Pharmacophore elucidation of phosphoiodyn A – Potent and selective peroxisome proliferator-activated receptor β/δ agonists with neuroprotective activity

Kinarivala, Nihar; Suh, Ji Ho; Botros, Mina; Webb, Paul; Trippier, Paul C.

doi:10.1016/j.bmcl.2016.03.028

Cited by 16 publications

(13 citation statements)

References 25 publications

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“…Previous studies have showed that increased PPARδ transactivation ameliorated mitochondrial dysfunction and improved neuron survival. 12 , 38 The present study revealed that melatonin upregulated the expression of PPARδ, which was consistent with previous studies reporting that melatonin upregulated PPARγ to stimulate the biogenesis of mitochondria. 13 In addition, melatonin could also upregulate PGC-1α that was a co-activator of PPARδ.…”

Section: Discussionsupporting

confidence: 93%

Melatonin Alleviates Neuronal Damage After Intracerebral Hemorrhage in Hyperglycemic Rats

Liang¹,

Wang²,

Zhu³

et al. 2020

DDDT

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Background: This study sought to investigate a novel effect of melatonin in reducing brain injury in an in vivo hyperglycemic intracerebral hemorrhage (ICH) model and further explore the mechanisms of protection. Methods: Hyperglycemia ICH was induced in Sprague-Dawley rats by streptozocin injection followed by autologous blood injection into the striatum. A combined approach including RNA-specific depletion, electron microscopy, magnetic resonance, Western blots, and immunohistological staining was applied to quantify the brain injuries after ICH. Results: Hyperglycemia resulted in enlarged hematoma volume, deteriorated brain edema, and aggravated neuronal mitochondria damage 3 days after ICH. Post-treatment with melatonin 2 hours after ICH dose-dependently improved neurological behavioral performance lasting out to 14 days after ICH. This improved neurological function was associated with enhanced structural and functional integrity of mitochondria. Mechanistic studies revealed that melatonin alleviated mitochondria damage in neurons via activating the PPARδ/PGC-1α pathway. Promisingly, melatonin treatment delayed until 6 hours after ICH still reduced brain edema and improved neurological functions. Melatonin supplementation reduces neuronal damage after hyperglycemic ICH by alleviating mitochondria damage in a PPARδ/PGC-1α-dependent manner. Conclusion: Melatonin may represent a therapeutic strategy with a wide therapeutic window to reduce brain damage and improve long-term recovery after ICH.

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Section: Discussionsupporting

confidence: 93%

Melatonin Alleviates Neuronal Damage After Intracerebral Hemorrhage in Hyperglycemic Rats

Liang¹,

Wang²,

Zhu³

et al. 2020

DDDT

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“…25 Etoposide is an anticancer agent that functions as a topoisomerase II inhibitor and is widely used to induce apoptosis in cells for screening of neuroprotective molecules. 26 To ensure that screened compounds do not simply act to displace or block etoposide from its binding site, we conducted a secondary screen on selected derivatives to determine protective effect to ameliorate apoptotic cell death in PC12 cells exposed to serum starvation. 25 Identical trends in activity were observed across both external insults; derivatives with greater protective effect than 1 to ameliorate etoposide-induced apoptosis also demonstrated greater protective effect to ameliorate serum starvation-induced apoptosis and vice versa (Supporting Information, Table S1).…”

Section: Resultsmentioning

confidence: 99%

Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2)

et al. 2017

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Neurodegenerative diseases share certain pathophysiological hallmarks that represent common targets for drug discovery. In particular, dysfunction of proteostasis and the resultant apoptotic death of neurons represent common pathways for pharmacological intervention. A library of aromatic carbamate derivatives based on the clinically available drug flupirtine was synthesized to determine a structure–activity relationship for neuroprotective activity. Several derivatives were identified that possess greater protective effect in human induced pluripotent stem cell-derived neurons, protecting up to 80% of neurons against etoposide-induced apoptosis at concentrations as low as 100 nM. The developed aromatic carbamates possess physicochemical properties desirable for CNS therapeutics. The primary known mechanisms of action of the parent scaffold are not responsible for the observed neuroprotective activity. Herein, we demonstrate that neuroprotective aromatic carbamates function to increase the Bcl-2/Bax ratio to an antiapoptotic state and activate autophagy through induction of beclin 1.

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“…PPAR-γ is a nuclear transcription factor belonging to the nuclear hormone receptor superfamily and is expressed in liver, kidney, the nervous system and tumours. 9 It can affect the expression of ROS and inflammatory factors by regulating macrophage activation. 10,11 In recent years, the role of PPAR-γ in IR has been extensively studied, most intensely for myocardial IR.…”

Section: Introductionmentioning

confidence: 99%

Bergenin Exerts Hepatoprotective Effects by Inhibiting the Release of Inflammatory Factors, Apoptosis and Autophagy via the PPAR-γ Pathway

Xiang

Chen

et al. 2020

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These authors contributed equally to this workObjective: Hepatic ischemia reperfusion (IR) limits the development of liver transplantation technology. The aim of this study was to explore the protective effects of Bergenin on hepatic IR, particularly the elimination of reactive oxygen species (ROS) and activation of the peroxisome proliferators activated receptor γ (PPAR-γ) pathway. Methods: Initial experiments were performed to confirm the non-toxicity of Bergenin. Mice were randomly divided into sham, IR, and IR + Bergenin (10, 20 and 40 mg/kg) groups, and serum and tissue samples were obtained at 2, 8 and 24 h for detection of liver enzymes (ALT and AST), inflammatory factors (TNF-α, IL-6 and IL-1β), ROS, cell death markers (Bcl-2, Bax, Beclin-1 and LC3) and related important pathways (PPAR-γ, P38 MAPK, NF-κB p65 and JAK2/STAT1). Results: Bergenin reduced the release of ROS, down-regulated inflammatory factors, and inhibited apoptosis and autophagy. Additionally, expression of PPAR-γ-related genes was increased and phosphorylation of P38 MAPK, NF-κB p65 and JAK2/STAT1-related proteins was decreased in Bergenin pre-treatment groups in a dose-dependent manner. Conclusion: Bergenin exerts hepatic protection by eliminating ROS, affecting the release of inflammatory factors, and influencing apoptosis-and autophagy-related genes via the PPAR-γ pathway in this model of hepatic IR injury.

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Pharmacophore elucidation of phosphoiodyn A – Potent and selective peroxisome proliferator-activated receptor β/δ agonists with neuroprotective activity

Cited by 16 publications

References 25 publications

<p>Melatonin Alleviates Neuronal Damage After Intracerebral Hemorrhage in Hyperglycemic Rats</p>

<p>Melatonin Alleviates Neuronal Damage After Intracerebral Hemorrhage in Hyperglycemic Rats</p>

Discovery of Aromatic Carbamates that Confer Neuroprotective Activity by Enhancing Autophagy and Inducing the Anti-Apoptotic Protein B-Cell Lymphoma 2 (Bcl-2)

<p>Bergenin Exerts Hepatoprotective Effects by Inhibiting the Release of Inflammatory Factors, Apoptosis and Autophagy via the PPAR-γ Pathway</p>

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