Guanabenz A Review of its Pharmacodynamic Properties and Therapeutic Efficacy in Hypertension

Holmes, B; Brogden, Rex N.; Heel, R. C.; Speight, T. M.; Avery, G. S.

doi:10.2165/00003495-198326030-00003

Cited by 112 publications

(89 citation statements)

References 23 publications

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“…GBZ, marketed as a clinically licensed antihypertensive drug (Wytensin), 54 has also recently been found to restore the glucose and lipid homeostasis in mice developing symptoms of metabolic syndrome. 55 Other studies have indicated the potential role of GBZ in neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Ishaq

Natarajan

2016

Signal Transduction Insights

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Supraphysiological concentrations (SPCs) of triiodo-l-thyronine (T3) have been used in the treatment of a number of nonviral diseases. However, the signaling mechanisms that regulate the function of T3 at these concentrations and their role in modulating cellular stress pathways and antiviral responses are unknown. Here, we have investigated the effects of SPCs of T3 on integrated stress response (ISR) signaling pathways and the replication of vesicular stomatitis virus (VSV). T3 amplified Poly IC-induced activation of RNA-dependent protein kinase, induced phosphorylation of eIF2α, stress granule (SG) formation, IRE1α phosphorylation, XBP1 splicing, and the expression of stress markers. T3 inhibited VSV replication by modulating SG formation and the expression of stress response markers. ISR activator guanabenz also inhibited VSV replication and amplified T3-induced anti-VSV response. To summarize, we have uncovered novel functions of T3 at SPCs as an activator of ISR signaling pathways and an inhibitor of VSV replication. This study offers a proof of principle of the concept that ISR activating agents like SPC of T3 and guanabenz can be potential antiviral agents.

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Section: Discussionmentioning

confidence: 99%

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Ishaq

Natarajan

2016

Signal Transduction Insights

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“…In addition to inhibiting eIF2a phosphatase, guanabenz is known to act as an alpha 2 adrenergic receptor agonist. 74 Given that examination of the influence of postinjury alpha 2 agonism on outcome has been limited, 75 the contribution of this mechanism to the beneficial effects of guanabenz we observed cannot be excluded. Finally, guanabenz has documented sedative effects.…”

Section: Figmentioning

confidence: 93%

Inhibition of Eukaryotic Initiation Factor 2 Alpha Phosphatase Reduces Tissue Damage and Improves Learning and Memory after Experimental Traumatic Brain Injury

Dash

Hylin

Hood

et al. 2015

Journal of Neurotrauma

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Patients who survive traumatic brain injury (TBI) are often faced with persistent memory deficits. The hippocampus, a structure critical for learning and memory, is vulnerable to TBI and its dysfunction has been linked to memory impairments. Protein kinase RNA-like ER kinase regulates protein synthesis (by phosphorylation of eukaryotic initiation factor 2 alpha [eIF2a]) in response to endoplasmic reticulum (ER) stressors, such as increases in calcium levels, oxidative damage, and energy/glucose depletion, all of which have been implicated in TBI pathophysiology. Exposure of cells to guanabenz has been shown to increase eIF2a phosphorylation and reduce ER stress. Using a rodent model of TBI, we present experimental results that indicate that postinjury administration of 5.0 mg/kg of guanabenz reduced cortical contusion volume and decreased hippocampal cell damage. Moreover, guanabenz treatment attenuated TBI-associated motor, vestibulomotor, recognition memory, and spatial learning and memory dysfunction. Interestingly, when the initiation of treatment was delayed by 24 h, or the dose reduced to 0.5 mg/kg, some of these beneficial effects were still observed. Taken together, these findings further support the involvement of ER stress signaling in TBI pathophysiology and indicate that guanabenz may have translational utility.

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“…Guanabenz -α2 adrenergic receptor agonist (Holmes et al, 1983). -Selectively binds GADD34, disrupting its association with PP1 (Tsaytler et al, 2011).…”

Section: Protein Solubilitymentioning

confidence: 99%

“…The pellet was washed with the same volume of LS, centrifuged again and the supernatant was discarded. The remaining pellet was re-extracted with the same Tsaytler et al, 2011).Action dependent on PERK and ATF6 to rescue mTDP-43 paralysis -Effective for the treatment of hypertension (Holmes et al, 1983). -Anti-prion activity: yeast and mammalian prions (Tribouillard-Tanvier et al, 2008a, 2008b.…”

mentioning

confidence: 99%

“…Sal is effective in reducing mutant superoxide dismutase-1 toxicity in a mouse model of familial ALS, demonstrating that it can protect the ER against misfolded protein stress . Guanabenz is an α2-adrenergic receptor agonist used in the treatment of hypertension (Holmes et al, 1983). This compound shows anti-prion activity (Tribouillard-Tanvier et al, 2008a, 2008b and protects against misfolded proteins in human cells by interfering with the stress-induced dephosphorylation of eIF2α (Tsaytler et al, 2011).…”

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confidence: 99%

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Chemical Genetic Screens for TDP-43 Modifiers and ALS Drug Discovery

Drapeau¹,

Parker²,

Kabashi³

et al. 2015

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE March 2015 REPORT TYPE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERUniversite de Montreal, L' 2900 Boul. Edouard-Montpetit Montreal H3T 1J4 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTOur objective was to screen libraries of several thousand compounds, including clinically approved drugs, for their ability to suppress the in vivo phenotypes observed in worm and fish models expressing mutant human TDP-43 related to ALS and validating hits in a mouse model. Our hypothesis was that chemical modifiers of TDP-43 in vivo function would provide new therapeutic approaches to ALS. Our screen of 3,750 FDA-approved compounds identified 20 active compounds, most of which were neuroleptics with the most potent being pimozide, as well as WithaferinA. In addition to the 4k FDA compounds, we screened 2k molecules that are structurally related to the neuroleptics as well as novel molecules. Also, we screened 4k novel derivatives of pimozide and identified several dozen active compounds. WithaferinA and pimozide were tested in TDP-43 and SOD1 mice. Results suggest that the beneficial effect of Withaferin A in mutant SOD1 mice may be due in part to an upregulation of heat shock proteins (Hsp27 and Hsp70) and to reduction in levels of misfolded SOD1 species. Motor behaviors were not significantly improved or possibly worsened by chronic treatment with pimozide. In addition, the spinal cord and brain of mice revealed and increase in TDP-43 aggregation, but no change in microgliosis, was noted. Neuromuscular transmission was improved acutely. Pimozide is being tested in an ALS clinical trial based on our neuromuscular biomarker. References……………………………………………………………………………. 18 SUBJECT TERMSAppendices INTRODUCTIONOur project was to screen libraries of small chemicals, including clinically approved drugs, for their ability to suppres...

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Guanabenz A Review of its Pharmacodynamic Properties and Therapeutic Efficacy in Hypertension

Cited by 112 publications

References 23 publications

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Inhibition of Eukaryotic Initiation Factor 2 Alpha Phosphatase Reduces Tissue Damage and Improves Learning and Memory after Experimental Traumatic Brain Injury

Chemical Genetic Screens for TDP-43 Modifiers and ALS Drug Discovery

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