2025
Nateghi, Sepide; Rezayof, Ameneh; Kouhkan, Fatemeh; Delphi, Ladan; Davisaraei, Yavar Bagheri; Rostami, Fatemeh; Tirgar, Fatemeh; Sepehri, Houri
In: Brain Research Bulletin, vol. 221, pp. 111227, 2025, ISSN: 1873-2747.
Abstract | Links | BibTeX | Tags: Animal, Animals, Anxiety, Behavior, Brain Neoplasms, Cell Line, Cognition, Emotions, GABA-A, GABA-A Receptor Agonists, GABAergic signaling, GBM animal model, Glioblastoma, Male, MicroRNAs, Muscimol, Non-coding RNAs, Prefrontal Cortex, Rat(s), Rats, Receptors, Signal Transduction, Tumor, Wistar
@article{nateghi_growth_2025,
title = {Growth of the prefrontal cortical glioblastoma altered cognitive and emotional behaviors via mediating miRNAs and GABA-a receptor signaling pathways in rats},
author = {Sepide Nateghi and Ameneh Rezayof and Fatemeh Kouhkan and Ladan Delphi and Yavar Bagheri Davisaraei and Fatemeh Rostami and Fatemeh Tirgar and Houri Sepehri},
doi = {10.1016/j.brainresbull.2025.111227},
issn = {1873-2747},
year = {2025},
date = {2025-02-01},
journal = {Brain Research Bulletin},
volume = {221},
pages = {111227},
abstract = {The present study investigated the impact of GABAergic signaling and miRNA expression on glioblastoma multiforme (GBM) growth within the medial prefrontal cortex (mPFC) and its associated cognitive and emotional impairments. The implantation of C6 cells into the mPFC induced GBM in this brain region (referred to as the mPFC-GBM) in male Wistar rats via stereotaxic surgery, as confirmed by Magnetic Resonance Imaging (MRI), and Hematoxylin and Eosin (H&E) staining. Repeated microinjections of muscimol, a potent GABAA receptor agonist, directly into the mPFC-GBM (1 µg/rat/2.5 μl) following tumor induction decreased tumor volume and weight, resulting in an increased survival rate. Conversely, a higher dose of muscimol (6 µg/rat/2.5 μl) increased tumor size and reduced survival. Behavioral alterations induced by GBM, including anxiety-like responses, exploratory behaviors, locomotor activity, and memory formation, were assessed using anxiety-like behavior task, the hole-board test, and the novel object recognition test. Muscimol treatment dose-dependently affected these behaviors in the animals with the mPFC-GBM, bringing their performance with that of the sham group at the dose of 1 µg/rat/2.5 μl. Changes in specific miRNAs expressions, including miR-208, -290-295, -345, -743 and -802 were associated with the growth of the mPFC-GBM under muscimol treatment. These findings suggest that GBM growth into the mPFC profoundly impacts cognitive and emotional behaviors which can be improved by muscimol treatment. Considering that the expression levels of targeted miRNAs could be influenced by the growth of the mPFC-GBM, both with or without muscimol treatment, these non-coding RNAs might serve as potential biomarkers for GBM.},
keywords = {Animal, Animals, Anxiety, Behavior, Brain Neoplasms, Cell Line, Cognition, Emotions, GABA-A, GABA-A Receptor Agonists, GABAergic signaling, GBM animal model, Glioblastoma, Male, MicroRNAs, Muscimol, Non-coding RNAs, Prefrontal Cortex, Rat(s), Rats, Receptors, Signal Transduction, Tumor, Wistar},
pubstate = {published},
tppubtype = {article}
}
The present study investigated the impact of GABAergic signaling and miRNA expression on glioblastoma multiforme (GBM) growth within the medial prefrontal cortex (mPFC) and its associated cognitive and emotional impairments. The implantation of C6 cells into the mPFC induced GBM in this brain region (referred to as the mPFC-GBM) in male Wistar rats via stereotaxic surgery, as confirmed by Magnetic Resonance Imaging (MRI), and Hematoxylin and Eosin (H&E) staining. Repeated microinjections of muscimol, a potent GABAA receptor agonist, directly into the mPFC-GBM (1 µg/rat/2.5 μl) following tumor induction decreased tumor volume and weight, resulting in an increased survival rate. Conversely, a higher dose of muscimol (6 µg/rat/2.5 μl) increased tumor size and reduced survival. Behavioral alterations induced by GBM, including anxiety-like responses, exploratory behaviors, locomotor activity, and memory formation, were assessed using anxiety-like behavior task, the hole-board test, and the novel object recognition test. Muscimol treatment dose-dependently affected these behaviors in the animals with the mPFC-GBM, bringing their performance with that of the sham group at the dose of 1 µg/rat/2.5 μl. Changes in specific miRNAs expressions, including miR-208, -290-295, -345, -743 and -802 were associated with the growth of the mPFC-GBM under muscimol treatment. These findings suggest that GBM growth into the mPFC profoundly impacts cognitive and emotional behaviors which can be improved by muscimol treatment. Considering that the expression levels of targeted miRNAs could be influenced by the growth of the mPFC-GBM, both with or without muscimol treatment, these non-coding RNAs might serve as potential biomarkers for GBM.
2022
Tirgar, Fatemeh; Azizi, Zahra; Hosseindoost, Saereh; Hadjighassem, Mahmoudreza
Preclinical gene therapy in glioblastoma multiforme: using olfactory ensheathing cells containing a suicide gene Journal Article
In: Life Sciences, vol. 311, no. Pt A, pp. 121132, 2022, ISSN: 1879-0631.
Abstract | Links | BibTeX | Tags: Animals, Antiviral Agents, Cancer, Cultured, Ganciclovir, GCV: gancyclovir, Genetic Therapy, Glioblastoma, Glioblastoma multiforme, Olfactory ensheathing cells, Rats, Simplexvirus, Suicide gene therapy, Thymidine Kinase, Thymidine kinase gene, Tumor Cells
@article{tirgar_preclinical_2022,
title = {Preclinical gene therapy in glioblastoma multiforme: using olfactory ensheathing cells containing a suicide gene},
author = {Fatemeh Tirgar and Zahra Azizi and Saereh Hosseindoost and Mahmoudreza Hadjighassem},
doi = {10.1016/j.lfs.2022.121132},
issn = {1879-0631},
year = {2022},
date = {2022-12-01},
journal = {Life Sciences},
volume = {311},
number = {Pt A},
pages = {121132},
abstract = {AIMS: Glioblastoma multiforme (GBM) is the most malignant type of brain tumor resistant to current treatments. Recently, suicide gene therapy with the Herpex Simplex Virus thymidine kinase (HSV-tk) gene has been developed with high therapeutic potency, even in clinical trials. The primary challenge to establishing a gene therapy strategy is how to transfer the desired gene into the tumor site. The olfactory ensheathing cells (OECs) secreting neurotropic and anti-inflammatory factors have a high migration capacity, making them applicable for gene therapy. We examined our new construct OECs containing the HSV-tk gene for their migration and tumoricidal ability in animal models of GBM.
MAIN METHODS: Isolated OECs were transduced by the HSV-tk gene (OEC-tks). OEC-tks or PBS were injected ipsilaterally or contralaterally into the tumor-bearing rats, followed by gancyclovir (GCV) or PBS administration. At the end of the treatment, tumor size, apoptosis, and animal survival were assessed.
KEY FINDINGS: Our findings demonstrated that tumor size was significantly decreased in OEC-tks ipsilateral and contralateral groups, followed by GCV injections. Furthermore, both groups' pro-apoptotic protein and gene expressions were up-regulated, whereas Bcl-2 protein expression was down-regulated. Besides, apoptosis in the OEC-tks ipsilateral/GCV group was higher in the intratumoral region, and this percentage was higher in the OEC-tks contralateral/GCV group in the peritumoral region. Interestingly, our new construct increased animal survival rate and reduced body weight loss.
SIGNIFICANCE: OECs could serve as a novel carrier for gene therapy, have a high migration capability to the GBM and eventually suppress tumor progression.},
keywords = {Animals, Antiviral Agents, Cancer, Cultured, Ganciclovir, GCV: gancyclovir, Genetic Therapy, Glioblastoma, Glioblastoma multiforme, Olfactory ensheathing cells, Rats, Simplexvirus, Suicide gene therapy, Thymidine Kinase, Thymidine kinase gene, Tumor Cells},
pubstate = {published},
tppubtype = {article}
}
AIMS: Glioblastoma multiforme (GBM) is the most malignant type of brain tumor resistant to current treatments. Recently, suicide gene therapy with the Herpex Simplex Virus thymidine kinase (HSV-tk) gene has been developed with high therapeutic potency, even in clinical trials. The primary challenge to establishing a gene therapy strategy is how to transfer the desired gene into the tumor site. The olfactory ensheathing cells (OECs) secreting neurotropic and anti-inflammatory factors have a high migration capacity, making them applicable for gene therapy. We examined our new construct OECs containing the HSV-tk gene for their migration and tumoricidal ability in animal models of GBM.
MAIN METHODS: Isolated OECs were transduced by the HSV-tk gene (OEC-tks). OEC-tks or PBS were injected ipsilaterally or contralaterally into the tumor-bearing rats, followed by gancyclovir (GCV) or PBS administration. At the end of the treatment, tumor size, apoptosis, and animal survival were assessed.
KEY FINDINGS: Our findings demonstrated that tumor size was significantly decreased in OEC-tks ipsilateral and contralateral groups, followed by GCV injections. Furthermore, both groups' pro-apoptotic protein and gene expressions were up-regulated, whereas Bcl-2 protein expression was down-regulated. Besides, apoptosis in the OEC-tks ipsilateral/GCV group was higher in the intratumoral region, and this percentage was higher in the OEC-tks contralateral/GCV group in the peritumoral region. Interestingly, our new construct increased animal survival rate and reduced body weight loss.
SIGNIFICANCE: OECs could serve as a novel carrier for gene therapy, have a high migration capability to the GBM and eventually suppress tumor progression.
MAIN METHODS: Isolated OECs were transduced by the HSV-tk gene (OEC-tks). OEC-tks or PBS were injected ipsilaterally or contralaterally into the tumor-bearing rats, followed by gancyclovir (GCV) or PBS administration. At the end of the treatment, tumor size, apoptosis, and animal survival were assessed.
KEY FINDINGS: Our findings demonstrated that tumor size was significantly decreased in OEC-tks ipsilateral and contralateral groups, followed by GCV injections. Furthermore, both groups' pro-apoptotic protein and gene expressions were up-regulated, whereas Bcl-2 protein expression was down-regulated. Besides, apoptosis in the OEC-tks ipsilateral/GCV group was higher in the intratumoral region, and this percentage was higher in the OEC-tks contralateral/GCV group in the peritumoral region. Interestingly, our new construct increased animal survival rate and reduced body weight loss.
SIGNIFICANCE: OECs could serve as a novel carrier for gene therapy, have a high migration capability to the GBM and eventually suppress tumor progression.