Sex-specific Gene Expression in Flupirtine-Treated Cln3Δex7/8 Mouse Brain

Gene expression is a powerful tool to understand structure-function relationships in the nervous system. This study reports global gene expression changes induced by flupirtine in brain of male and female Cln3Δex7/8 mice, exposing potential flupirtine targets at the molecular level. Gene expression analysis of male and female Cln3Δex7/8 mouse brain was determined following oral administration of flupirtine for 14 weeks, using Mouse Genome 430 2.0 array Chips and an Affymetrix platform. Fifty-six genes in males and 79 in females were differentially expressed in flupirtine- versus vehicle-treated Cln3Δex7/8 mouse brain. Flupirtine altered several pathways in Cln3Δex7/8 mouse brain: apoptosis, the complement cascade, NF-kB, and p38α MAPK signaling pathways. Gene-gene network analysis highlighted networks and processes functionally pertinent to flupirtine treatment. These encompassed neurodegeneration, neuro-inflammation, and implicated neurological disorders such as Alzheimer and Parkinson disease. Flupirtine mediates its action in males and females through distinctive actionable targets in the same pathways. This work consolidates the groundwork for considering flupirtine as a treatment option in human CLN3 disease

Flupirtine Derivatives as Potential Treatment for the Neuronal Ceroid Lipofuscinoses

OBJECTIVE: Neuronal Ceroid Lipofuscinoses (NCL) are fatal inherited neurodegenerative diseases with established neuronal cell death and increased ceramide levels in brain, hence, a need for disease-modifying drug candidates, with potential to enhance growth, reduce apoptosis and lower ceramide in neuronal precursor PC12 cells and human NCL cell lines using enhanced flupirtine aromatic carbamate derivatives in vitro. METHODS: Aromatic carbamate derivatives were tested by establishing growth curves under pro-apoptotic conditions and activity evaluated by trypan blue and JC-1 staining, as well as a drop in pro-apoptotic ceramide in neuronal precursor PC12 cells following siRNA knockdown of the RESULTS: Retigabine, the benzyl-derivatized carbamate and an allyl carbamate derivative were neuroprotective in CLN3-defective PC12 cells and rescued CLN1-/CLN2-/CLN3-/CLN6-/CLN8 patient-derived lymphoblasts from diminished growth and accelerated apoptosis. All drugs decreased ceramide in CLN1-/CLN2-/CLN3-/CLN6-/CLN8 patient-derived lymphoblasts. Increased INTERPRETATION: These findings establish that compounds analogous to flupirtine demonstrate anti-apoptotic activity with potential for treatment of NCL disease and use of ceramide as a marker for these diseases

Exogenous Flupirtine as Potential Treatment for CLN3 Disease

CLN3 disease is a fatal neurodegenerative disorder affecting children. Hallmarks include brain atrophy, accelerated neuronal apoptosis, and ceramide elevation. Treatment regimens are supportive, highlighting the importance of novel, disease-modifying drugs. Flupirtine and its new allyl carbamate derivative (compound 6) confer neuroprotective effects in CLN3-deficient cells. This study lays the groundwork for investigating beneficial effects in Cln3Δex7/8 mice. WT/Cln3Δex7/8 mice received flupirtine/compound 6/vehicle for 14 weeks. Short-term effect of flupirtine or compound 6 was tested using a battery of behavioral testing. For flupirtine, gene expression profiles, astrogliosis, and neuronal cell counts were determined. Flupirtine improved neurobehavioral parameters in open field, pole climbing, and Morris water maze tests in Cln3Δex7/8 mice. Several anti-apoptotic markers and ceramide synthesis/degradation enzymes expression was dysregulated in Cln3Δex7/8 mice. Flupirtine reduced astrogliosis in hippocampus and motor cortex of male and female Cln3Δex7/8 mice. Flupirtine increased neuronal cell counts in male mice. The newly synthesized compound 6 showed promising results in open field and pole climbing. In conclusion, flupirtine improved behavioral, neuropathological and biochemical parameters in Cln3Δex7/8 mice, paving the way for potential therapies for CLN3 disease

Associations of excess weight gain during pregnancy with long-term maternal overweight and obesity: Evidence from 21 y postpartum follow-up

Background: The contribution of gestational weight gain (GWG) to the development of obesity may have important implications for mothers in their later lives. However, whether GWG is a strong predictor of body mass index (BMI) 2 decades after the index pregnancy is unknown

Does hypertensive disorder of pregnancy predict offspring blood pressure at 21 years? Evidence from a birth cohort study

Although few studies found that the offspring of women who experienced preeclampsia have higher blood pressure (BP) at childhood and adolescence, no study has observed whether this association exists for adult offspring. To examine whether maternal hypertensive disorder of pregnancy (HDP) predicts adult offspring BP. We followed a sub-sample of 2608 mother-offspring pairs for 21 years from an original cohort of 7223 singleton infants whose mothers gave birth in Brisbane, Australia between 1981 and 1983. HDP was defined as diastolic BP (DBP) over 90 mm Hg on at least two occasions beyond 20 weeks gestation associated with proteinuria and/or excessive fluid retention. Adult offspring's systolic BP (SBP) and DBP were measured at 21 years. Multivariable regressions were used to examine the independent associations of HDP with offspring BP. Unadjusted regression analysis showed that offspring of women who experienced HDP have 3.46 mm Hg greater SBP and 3.02 mm Hg greater DBP at 21 years. This association remained consistent after adjusting for potential confounding and mediating factors including offspring gender, age, percentile birth weight for gestation, placenta weight and body mass index (BMI) at 21 year, maternal age, education, racial origin, and smoking during pregnancy and their pre-pregnancy BMI. Findings of this study suggest that maternal HDP predicts adult offspring BP

Tailored quinolines demonstrates flexibility to exert antitumor effects through varied mechanisms - a medicinal perspective

Quinoline is considered to be a privileged heterocyclic ring owing to its presence in diverse scaffolds endowed with promising activity profiles. In particular, quinoline containing compounds have exhibited substantial antiproliferative effects through diverse mechanism of actions which indicates that the heteroaryl unit is flexible as well as accessible to subtle structural changes that enables its inclusion in chemically distinct antitumor constructs.Herein, we describe a medicinal chemistry perspective on quinolines as anticancer agents by digging into the peer reviewed literature as well as patents published in the past few years.This review will serve as a guiding tool for medicinal chemists and chemical biologist to gain insights about the benefits of quinoline ring installation to tune the chemical architectures for inducing potent anticancer effects.Quinoline ring containing anticancer agents presents enough optimism and promise in the field of drug discovery to motivate the researchers towards the continued explorations on such scaffolds. It is highly likely that adequate efforts in this direction might yield some potential cancer therapeutics in future

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

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

Small Molecules that Rescue Multiple Phenotypic Aberrations in an iPSC-Derived Neuron Model of CLN3 Disease

The neuronal ceroid lipofuscinoses (NCLs) commonly referred to as Batten disease are a family of rare lysosomal storage disorders (LSDs). The most common form of NCL occurs in children harboring a mutation in the CLN3 gene. This form is lethal with no existing cure or treatment beyond symptomatic relief. The pathophysiology of CLN3 disease is complex and poorly understood, with the current in vivo and in vitro models failing to identify pharmacological targets for therapeutic intervention. This study reports the characterization of the first CLN3 patient-specific induced pluripotent stem cell (iPSC)-derived model of the blood-brain barrier (BBB) and adds to the few available iPSC-derived neuron models of the disease. Upon differentiation, hallmarks of CLN3 disease were displayed including lipofuscin and subunit C of mitochondrial ATP synthase accumulation, mitochondrial dysfunction and aberrant lysosomal pH. Small molecules were identified that cleared subunit C accumulation by the mTOR-independent modulation of autophagy, conferred protective effects through induction of Bcl-2 and rescued mitochondrial dysfunction. </div