There is a bidirectional relationship between epilepsy-related stigma (ERS) and medical outcomes. ERS negatively influences treatment adherence and disease management, whereas insufficient medical improvement can, in turn, exacerbate ERS. ERS remains a significant challenge, often leading to delays in diagnosis, limiting appropriate therapies, and creating difficulties in social integration for patients with epilepsy. Even when treatment successfully achieves seizure cessation, failure to address ERS can limit patient social integration, reduce quality of life, and hamper long-term psychosocial recovery. Previous studies suggest that a holistic and personalized medicine approach that addresses both the medical and psychosocial aspects of epilepsy, with a particular focus on reducing ERS, can significantly improve diagnosis and treatment outcomes. Integrating culturally sensitive mental health support and community-specific advocacy initiatives targeting ERS reduction into the routine management of epilepsy can promote clinical and psychosocial outcomes and help patients in their reintegration into normal daily life. Key initiatives may include personalized counseling to mitigate the emotional and psychological impact of ERS, targeted cultural competency training for healthcare professionals, and public awareness campaigns. Integrating these strategies into comprehensive epilepsy care is particularly important for marginalized populations, where poverty and limited healthcare access exacerbate ERS. A personalized anti-ERS plan that integrates individualized clinical management with targeted interventions designed for the specific ERS experiences of each patient can improve treatment adherence, enhance cognitive and emotional well-being, and promote better social integration by addressing both the psychological and social dimensions of ERS.

Medically intractable temporal lobe epilepsy is associated with potential neuronal and glial damage in key brain structures, including the hippocampus and amygdala. This study aimed to examine apoptosis, caspase expression, and glial activation markers in these regions, and to evaluate their associations with clinical variables. Hippocampal and amygdala tissues from 17 patients with medically intractable epilepsy and autopsy-derived non-epileptic controls were examined for cellular apoptosis (TUNEL), caspase-3, -9, and -12, as well as GFAP (astrocytic marker) and IBA1 (microglial marker) expression using immunohistochemistry. Correlation analyses were performed to evaluate associations between these molecular markers and various clinical variables. TUNEL-positive cells and caspase-3 expression were significantly increased in both the hippocampus and amygdala of patients with medically intractable epilepsy compared to control subjects. Caspase-9 and caspase-12 were selectively elevated in the amygdala, while GFAP was upregulated in both regions, and IBA1 showed no significant differences. Protein expression patterns varied with age, sex, psychiatric comorbidities, seizure type and frequency, traumatic brain injury, and antiseizure drug treatment. Age at seizure onset, epilepsy duration, and total seizure numbers were associated with distinct molecular profiles. The epileptic hippocampal and amygdala tissues exhibit distinct, region-specific changes in apoptotic and glial markers. These findings suggest that apoptosis and glial alterations may contribute to region-specific pathological mechanisms underlying medically intractable temporal lobe epilepsy and may be influenced by clinical disease characteristics.

Objectives The Notch signaling pathway is integral to the development, maintenance, and function of the CNS by regulating neural stem cell fate, neurogenesis, and glial activity. Notch1, a key receptor in this pathway, is essential not only for synaptic plasticity but also for maintaining proper neuron-glia interactions. Dysregulation of Notch signaling has been implicated in various neurological disorders. However, the role of this pathway in absence epilepsy requires further elucidation. Methods Here, we used a combination of bioinformatics, molecular, and histological analyses to investigate the expression patterns and correlations among Notch1, its regulators (NLE1 and Jagged1), and cellular markers GFAP and NeuN in human datasets and the WAG/Rij rat strain, a commonly used experimental model for absence seizures. Results Our findings revealed region-specific expression correlations in healthy human brain tissue and age-related expression changes in WAG/Rij and Wistar rat strains. Furthermore, WAG/Rij rats showed significant changes in the expression of Notch1, NLE1, Jagged1, GFAP, and NeuN compared to Wistar rat controls, with altered gene correlations suggesting disrupted Notch signaling. Moreover, significant alterations in the neuron-glial ratio, along with changes in the immunohistological expression patterns of these markers, were observed. Conclusion These findings suggest that impaired Notch pathway dynamics may play a role in the pathophysiology of absence seizures and point to potential molecular mechanisms for future therapeutic investigation.

Neuroinflammation is a key response to disturbed CNS homeostasis, largely mediated by activated microglia, and excessive microglia-driven inflammation can negatively impact neurogenesis. ZEB1 plays a crucial role in neurogenesis and brain development by influencing neural stem cell (NSC) maintenance, proliferation, and differentiation. This study aimed to evaluate how the knockdown of ZEB1 influences the behavior of NSCs in inflammatory environments. NSCs were isolated from the subventricular zone of rats, and ZEB1 knockdown was achieved using ZEB1 siRNA. A conditioned medium derived from lipopolysaccharide-activated microglia was utilized to induce inflammatory responses in NSCs. The silencing of ZEB1 in NSCs significantly reduced the expression of ZEB1. Furthermore, ZEB1 knockdown in NSCs resulted in a significant decrease in neurosphere formation, cell migration ability, reactive oxygen species generation, and various cytokine levels under both non-inflammatory and inflammatory conditions. These findings reveal the regulatory role of ZEB1 in the modulation of NSC behavior, suggesting that targeting ZEB1 may provide a potential therapeutic strategy for neuroinflammatory CNS disorders.

Gliomas are the most common lethal tumors of the brain associated with a poor prognosis and increased resistance to chemo-radiotherapy. Circular RNAs (circRNAs), newly identified noncoding RNAs, have appeared as critical regulators of therapeutic resistance among multiple cancers and gliomas. Since circRNAs are aberrantly expressed in glioma and may act as promoters or inhibitors of therapeutic resistance, we categorized alterations of these specific RNAs expression in therapy resistant-glioma in three different classes, including chemoresistance, radioresistance, and glioma stem cell (GSC)-regulation. circRNAs act as competing endogenous RNA, sponging target microRNA and consequently affecting the expression of genes related to glioma tumorigenesis and resistance. By doing so, circRNAs can modulate the critical cellular pathways and processes regulating glioma resistance, including DNA repair pathways, GSC, epithelial-mesenchymal transition, apoptosis, and autophagy. Considering the poor survival and increased resistance to currently approved treatments for glioma, it is crucial to increase the knowledge of the resistance regulatory effects of circRNAs and their underlying molecular mechanisms. Herein, we conducted a comprehensive search and discussed the existing knowledge regarding the important role eof circRNAs in the emergence of resistance to therapeutic interventions in glioma. This knowledge may serve as a basis for enhancing the effectiveness of glioma therapeutic strategies.

5-aminolevulinic acid (5-ALA) is a widely recognized and effective tool for improving tumor resections during surgical interventions but may directly interact with cells in the tumor microenvironment. Nevertheless, there remains an ongoing debate regarding the impact of 5-ALA on neural stem cells (NSCs). This study aims to investigate the effects of 5-ALA on both NSCs and oligodendrocyte progenitor cells (OPCs). In this study, NSCs were isolated from the subventricular zones of rat brains and differentiated into OPCs. Both NSCs and OPCs were subsequently treated with 5-ALA, and their effects were evaluated through immunostaining and colony-formation assays. Our findings show that 5-ALA treatment induces PPIX accumulation in both NSCs and OPCs, with NSCs exhibiting higher levels presumably due to their greater proliferation rate. Furthermore, our results indicate that prolonged PPIX accumulation impairs NSC clonogenicity. These results underscore possible interactions of 5-ALA-induced PPIX with NSCs. 5-ALA shows promise as a potential marker for NSCs, but may also be of value for specifically targeting NSCs through activation of porphyrins using light or radiotherapy.

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide, presenting a significant challenge due to the lack of effective therapies. Neural stem cells (NSCs) have shown promising potential in preclinical studies as a therapy for TBI. However, their application is limited by challenges related to poor survival and integration within the injured brain. This study investigated the effect of a novel nano-scaffold containing stromal cell-derived factor 1 (SDF-1) on NSC behavior and synaptogenesis after TBI. Using an innovative design, we successfully fabricated a nano-scaffold with Young’s modulus of approximately 3.21 kPa, which aligns closely with the mechanical properties exhibited by neural tissue. This achievement marks the first time such a scaffold has been created and has promising implications for its potential use in neural tissue engineering applications. Our findings demonstrate that the nano-scaffold enhances NSC proliferation, migration, and differentiation capacity in vitro. Moreover, when transplanted into the injured brain, the nano-scaffold promotes the survival and integration of NSCs, leading to increased synaptogenesis and functional recovery. These findings suggest that using the novel nano-scaffold containing SDF-1 could provide a promising approach to treating TBI by improving NSC behavior and promoting synaptogenesis.

Repetitive cortical spreading depression (CSD) can lead to cell death in immature brain tissue. Caspases are involved in neuronal cell death in several CSD-related neurological disorders, such as stroke and epilepsy. Yet, whether repetitive CSD itself can induce caspase activation in adult or juvenile tissue remains unknown. Inducing repetitive CSD in somatosensory cortices of juvenile and adult rats in vivo, we thus aimed to investigate the effect of repetitive CSD on the expression caspase-3, caspase-8, caspase-9, and caspase-12 in different brain regions using immunohistochemistry and western blotting techniques. Higher numbers of dark neurons and TUNEL-positive cells were observed in the hippocampal CA1 and CA3 regions as well as in the entorhinal and somatosensory cortices after CSD in juvenile rats. This was accompanied by higher expressions of caspase-3, caspase-8, and caspase-9. Caspase-12 levels remained unchanged after CSD, suggesting that endoplasmic reticulum stress is not involved in CSD-triggered apoptosis. Changes in caspase expression were paralleled by a decrease of procaspase-3, procaspase-8, and procaspase-9 in juvenile rat brain tissue subjected to CSD. In contrast, repetitive CSD in adult rats did not result in the upregulation of caspase signaling. Our data points to a maturation-dependent vulnerability of brain tissue to repetitive CSD with a higher degree of apoptotic damage and caspase upregulation observed in juvenile tissue. Findings suggest a key role of caspase signaling in CSD-induced cell death in the immature brain. This implies that anti-apoptotic treatment may prevent CSD-related functional deficits in the immature brain.

Introduction: Astrocyte dysfunction plays a crucial role in epileptogenesis by impacting neuronal excitability and synaptic transmission. This study investigates how specific small molecules (SMs) affect the survival of astrocytes derived from various brain regions (the neocortex, hippocampus, or amygdala) of patients with medically refractory epilepsy. Methods: This study evaluated astrocyte responses to three distinct SMs (valproate, forskolin, and GSK3 inhibitor/WNT activator CHIR99021), individually or in combined forms, to determine their differential effects on astrocyte survival. Results: The effects of SMs on astrocyte survival varied based on the brain tissue source and individual patient differences. Astrocytes from the amygdala of two patients showed heightened sensitivity to the SMs, while astrocytes from the neocortex of one patient exhibited decreased viability following treatment with CHIR99021 and valproate. Moreover, astrocytes from the hippocampus exhibited a significant decrease in viability in one patient, whereas no significant changes were observed in other patients. Conclusion: Variability in astrocyte responses to SMs, influenced by brain region and patient differences, may highlight their role in shaping diverse therapeutic outcomes in individuals. Further studies are required to clarify the factors involved in the different behaviors of astrocytes in response to SMs in epilepsy.

BACKGROUND:Glioblastoma (GBM) is an aggressive primary brain cancer with a poor prognosis. Preclinical animal models are essential for studying GBM pathophysiology and therapy; however, existing models often fail to fully capture the tumor's heterogeneity and the partially immunodeficient microenvironment critical to its progression. NEW METHOD:We developed a novel GBM model using the stereotactic implantation of primary patient-derived GBM cells from various donors into the brains of rats subjected to transient, partial immune suppression. RESULTS:This model combines the biological heterogeneity of patient-derived cells with the anatomical advantages of a larger rodent brain, improving spatial tumor localization. The use of a mixed primary cell population better recapitulates human GBM heterogeneity. Furthermore, the model's partially preserved immune environment allows for the investigation of tumor-immune interactions. COMPARISON WITH EXISTING METHODS:Unlike fully immunodeficient models, our approach maintains a more physiologically relevant, partially intact immune system. Compared to murine models, the rat brain offers superior spatial resolution for tumor analysis and intervention. CONCLUSIONS:This method provides a reliable and translational platform that enhances the fidelity of preclinical GBM research. It offers an improved tool for drug evaluation and the development of personalized therapeutic strategies by more accurately mimicking the complex and heterogeneous nature of human GBM.

N-methyl-D-aspartate receptors (NMDARs), a subclass of glutamate-gated ion channels, play an integral role in the maintenance of synaptic plasticity and excitation-inhibition balance within the central nervous system (CNS). Any irregularities in NMDAR functions, whether hypo-activation or over-activation, can destabilize neural networks and impair CNS function. Several decades of experimental and clinical investigations have demonstrated that NMDAR dysfunction is implicated in the pathophysiology of various neurological disorders. Despite designing a long list of compounds that differentially modulate NMDARs, success in developing drugs that can selectively and effectively regulate various NMDAR subtypes while showing encouraging efficacy in clinical settings remains limited. A better understanding of the basic mechanism of NMDAR function, particularly its selective regulation in pathological conditions, could aid in designing effective drugs for the treatment of neurological conditions. Here, we reviewed the experimental and clinical investigations that studied the effects of available NMDAR modulators in various neurological disorders and weighed up the pros and cons of the use of these substances on the improvement of functional outcomes of these disorders. Despite numerous efforts to develop NMDAR modulatory drugs that did not produce the desired outcomes, NMDARs remain a significant target for advancing novel drugs to treat neurological disorders. This article reviews the complexity of NMDAR signaling dysfunction in different neurological diseases, the efforts taken to examine designed compounds targeting specific subtypes of NMDARs, including challenges associated with using these substances, and the potential enhancements in drug discovery for NMDAR modulatory compounds by innovative technologies.

Although tetrahydrocannabinol (THC) and cannabidiol (CBD) have been individually studied for their neuroprotective roles, few studies have addressed the effects of their balanced 1:1 formulation Satinex (STX) under pathologic conditions like hypoxia. Moreover, the effect of STX on embryonic neural stem/progenitor cells (ENS/PCs) derived from the rat embryonic brain, which are highly vulnerable during early development, remains unexplored. Considering the pivotal role of hypoxia in numerous neuropathological situations, this study examined the impact of STX on rat ENS/PCs exposed to chemically induced hypoxia. ENS/PCs were isolated from rat embryos and subjected to hypoxia using 100 µM cobalt (II) chloride hexahydrate (CoCl₂0.6 H₂O) for 48 h. Cytotoxic activity of STX andCoCl2was assessed using the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2 H-tetrazolium (MTT) assay, while stem cell identity was confirmed via flow cytometry (Nestin, SOX2). STX (0.1 and 0.5 µM) was applied under both normoxic and hypoxic conditions. Expression levels of hypoxia-inducible factor 1-alpha (Hif1α) mRNA, autophagy markers (Beclin-1, microtubule-associated protein 1 light chain 3-II [LC3-II]), and pro-inflammatory proteins nuclear factor kappa B [NF-κB], Toll-like receptor 2 [TLR2], Toll-like receptor 4 [TLR4]) were assessed using reverse transcription polymerase chain reaction (RT-PCR) and western blot techniques following STX treatment. Based on flow cytometric assays, over 70

Objective(s): Toll-like receptors (TLRs) have been implicated in the pathogenesis of glioma as principal regulators of inflammation and innate immune function. Considering the heterogeneous nature of gliomas, ranging from low to high grade with different therapeutic responses, investigating the differences in the levels of TLR2 and TLR4 and associated inflammatory markers in these distinct groups is of great clinical significance.Materials and Methods: In this study, we investigated changes in the protein expression levels of TLR2 and TLR4, along with key inflammatory mediators, including nuclear factor kappa B (NF-κB) as a downstream signaling molecule, and tumor necrosis factor-alpha (TNF-α), a target of NF-κB activation, by using western blotting. Primary human cells were isolated from surgically resected tissue samples of patients with low- and high-grade gliomas and were compared to cells derived from the human epileptic brain. In vitro cell characterization was performed via immunocytochemistry using markers specific to each group.Results: Protein levels were assessed by western blotting. TLR2 expression was significantly higher in the high-grade glioma group compared to the low-grade group. The expression of TLR2 and TLR4 was significantly greater in the epilepsy group compared to the low-grade glioma group. No remarkable differences were detected in the levels of NF-κB and TNF-α between high and low-grade gliomas. Conclusion: Our results revealed distinct patterns of TLR expression between low- and high-grade gliomas, underscoring the potential involvement of TLRs in the cellular heterogeneity of gliomas.

Mutations occurring in the MeCp2, CDKL5 and BDNF genes have been linked to epileptogenesis in various epilepsy syndromes. This study employed bioinformatics analysis of transcriptomic data to examine the interrelationship among these genes in both epileptic and healthy individuals. Moreover, we assessed the expression of MeCp2, CDKL5 and BDNF at both mRNA and protein levels in human hippocampal tissues obtained from 22 patients undergoing epilepsy surgery for mesial temporal lobe epilepsy (MTLE) as well as from 25 autopsied specimens. Bioinformatics findings suggest that MeCp2, CDKL5 and BDNF genes play a role in regulating genes associated with epilepsy and disruptions in these genes may contribute to epilepsy development. Furthermore, the study reveals significantly lower MeCp2 and CDKL5 protein levels in the epileptic hippocampus compared to controls. Positive correlations are observed between MeCp2 and CDKL5 mRNA expression in autopsied samples and between CDKL5 and BDNF mRNA expression in epileptic hippocampal tissues. Differences in mRNA expression correlation patterns of MeCp2 and CDKL5 with BDNF are found between epileptic and control hippocampal tissues. Moreover, a significant positive correlation between MeCp2 and CDKL5 protein expression is noted in control hippocampal tissues. Our data suggest that altered expression of MeCp2, CDKL5 and BDNF within the hippocampus may contribute to epileptogenic processes in MTLE, impacting seizure characteristics, surgical outcomes and responses to antiepileptic drugs. Alterations in the expression of MeCp2, CDKL5 and BDNF within the hippocampus might contribute to the epileptogenic processes in MTLE. These changes could be linked to distinct functional consequences in epilepsy.