Overall survival in malignant glioma is significantly prolonged by neurosurgical delivery of etoposide and temozolomide from a thermo-responsive biodegradable paste

Purpose: High-grade glioma (HGG) treatment is limited by the inability of otherwise potentially efficacious drugs to penetrate the blood brain barrier. We evaluate the unique intra-cavity delivery mode and translational potential of a blend of poly(DL-lactic acid-co-glycolic acid) (PLGA) and poly(ethylene glycol) (PEG) paste combining temozolomide and etoposide to treat surgically resected HGG. Experimental Design: To prolong stability of temozolomide pro-drug, combined in vitro drug release was quantitatively assessed from low pH-based PLGA/PEG using advanced analytical methods. In vitro cytotoxicity was measured against a panel of HGG cell lines and patient-derived cultures using metabolic assays. In vivo safety and efficacy was evaluated using orthotopic 9L gliosarcoma allografts, previously utilized pre-clinically to develop Gliadel®. Results: Combined etoposide and temozolomide in vitro release (22 and 7 days respectively) was achieved from a lactic acid-based PLGA/PEG paste, used to enhance stability of temozolomide prodrug. HGG cells from central-enhanced regions were more sensitive to each compound relative to primary lines derived from the HGG invasive margin. Both drugs retained cytotoxic capability upon release from PLGA/PEG. In vivo studies revealed a significant overall survival benefit in post-surgery 9L orthotopic gliosarcomas treated with intra-cavity delivered PLGA/PEG/temozolomide/etoposide and enhanced with adjuvant radiotherapy. Long-term survivorship was observed in over half the animals with histological confirmation of disease-free brain. Conclusions: The significant survival benefit of intra-cavity chemotherapy demonstrates clinical applicability of PLGA/PEG paste-mediated delivery of temozolomide and etoposide adjuvant to radiotherapy. PLGA/PEG paste offers a future platform for combination delivery of molecular targeted compounds

Neurosurgical application of olaparib from a thermo-responsive paste potentiates DNA damage to prolong survival in malignant glioma

Background: There is increased pan-cancer specific interest in repurposing the poly adenosine diphosphate-ribose polymerase-1 (PARP-1) inhibitor, olaparib, for newly diagnosed or recurrent isocitrate dehydrogenase wild type glioblastoma. We explore whether intra-cavity delivery of olaparib confers a survival benefit in a pre-clinical high-grade glioma model. Methods: Primary tumour RNA sequencing data was used to determine PARP-1 as a target in the glioblastoma infiltrative margin. We assessed radiosensitization conferred by olaparib alone and concomitant to genotoxic insults in vitro using clonal growth assays, cell cycle analysis and immunocytochemistry, and in vivo upon post-surgical delivery from a temperature-sensitive polymeric paste. Results: RNA-sequencing confirmed PARP-1 as a viable therapy target in glioblastoma infiltrative disease. Acute exposure of glioma cells to olaparib impaired proliferation and induced late-stage apoptosis associated with DNA damage in vitro, potentiated by radiation. Using high-grade glioma orthotopic allografts, a long-term overall survival benefit was observed upon interstitial olaparib delivery concomitant with radiotherapy, compared to systemic olaparib and standard glioblastoma treatment. Combined delivery of olaparib with either temozolomide or etoposide increased long-term survival, suggestive of olaparib functioning as DNA damage sensitizer. Conclusions: Collectively, our data support a rationale for localized olaparib delivery concomitant with the current clinical regimen for malignant glioma treatment

Endocannabinoid basis of personality—Insights from animal model of social behavior

Rationale: The endocannabinoid system is known to be involved in learning, memory, emotional processing and regulation of personality patterns. Here we assessed the endocannabinoid profile in the brains of mice with strong characteristics of social dominance and submissiveness.Methods: A lipidomics approach was employed to assess the endocannabinoidome in the brains of Dominant (Dom) and Submissive (Sub) mice. The endocannabinoid showing the greatest difference in concentration in the brain between the groups, docosatetraenoyl ethanolamine (DEA), was synthesized, and its effects on the physiological and behavioral responses of Dom and Sub mice were evaluated. mRNA expression of the endocannabinoid receptors and enzymes involved in PUFA biosynthesis was assessed using qRT-PCR.Results: Targeted LC/MS analysis revealed that long-chain polyunsaturated ethanolamides including arachidonoyl ethanolamide (AEA), DEA, docosatrienoyl ethanolamide (DTEA), eicosatrienoyl ethanolamide (ETEA), eicosapentaenoyl ethanolamide (EPEA) and docosahexaenoyl ethanolamide (DHEA) were higher in the Sub compared with the Dom mice. Untargeted LC/MS analysis showed that the parent fatty acids, docosatetraenoic (DA) and eicosapentaenoic (EPA), were higher in Sub vs. Dom. Gene expression analysis revealed increased mRNA expression of genes encoding the desaturase FADS2 and the elongase ELOVL5 in Sub mice compared with Dom mice. Acute DEA administration at the dose of 15 mg/kg produced antinociceptive and locomotion-inducing effects in Sub mice, but not in Dom mice. Subchronic treatment with DEA at the dose of 5 mg/kg augmented dominant behavior in wild-type ICR and Dom mice but not in Sub mice.Conclusion: This study suggests that the endocannabinoid system may play a role in the regulation of dominance and submissiveness, functional elements of social behavior and personality. While currently we have only scratched the surface, understanding the role of the endocannabinoid system in personality may help in revealing the mechanisms underlying the etiopathology of psychiatric disorders

Phytoecdysteroids: understanding their anabolic activity

Phytoecdysteroids, polyhydroxylated ketosteroids, are the plant analogues of insect growth hormones. Although their role in insect molting is well characterized, their function in plants is less clear. Lacking the properties of classic plant hormones, phytoecdysteroids may be involved in plant growth and defense. One of the main benefits of phytoecdysteroids may be their therapeutic effects on mammals, including humans. Their claimed medicinal properties include anabolic, adaptogenic, hepatoprotective, and hypoglycemic activity. Although ethnobotanical use has been supported by some evidence, the research is quite limited, lacking the scientific rigor necessary to be convincing. Two ecdysteroid containing plants, Ajuga turkestanica, and Spinacia olearaceae (Spinach), were selected as beneficial sources of phytoecdysteroids. Cultivation, analysis of ecdysteroid content, and characterization of anabolic activity were performed to support future medicinal use. Phytoecdysteroids' anabolic activity, one of their most interesting properties due to the claimed lack of androgenic effect, was studied. Anabolic activity was confirmed in animal studies and a cellular model of skeletal muscle. The cellular model was used to characterize ecdysteroids' effect on protein incorporation and to elucidate the signal transduction pathway involved. Ecdysteroid's lack of androgenic activity was confirmed in vivo and in vitro, with ecdysteroids showing no specific binding to the androgen receptor. Identification of mammalian nuclear receptors homologous with the insect nuclear ecdysone receptor led to binding and activation assays of potential receptors using ecdysteroids. The discovery of a lesser known membrane bound G Protein Coupled Receptor (GPCR) insect ecdysone receptor, DoEcR, suggested the existence of a hypothetical mammalian membrane bound GPCR ecdysone receptor. Use of specific inhibitors supported the involvement of G protein signaling, Phospholipase C (PLC), Inositol Phosphate 3 Receptor (IP3R), and Akt. Ecdysteroid stimulated activation of Akt confirmed its role in the anabolic effect. Ecdysteroid generated increases in intracellular calcium were also characterized, with the rapid flux in Ca2+ linked with Akt activation and anabolic activity. The evidence produced suggests the involvement of a putative mammalian GPCR ecdysteroid receptor mediating the anabolic effect through the rapid activation of the PLC/IP3R pathway, generating Ca2+ flux which leads to activation of the Phosphoinositide 3 Kinase/Akt pathway, eventually causing increases in protein incorporation.Ph.D.Includes bibliographical references (p. 131-142)by Jonathan Isaac Gorelick-Feldma

Ecdysteroid Content and Therapeutic Activity in Elicited Spinach Accessions

While spinach is an established nutritionally important crop, its medicinal value is not as well known. Spinach is rich in ecdysteroids, insect hormone analogs with a number of medicinal properties including anti-oxidative, anti-inflammatory and even anabolic activity. However, the potential of spinach as a medicinal plant has not yet been developed. In this study, the ecdysteroid content of spinach was optimized to increase its therapeutic value. Spinach seeds from various sources were grown under controlled hydroponic conditions and analyzed for ecdysteroid content and related anabolic activity. Variations in ecdysteroid content and the related anabolic activity were observed among spinach accessions. A selected variety, Spinacia oleracea cv. Turkey, was exposed to various physical and chemical elicitors to increase and stabilize ecdysteroid content. A number of elicitors, including methyl salicylate and mechanical damage, significantly increased ecdysteroid content and anabolic activity 24 h after exposure. The effect was transient and disappeared 48 h thereafter. Further work is needed to identify the most suitable germplasm and elicitation conditions for optimal ecdysteroid content

Medicinal Properties of Lilium candidum L. and Its Phytochemicals

Lilium candidum L., known as Madonna, meadow, or white lily, is a bulbous plant from the Liliaceae family, originating in the Middle East. L. candidum has been abundantly used in folk medicine since ancient times to relieve a variety of ailments, including age-related diseases, burns, ulcers, and coughs. The aim of this article is to investigate the anti-inflammatory and anti-diabetic activities of L. candidum extracts and its active phytochemicals. Some active volatile phytochemicals were identified using gas chromatography–mass spectrometry (GC-MS) analysis. Significant (p < 0.001) anti-diabetic properties of the extracts kaempferol, linalool, citronellal, and humulene were demonstrated by an elevation in glucose uptake by adipocytes. The significant (p < 0.01) effect of the plant extracts kaempferol, citronellal, and humulene on the secretion of pro-inflammatory cytokines interleukin 6 (IL-6) and interleukin 8 (IL-8) was demonstrated using enzyme-linked immunosorbent assay. Altogether, L. candidum and its rich collection of phytochemicals hold promising medicinal potential, and further investigations of its therapeutic prospects are encouraged