rat glioma
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Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 299
Author(s):  
Fernanda Murtinheira ◽  
Mafalda Migueis ◽  
Ricardo Letra-Vilela ◽  
Mickael Diallo ◽  
Andrea Quezada ◽  
...  

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective forms of the 520 kDa multidomain protein, sacsin. Sacsin function is exclusively studied on neuronal cells, where it regulates mitochondrial network organization and facilitates the normal polymerization of neuronal intermediate filaments (i.e., neurofilaments and vimentin). Here, we show that sacsin is also highly expressed in astrocytes, C6 rat glioma cells and N9 mouse microglia. Sacsin knockout in C6 cells (C6Sacs−/−) induced the accumulation of the glial intermediate filaments glial fibrillary acidic protein (GFAP), nestin and vimentin in the juxtanuclear area, and a concomitant depletion of mitochondria. C6Sacs−/− cells showed impaired responses to oxidative challenges (Rotenone) and inflammatory stimuli (Interleukin-6). GFAP aggregation is also associated with other neurodegenerative conditions diagnosed in infants, such as Alexander disease or Giant Axonal Neuropathy. Our results, and the similarities between these disorders, reinforce the possible connection between ARSACS and intermediate filament-associated diseases and point to a potential role of glia in ARSACS pathology.


2021 ◽  
Vol 67 (6) ◽  
pp. 849-854
Author(s):  
Arina Kokorina ◽  
Artem Rafaelyan ◽  
Ksenia Chemodakova ◽  
Natalia Pak ◽  
Viktor Aleksandrov ◽  
...  

The aim of the study was to compare the level of accumulation of protoporphyrin IX (ППIX) in the brain of rats in normal conditions and in experimental C6 glioma. Materials and methods. In an experiment on 15 rats, one group of animals (n=5) was intracranially implanted with rat glioma of the C6 line. 14 days after tumor implantation, the animals were injected into the lateral vein of the tail with a photosensitizer — a preparation of 5-aminolevulinic acid (5-ALA) Alasens at a dose of 100 mg / kg. Another group consisted of 5 intact rats, which were also injected with Alasens. The rats were euthanized 4–5 hours after the injection of the photosensitizer, and fluorescent metabolic navigation was performed with illumination of the brain with light with wavelengths of 417 and 435 nm. For objectification, fluorescence biospectroscopy was performed. Similar manipulations were performed with animals of another group (n=5) — intact rats that did not receive Alasens. Results. In contrast to humans, in rats, the 5-ALA metabolite — PPIX accumulates in healthy brain tissue, while the fluorescence intensity does not differ from that visualized in the tumor area. It was also noted that the light of the blue spectrum promotes weak fluorescence of the white matter of the rat brain in the absence of exogenous 5-ALA, which can potentially be explained by the activation of endogenous PPIX or other fluorophores. Conclusion. After the administration of Alasens (5-ALA preparation), the accumulation of PPIX by the rat brain tissue occurs not only by malignant cells, but also by normal brain tissue without signs of malignancy or other pathological changes. A more thorough study of this phenomenon is required, since significant differences in the metabolism of 5-ALA in humans and laboratory animals will call into question the correctness of translation of experimental results into clinical practice.


Author(s):  
Riccardo Serra ◽  
Antonella Mangraviti ◽  
Noah L Gorelick ◽  
Tovi Shapira-Furman ◽  
Safwan Alomari ◽  
...  
Keyword(s):  

2021 ◽  
Author(s):  
Kazuki Komiyama ◽  
Keiya Iijima ◽  
Reika Kawabata-Iwakawa ◽  
Kazuyuki Fujihara ◽  
Toshikazu Kakizaki ◽  
...  

Abstract Patients with glioma often demonstrate epilepsy. We previously found burst discharges in the peritumoral area in patents with malignant brain tumors during biopsy. Therefore, we hypothesized that the peritumoral area may possess an epileptic focus and that biological alterations in the peritumoral area may cause epileptic symptoms in patients with glioma. To test our hypothesis, we developed a rat model of glioma and characterized it at the cellular and molecular levels. We first labeled rat C6 glioma cells with tdTomato, a red fluorescent protein (C6-tdTomato) and implanted them into the somatosensory cortex of VGAT-Venus rats, which specifically expressed Venus, a yellow fluorescent protein in GABAergic neurons. We observed that the density of GABAergic neurons was significantly decreased in the peritumoral area of rats with glioma compared with the contralateral healthy side. By using a combination technique of laser capture microdissection and RNA sequencing(LCM-seq) of paraformaldehyde-fixed brain sections, we demonstrated that 19 genes were differentially expressed in the peritumoral area and that five of them were associated with epilepsy and neurodevelopmental disorders. In addition, the canonical pathways actively altered in the peritumoral area were predicted to cause a reduction in GABAergic neurons. These results suggest that biological alterations in the peritumoral area may be a cause of glioma-related epilepsy.


Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6923
Author(s):  
Saul Vislei Simões da Silva ◽  
Orlando Maia Barboza ◽  
Jéssica Teles Souza ◽  
Érica Novaes Soares ◽  
Cleonice Creusa dos Santos ◽  
...  

Quercetin (Q) is a bioflavonoid with biological potential; however, poor solubility in water, extensive enzymatic metabolism and a reduced bioavailability limit its biopharmacological use. The aim of this study was to perform structural modification in Q by acetylation, thus, obtaining the quercetin pentaacetate (Q5) analogue, in order to investigate the biological potentials (antioxidant, antileishmania, anti-inflammatory and cytotoxicity activities) in cell cultures. Q5 was characterized by FTIR, 1H and 13C NMR spectra. The antioxidant potential was evaluated against the radical ABTS•+. The anti-inflammatory potential was evaluated by measuring the pro-inflammatory cytokine tumor necrosis factor (TNF) and the production of nitric oxide (NO) in peritoneal macrophages from BALB/c mice. Cytotoxicity tests were performed using the AlamarBlue method in cancer cells HepG2 (human hepatocarcinoma), HL-60 (promyelocytic leukemia) and MCR-5 (healthy human lung fibroblasts) as well as the MTT method for C6 cell cultures (rat glioma). Q and Q5 showed antioxidant activity of 29% and 18%, respectively, which is justified by the replacement of hydroxyls by acetyl groups. Q and Q5 showed concentration-dependent reductions in NO and TNF production (p < 0.05); Q and Q5 showed higher activity at concentrations > 40µM when compared to dexamethasone (20 µM). For the HL-60 lineage, Q5 demonstrated selectivity, inducing death in cancer cells, when compared to the healthy cell line MRC-5 (IC50 > 80 µM). Finally, the cytotoxic superiority of Q5 was verified (IC50 = 11 µM), which, at 50 µM for 24 h, induced changes in the morphology of C6 glioma cells characterized by a round body shape (not yet reported in the literature). The analogue Q5 had potential biological effects and may be promising for further investigations against other cell cultures, particularly neural ones.


Author(s):  
Larissa Menezes da Silveira ◽  
Nathalia Stark Pedra ◽  
Natália Pontes Bona ◽  
Luiza Spohr ◽  
Francieli da Silva dos Santos ◽  
...  

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi174-vi174
Author(s):  
Luana Schaab ◽  
Yann Ferry ◽  
Mehmet Ozdas ◽  
Bettina Kritzer ◽  
Sulayman Mourabit ◽  
...  

Abstract Diffuse midline glioma (DMG) is a devastating and incurable childhood brain cancer. With a median survival of only 9 to 11 months, over 90% of children affected by DMG die within two years of diagnosis. Despite decades of research and a growing understanding of the biology of these tumors, there have been no advancements in therapies for DMGs. Tumor heterogeneity and diffuse infiltration in inoperable brain regions make these tumors uniquely difficult to manage both surgically and pharmacologically. Therefore, there is an urgent need for the exploration of novel treatment regimens. Focused Ultrasound (FUS) is an emerging technology with significant clinical potentials. Sonodynamic therapy (SDT) is an up-and-coming treatment strategy aiming to non-invasively eliminate tumor cells by acting through compounds known as sonosensitizers, which render tumor cells sensitive to ultrasound energy. Recently, 5-Aminolevulinic acid (5-ALA), an FDA-approved molecule, has been proposed as a sono-sensitizing agent. 5-ALA mediated SDT prolonged survival in C6 rat glioma models by selective elimination of tumor cells upon sonication. Mechanistically, it is thought that 5-ALA uptake and metabolic conversion into Protoporphyrin IX (PpIX) occurs preferentially in tumor cells due to differential activity of enzymes involved in heme metabolism. Here, we investigated SDT in DMG cells treated with 5-ALA. PpIX fluorescence increased linearly up to 24 h upon 5-ALA treatment and accumulated significantly more (1.6-fold, p &lt; 0.01) when compared to C6 cells. Consequently, FUS sonication of 5-ALA treated DMG cells at 250 kHz significantly (p &lt; 0.05) decreased DMG cell viability compared to treatment with 5-ALA or FUS alone. Here, we show the first 5-ALA mediated sonodynamic effect in DMG cells, leading to enhanced cell death. Our findings provide a rationale for considering clinical investigation of 5-ALA mediated sonodynamic therapy in DMG.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi176-vi177
Author(s):  
Christopher Hong ◽  
Ranjini Sundaram ◽  
Ranjit Bindra

Abstract Our group has demonstrated that IDH1/2 mutated gliomas harbor intrinsic homologous recombination (HR) defects mediated by the oncometabolite, 2-HG, rendering them sensitive to PARP inhibitors. Here, we studied the efficacy of pamiparib, a CNS-penetrant PARP inhibitor with potent PARP trapping ability, in combination with temozolomide (TMZ) and radiation therapy (RT) in IDH1/2 mutated gliomas. We also studied the pharmacokinetics of BGB290 to demonstrate CNS penetrance. We performed a series of DNA repair functional studies with in vitro short- and long-term viability assays, as well as in vivo studies utilizing an orthotopically injected rat glioma model with bioluminescence. Pharmacokinetics was measured with a previously validated LCMS/MS technique. Short-term and long-term viability assays in paired isogenic IDH1 wildtype and mutant cell lines showed the IDH1 mutation conferred enhanced sensitivity to pamiparib with several-fold decreases in IC50, as well as TMZ and RT as expected. Combination treatment with pamiparib and TMZ or RT also demonstrated synergistic interactions in these same cell lines, dependent upon IDH1 mutation status. An ELISA assay confirmed PARylation inhibition by pamiparib at the nanomolar range in a dose-dependent manner. Pharmacokinetic analysis demonstrated favorable CNS penetration with tumor:plasma ratios ( &gt;0.20) observed with low (3 mg/kg) and high (6 mg/kg) doses of pamiparib, orally administered BID to rats harboring intrinsic rat glioma intracranial tumors. These levels persisted between 2 and 8 hours after last dosing. Pamiparib also selectively penetrated tumors over normal brain with normal brain:plasma ratios under 0.20. These data suggest pamiparib may selectively target IDH1/2 mutated gliomas and act synergistically with TMZ and RT to exploit intrinsic HR defects associated with these tumors. Pharmacokinetic analysis suggest favorable CNS penetration after standard bid oral administration. As such, these results lay the groundwork for study of pamiparib with TMZ and/or RT in patients with IDH1/2 mutated gliomas.


2021 ◽  
Author(s):  
Hideki Kashiwagi ◽  
Shinji Kawabata ◽  
Kohei Yoshimura ◽  
Yusuke Fukuo ◽  
Takuya Kanemitsu ◽  
...  

Abstract Boron neutron capture therapy (BNCT) is a biologically targeted, cell-selective particle irradiation therapy that utilizes the nuclear capture reaction of boron and neutron. Recently, accelerator neutron generators have been used in clinical settings, and expectations for developing new boron compounds are growing. In this study, we focused on serum albumin, a well-known drug delivery system, and developed maleimide-functionalized closo-dodecaborate albumin conjugate (MID-AC) as a boron carrying system for BNCT. Our biodistribution experiment involved F98 glioma-bearing rat brain tumor models systemically administered with MID-AC and demonstrated accumulation and long retention of boron. Our BNCT study with MID-AC observed statistically significant prolongation of the survival rate compared to the control groups, with results comparable to BNCT study with boronophenylalanine (BPA) which is the standard use of in clinical settings. Each median survival time was as follows: untreated control group; 24.5 days, neutron-irradiated control group; 24.5 days, neutron irradiation following 2.5 hours after termination of intravenous administration (i.v.) of BPA; 31.5 days, and neutron irradiation following 2.5 or 24 hours after termination of i.v. of MID-AC; 33.5 or 33.0 days, respectively. The biological effectiveness factor of MID-AC for F98 rat glioma was estimated based on these survival times and found to be higher to 12. This tendency was confirmed in BNCT 24 hours after MID-AC administration. MID-AC induces an efficient boron neutron capture reaction because the albumin contained in MID-AC is retained in the tumor and has a considerable potential to become an effective delivery system for BNCT in treating high-grade gliomas.


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