Garcia-Martin, A. | Search bioRxiv

bioRxiv2026

Predictive value of brain 18F-FDG PET neuroimaging in a mouse model of sudden death

Sudden unexpected death (SUD) is a major cause of mortality in neurological disorders, with poorly understood mechanisms and no reliable biomarkers. Brain-heart axis dysfunction has been implicated in SUD pathogenesis. Using the FUSdelta14 mouse model, we tested whether cerebral glucometabolism, assessed by 18F-FDG PET, reflects autonomic dysregulation and predicts SUD vulnerability. 18F-FDG PET/CT and ECG were acquired at 10 weeks of age (FUSdelta14/delta14 n=12, FUS+/delta14 n=14, FUS+/+ n=12). Heart rate variability was analyzed in time and frequency domains, brain uptake via volume of interest and voxel-wise approaches, and correlations assessed by Pearson's analysis. A classification-tree model tested SUD predictability within the FUSdelta14/delta14 group. Female FUSdelta14/delta14 mice showed reduced 18-FFDG uptake in basal forebrain septum, left amygdala, and brainstem, with increased uptake in hypothalamus and right midbrain, alongside cardiac size, metabolic and heart rate variability alterations. 50% experienced SUD; in this subgroup, PET showed cortical hypometabolism (insular, entorhinal) and hypermetabolism in hypothalamus, amygdala, septum, and brainstem. Although brainstem uptake was able to singlehandedly predict SUD in this particular FUSdelta14/delta14 group (AUC=0.787), cross-validation also highlighted cortical metabolism as a relevant feature (UsageRate=0.38 and 0.44, respectively). 18F-FDG PET identifies region-specific metabolic signatures of brain-heart axis dysfunction linked to SUD, supporting its potential as a non-invasive biomarker for risk stratification.

neuroscience↗

bioRxiv2024

Etrinabdione (VCE-004.8), a B55a activator, promotes angiogenesis and arteriogenesis in critical limb ischemia.

BackgroundVasculogenic therapies explored for the treatment of peripheral artery disease (PAD) have encountered minimal success in clinical trials. Addressing this, B55, an isoform of protein phosphatase 2A (PP2A), emerges as pivotal in vessel remodeling through activation of hypoxia-inducible factor 1 (HIF-1). This study delves into the pharmacological profile of VCE-004.8 (Etrinabdione) and evaluates its efficacy in a preclinical model of critical limb ischemia, with a focus on its potential as a PP2A/B55 activator to induce angiogenesis and arteriogenesis. MethodsVascular endothelial cells were used for in vitro experiments. Aorta ring assay was performed to explore sprouting activity. Matrigel plug-in assay was used to assess the angiogenic potential. Critical limb ischemia (CLI) in mice was induced by double ligation in the femoral arteria. Endothelial vascular and fibrotic biomarkers were studied by immunohistochemistry and qPCR. Arteriogenesis was investigated by microvascular casting and micro-CT. Proteomic analysis in vascular tissues was analyzed by LC-MS/MS. Ex-vivo expression of B55 and biomarkers were investigated in artery samples from PAD patients. ResultsVCE-004.8 exhibited the ability to induce B55 expression and activate the intersecting pathways B55/AMPK/Sirtuin 1/eNOS and B55/PHD2/HIF-1. VCE-004.8 prevented OxLDL and H2O2-induced cytotoxicity, senescence, and inflammation in endothelial cells. Oral VCE-004.8 increased aorta sprouting in vitro and angiogenesis in vivo. In CLI mice VCE-004.8 improved collateral vessel formation and induced endothelial cells proliferation, angiogenic gene expression and prevented fibrosis. The expression of B55, Caveolin 1 and Sirtuin-1 is reduced in arteries from CLI mice and PAD patient, and the expression of these markers was restored in mice treated with VCE-004.8. ConclusionsThe findings presented in this study indicate that Etrinabdione holds promise in mitigating endothelial cell damage and senescence, while concurrently fostering arteriogenesis and angiogenesis. These observations position Etrinabdione as a compelling candidate for the treatment of PAD, and potentially other cardiovascular disorders. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIThe phosphatase PPA2/B55 stabilizes endothelial cells (ECs) in response to cell stress conditions, thereby protecting ECs from apoptosis and promoting angiogenesis. C_LIO_LIEtrinabdione (VCE-004.8) functions as a potent activator of PPA2/B55 inducing PHD2 dephosphorylation at ser125 and fostering HIF activation. C_LIO_LIVCE-004.8 prevents vascular damage in preclinical models of systemic and cardiac fibrosis and alleviates blood-brain barrier disruption in neuroinflammatory conditions. C_LIO_LIVCE-004.8 is also a dual agonist of PPAR{psi} and CB2 receptors and shows antiinflammatory activity. C_LIO_LIOral VCE-004.8 has meet the primary endpoints of safety and tolerability in a Phase IIa clinical trial with systemic sclerosis patients (clinicaltrial.gov: NCT03745001). C_LI What New Information Does This Article Contribute?O_LIEtrinabdione induces HIF-1 expression in endothelial cells through a novel pathway that potentially involves two axes: B55/PHD2 and B55/AMPK/Sirt1 signaling that may converge on HIF stabilization. C_LIO_LIEtrinabdione prevented endothelial cell damage and senescence, while inducing arteriogenesis and angiogenesis in CLI mice. C_LIO_LIIn arteries of patients with PAD and in CLI mouse models, the expression levels of B55, Caveolin 1, and Sirtuin 1 are diminished. However, treatment with Etrinabdione specifically in CLI mice prompts an increase in the levels of these proteins. C_LIO_LIEtrinabdione triggers neovascularization and angiogenesis specifically within hypoxic tissue in a critical ischemia model, with no impact on healthy tissue. C_LI

pharmacology and toxicology↗

bioRxiv2020

Δ9-Tetrahydrocannabinolic Acid markedly alleviates liver fibrosis and inflammation in murine models of chemically- and obesity-induced liver injury

BackgroundNon-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the Western world, and it is closely associated to obesity, type 2 diabetes mellitus, and dyslipidemia. Hepatocellular stellate cells (HSCs) activation by oxidative stress and inflammation is the hallmark of liver fibrosis and leads to cirrhosis and liver failure resistant to pharmacological management. Cannabinoids have been suggested as a potential therapy for liver fibrosis, prompting us to explore the antifibrotic and anti-inflammatory effects of {Delta}9-THCA-A, a major non-psychotropic cannabinoid from Cannabis sativa L., in animal models of NAFLD. MethodsNon-alcoholic liver fibrosis was induced in mice by CCl4 treatment or, alternatively, by 23-week high fat diet (HFD) feeding. {Delta}9-THCA was administered daily intraperitoneally during the CCl4 treatment or during the last 3 weeks in HFD-fed mice. Liver fibrosis and inflammation were assessed by immunochemistry and qPCR. Blood glucose and plasma insulin, leptin and triglyceride levels were measured in HFD mice. Results{Delta}9-THCA significantly attenuated CCl4-induced liver fibrosis and inflammation and reduced T cell and macrophage infiltration. Mice fed HFD for 23 weeks developed severe obesity (DIO), fatty liver and marked liver fibrosis, accompanied by immune cell infiltration. {Delta}9-THCA, significantly reduced body weight and adiposity, improved glucose tolerance, and drastically attenuated DIO-induced liver fibrosis and immune cell infiltration. Conclusions{Delta}9-THCA prevents liver fibrogenesis in vivo, providing a rationale for additional studies on the medicinal use of this cannabinoid, as well as cannabis preparations containing it, in the treatment of liver fibrosis and the management of NAFLD.

pharmacology and toxicology↗