidates for repurposing were retrieved from the DrugBank database. The curated active/inactive datasets were used to build and validate ligand-based predictive models using Bemis–Murcko structural scaffolds, plain ring systems, flexophore similarities and molecular descriptors. Further, molecular docking studies were performed on both active and inactive conformations of the TRPV1 channel to predict the binding affinities of repurposing candidates. Variables obtained from calculated scaffold-based activity scores, molecular descriptors criteria and molecular docking were used to build a multi-class neural network as an integrated machine learning algorithm to predict TRPV1 antagonists and agonists. The proposed predictive model had a higher accuracy for classifying TRPV1 agonists than antagonists, the ROC AUC values being 0.980 for predicting agonists, 0.972 for antagonists and 0.952 for inactive molecules. After screening the approved drugs with the validated algorithm, repaglinide (antidiabetic) and agomelatine (antidepressant) emerged as potential TRPV1 antagonists, and protokylol (bronchodilator) as an agonist. Further studies are required to confirm the predicted activity on TRPV1 and to assess the candidates’ efficacy in alleviating pain.

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Development of telmisartan in the therapy of spinal cord injury: pre-clinical study in rats

Cited by 7 publications

References 52 publications

Role of PPAR-β/δ/miR-17/TXNIP pathway in neuronal apoptosis after neonatal hypoxic-ischemic injury in rats

Role of PPAR-β/δ/miR-17/TXNIP pathway in neuronal apoptosis after neonatal hypoxic-ischemic injury in rats

Telmisartan, an Antagonist of Angiotensin II Receptors, Accentuates Voltage-Gated Na+ Currents and Hippocampal Neuronal Excitability

In Silico Drug Repurposing Framework Predicts Repaglinide, Agomelatine and Protokylol as TRPV1 Modulators with Analgesic Activity

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