Progress in establishing environmental risk factors and, consequently, prophylactic measures for glial tumors, particularly for glioblastomas, is of utmost importance, considering the dismal prognosis and limited treatment options. This report surveyed updates on established and recently identified factors that can predispose a patient to glioma formation while highlighting possible mechanistic links and further research directions. In addition to established factors that increase the risk of glioma, i.e., brain irradiation and several genetic syndromes, another group consists of likely factors contributing to such risks, such as the use of tobacco and those yielding ambiguous results (e.g., UV exposure). Oxidative stress is a common denominator for several types of exposure, and a mechanistic background for other factors remains elusive. Nevertheless, the analysis of clinical and basic research strongly suggests that, apart from the effect of environmental stressors on DNA alterations and mutation burden, the impact of modifying the tumor microenvironment should be considered. Identifying the involvement of environmental hazards in gliomagenesis and glial tumor progression would lower overall risk by modifying clinical practice, patient management, and lifestyle choices. Further verifying the environmental hazards in glioma formation and progression would have far-reaching implications for neurologists, neurosurgeons, and patients.

Subependymal giant cell astrocytoma (SEGA) is most often found in patients with TSC (Tuberous Sclerosis Complex). Although it has been classified as a benign tumor, it may create a serious medical problem leading to grave consequences, including young patient demise. Surgery and chemotherapy belong to the gold standard of treatment. A broader pharmacological approach involves the ever-growing number of rapalogs and ATP-competitive inhibitors, as well as compounds targeting other kinases, such as dual PI3K/mTOR inhibitors and CK2 kinase inhibitors. Novel approaches may utilize noncoding RNA-based therapeutics and are extensively investigated to this end. The purpose of our review was to characterize SEGA and discuss the latest trends in the diagnosis and therapy of this disease.

In the original publication [...].

Protein kinase CK2 has become a target of experimental antiglioma therapies as laboratory data are almost uniformly favorable and the number of synthetized CK2 inhibitors is rapidly growing. The evidence of their use for other brain tumors is on the increase as well. Great expectations are entrusted in naturally occurring compounds capable of inhibiting CK2 kinase. These compounds are extracted and purified by means of biochemistry methods and are amenable for innovative drug delivery systems as well. CK2 kinase inhibitors have been proven suitable for combined therapies with other investigational antiglioma agents and treatment modalities. However a greater share of efforts should be undertaken towards inhibiting functions relatively specific for glial tumors including infiltrative growth and invasiveness or maintenance of glioma initiating cells. Many of these function appear to converge on mTOR and JAK/STAT pathways which are being meticulously studied in this respect. Protein kinase CK2 holds therapeutic promise especially when combined with other agents aimed at molecular signatures of gliomas.

Subacute sclerosing panencephalitis (SSPE) is a fatal, slowly progressive brain disorder caused by a mutated measles virus. Both subacute inflammatory and neurodegenerative mechanisms appear to play significant roles in the pathogenesis. TAR DNA-binding protein 43 (TDP-43) inclusions are a common co-pathology in several neurodegenerative disorders with diverse pathogenesis. In the present study, we examined brains of 16 autopsied SSPE patients for the presence of TDP-43 pathology and possible associations with tau pathology. Immunohistochemical staining identified TDP-43 inclusions in 31% of SSPE cases. TDP-43 pathology was widely distributed in the brains, most severely in the atrophied cerebral cortex (temporal and parietal), and most frequently as tangle- and thread-like neuronal cytoplasmic inclusions. It was associated with longer disease duration (>4 years) and tau pathology (all TDP-43-positive cases had tau-positive neurofibrillary tangles). This study demonstrates for the first time an association between TDP-43 pathology and SSPE. The co-occurrence of TDP-43 and tau aggregates and correlation with the disease duration suggest that both pathological proteins are involved in the neurodegenerative process induced by viral inflammation.

Sixty-three patients admitted to 5 hospitals in 2014–2020 for the treatment of severe hypertensive brainstem hemorrhage by CT-guided and bone marker-oriented transcerebellar aspiration were enrolled in this study. The puncture accuracy, duration of hematoma removal, tracheal decannulation, postoperative complications, postoperative consciousness recovery time, Glasgow Outcome Scale (GOS) score, and prognosis outcome at follow-up were retrospectively analyzed. Additionally, the relationship between admission Glasgow Coma Scale (GCS) score and GOS score, and between hematoma volume and prognosis of patients was analyzed at follow-up. Results showed that CT localization–based and bone marker oriented transcerebellar hematoma aspiration in the treatment of severe hypertensive brainstem hemorrhage ensures high puncture accuracy, relatively low surgery risk, and good prognosis. The prognosis relates to the state of consciousness and hematoma volume.

EDITORIAL article Front. Neurol., 14 August 2023Sec. Endovascular and Interventional Neurology Volume 14 - 2023 | https://doi.org/10.3389/fneur.2023.1258677

White matter damage (WMD), one of the research hotspots of subarachnoid hemorrhage (SAH), mainly manifests itself as myelin injury and oligodendrocyte differentiation disorder after SAH, although the specific mechanism remains unclear. Dexamethasone-induced Ras-related protein 1(Dexras1) has been reported to be involved in nervous system damage in autoimmune encephalitis and multiple sclerosis. However, whether Dexras1 participates in dysdifferentiation of oligodendrocytes and myelin injury after SAH has yet to be examined, which is the reason for creating the research content of this article. Here, intracerebroventricular lentiviral administration was used to modulate Dexras1 levels in order to determine its functional influence on neurological injury after SAH. Immunofluorescence, transmission electron microscopy, and Western blotting methods, were used to investigate the effects of Dexras1 on demyelination, glial cell activation, and differentiation of oligodendrocyte progenitor cells (OPCs) after SAH. Primary rat brain neurons were treated with oxyhemoglobin to verify the association between Dexras1 and cAMP-CREB. The results showed that Dexras1 levels were significantly increased upon in vivo SAH model, accompanied by OPC differentiation disturbances and myelin injury. Dexras1 overexpression significantly worsened OPC dysdifferentiation and myelin injury after SAH. In contrast, Dexras1 knockdown ameliorated myelin injury, OPC dysdifferentiation, and glial cell activation. Further research of the underlying mechanism discovered that the cAMP-CREB pathway was inhibited after Dexras1 overexpression in the in vitro model of SAH. This study is the first to confirm that Dexras1 induced oligodendrocyte dysdifferentiation and myelin injury after SAH by inhibiting the cAMP-CREB pathway. This present research may reveal novel therapeutic targets for the amelioration of brain injury and neurological dysfunction after SAH.

Glioma cells use intermediate levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) for growth and invasion, and suppressing these reactive molecules thus may compromise processes that are vital for glioma survival. Increased oxidative stress has been identified in glioma cells, in particular in glioma stem-like cells. Studies have shown that these cells harbor potent antioxidant defenses, although endogenous protection against nitrosative stress remains understudied. The enhancement of oxidative or nitrosative stress offers a potential target for triggering glioma cell death, but whether oxidative and nitrosative stresses can be combined for therapeutic effects requires further research. The optimal approach of harnessing oxidative stress for anti-glioma therapy should include the induction of free radical-induced oxidative damage and the suppression of antioxidant defense mechanisms selectively in glioma cells. However, selective induction of oxidative/nitrosative stress in glioma cells remains a therapeutic challenge, and research into selective drug delivery systems is ongoing. Because of multifactorial mechanisms of glioma growth, progression, and invasion, prospective oncological therapies may include not only therapeutic oxidative/nitrosative stress but also inhibition of oncogenic kinases, antioxidant molecules, and programmed cell death mediators.

ObjectivesWe investigated the involvement of the proteasome in the mechanism of preconditioning with hyperbaric oxygen (HBO-PC). MethodsThe experiments were performed on male Wistar rats subjected to a transient global cerebral ischemia of 5 min duration (2-vessel occlusion model) and preconditioned or not with HBO for 5 preceding days (1 h HBO at 2.5 atmosphere absolute [ATA] daily). In subgroups of preconditioned rats, the proteasome inhibitor MG132 was administered 30 min prior to each preconditioning session. Twenty-four hours and 7 days post-ischemia, after neurobehavioral assessment, the brains were collected and evaluated for morphological changes and quantitative immunohistochemistry of cell markers and apoptosis-related proteins. ResultsWe observed reduced damage of CA1 pyramidal cells in the HBO preconditioned group only at 7 days post-ischemia. However, both at early (24 h) and later (7 days) time points, HBO-PC enhanced the tissue expression of 20S core particle of the proteasome and of the nestin, diminished astroglial reactivity, and reduced p53, rabbit anti-p53 upregulated modulator of apoptosis (PUMA), and rabbit anti-B cell lymphoma-2 interacting mediator of cell death (Bim) expressions in the hippocampus and cerebral cortex. HBO-PC also improved T-maze performance at 7 days. Proteasome inhibitor abolished the beneficial effects of HBO-PC on post-ischemic neuronal injury and functional impairment and reduced the ischemic alterations in the expression of investigated proteins. SignificancePreconditioning with hyperbaric oxygen-induced brain protection against severe ischemic brain insult appears to involve the proteasome, which can be linked to a depletion of apoptotic proteins and improved regenerative potential.

In gliomas, casein kinase 2 (CK2) plays a dominant role in cell survival and tumour invasiveness and is upregulated in many brain tumours. Among CK2 inhibitors, benzimidazole and isothiourea derivatives hold a dominant position. While targeting glioma tumour cells, they show limited toxicity towards normal cells. Research in recent years has shown that these compounds can be suitable as components of combined therapies with hyperbaric oxygenation. Such a combination increases the susceptibility of glioma tumour cells to cell death via apoptosis. Moreover, researchers planning on using any other antiglioma investigational pharmaceutics may want to consider using these agents in combination with CK2 inhibitors. However, different compounds are not equally effective when in such combination. More research is needed to elucidate the mechanism of treatment and optimize the treatment regimen. In addition, the role of CK2 in gliomagenesis and maintenance seems to have been challenged recently, as some compounds structurally similar to CK2 inhibitors do not inhibit CK2 while still being effective at reducing glioma viability and invasion. Furthermore, some newly developed inhibitors specific for CK2 do not appear to have strong anticancer properties. Further experimental and clinical studies of these inhibitors and combined therapies are warranted.

Intratumoral hemorrhage (ITH) as a variant of intracranial hemorrhage (ICH) is a known, albeit rare, clinical entity. Hemorrhages within brain neoplasms seem to remain underreported, including angiomatous meningioma and pilocytic astrocytoma as well as sarcoma spread to CNS in pediatric cases. Neuropathological studies remain a valuable part of ITH assessment. New experimental therapies for brain tumors, including combinations with hyperbaric oxygen or treatment with kinase inhibitors need to be evaluated for their effect on brain tumor vascularization. A growing body of scientific evidence points towards the need to strengthen the significance of vascular component in brain tumor classification.

The genetic alterations related to many kinases are responsible for the formation of glial tumours. In addition it is the cell kinases that keep the cancerous signalling machinery in motion, thus enabling tumour cell growth, motility and invasion. Kinase inhibitors may have a potential to surpass the classical oncolytic treatment for gliomas. However, overcoming drug resistance mechanisms and limited blood-brain barrier (BBB) permeability are the remaining daunting issues. Latest research explores novel kinase inhibitors, yielding several promising results, including those from CK2 inhibition studies, as well as the possibility of relabelling the inhibitors previously approved for tumours other than glial tumours.

Iron metabolism disturbances play an important role in early brain injury (EBI) after subarachnoid hemorrhage (SAH), and hepcidin largely influences iron metabolism. Importantly, iron metabolism may be associated with ferroptosis, recently a nonapoptotic iron-dependent form of cell death that may have a great impact on brain injury after SAH. We investigated hepcidin on iron metabolism and ferroptosis involving divalent metal transporter 1 (DMT1), and ferroportin-1 (FPN1) in a rat model of SAH. Male Sprague-Dawley rats were subjected to the endovascular perforation to induce SAH, and treated with heparin (inhibitor of hepcidin), or oncostatin M (OSM, inducer of hepcidin), or ebselen (inhibitor of DMT1) by intracerebroventricular injections. Hepcidin, DMT1, FPN1 and glutathione peroxidase 4 (GPX4), were detected by western blot and immunofluorescence. Iron metabolism was detected through Perl's iron staining and iron content assay. Ferroptosis, the ROS production, lipid peroxidation (LPO) was evaluated by monitoring methane dicarboxylic aldehyde (MDA), glutathione (GSH), glutathione peroxidase 4 (GPX4) activity, and transmission electron microscopy. Neurological deficit scores, Evans blue staining and brain water content were also determined to detect EBI 72 h after SAH. Our results showed that inhibition of DMT1 by ebselen could suppress iron accumulation and lipid peroxidation, and thereby alleviate ferroptosis and EBI in SAH rats. Heparin downregulated the expression of hepcidin and DMT1, increased FPN1, and exerted protective effects that were equivalent to those of ebselen on ferroptosis and EBI. In addition, OSM increased the expression of hepcidin and DMT1, decreased FPN1, and aggravated ferroptosis and EBI, while the effect on ferroptosis was reversed by ebselen. Therefore, the study revealed that hepcidin could regulate iron metabolism and contribute to ferroptosis via DMT1 signaling activation in rats with EBI after SAH.

Intracranial bleeding occurs in a substantial percentage of patients with neurotrauma and may gravely impact clinical outcomes. Hyperbaric oxygen (HBO) has been tested for traumatic brain injury (TBI), however its effect on the hemorrhagic component of TBI remains poorly understood. The characteristics of intracranial bleeding vary in different animal models of TBI. HBO appears to combat vascular injury and to reduce hemorrhagic complications. While the number of studies is limited, a decrease in intracranial bleeding and protection from BBB destruction may determine the effectiveness of HBO in TBI. Based on the results of experimental and clinical studies, this review advocates that intracranial bleeding in the course of TBI is the indispensable aspect of outcome assessment and postulate the search for new markers of traumatic vascular injury responsive to oxygen treatment.

Tumours of astroglial origin, both malignant glioblastoma (GBM) and benign subependymal giant cell astrocytoma (SEGA), pose a serious medical problem. Casein kinase 2 (CK2), a member of the serine/threonine kinase family, has antiapoptotic properties and plays a vital role in glial tumour cell survival. It contributes to invasive cell growth and is often upregulated in malignant neoplastic cells; however, its role in benign tumours of astrocytic origin is less understood. In the present study we investigated the effects of small molecule CK2 inhibitors on proliferation and viability of glioma cells in vitro. The experiments were conducted on commercial T98G malignant glioma cell line and the SEGA cell line, derived from a paediatric case of tuberous sclerosis complex (TSC). Cell cultures were incubated with selected CK2 inhibitors: 4,5,6,7-tetrabromo-1H-benzimidazole (TBI), 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) and 4,5,6,7-tetrabromo-1H-benzotriazole (TBB) at 0.1, 1, 10, 25, 50, 75 and 100 µM concentrations for 24 and 48 hours. Cell proliferation was assessed using a cell counter and cell viability was evaluated by MTT assay. TBB at 75 µM and 100 µM, and TBI starting from 25 µM, both reduced T98G cell proliferation after 24 hours, while DMAT was ineffective. All tested small molecule CK2 inhibitors appear to reduce T98G cell growth and viability after 48 hours, although TBI appeared to be the most effective and reduced cell growth in the 50-100 µM dose range. TBI also showed potential efficacy in reducing the number and viability of SEGA cells after 48 hours. Proliferation and viability of SEGA cells have proven resistant to TBB treatment. DMAT only reduced the viability of SEGA cells at 24 (at 100 µM) and 48 hours (10-100 µM). Importantly, normal human astrocyte cells were found to be moderately resistant to TBB, while their viability was mildly reduced at higher doses of DMAT and TBI. In conclusion, CK2 appears to play a role not only in malignant glioma cells but it can also sustain the viability and proliferation of benign astrocytoma cells. The obtained antitumor effects of CK2 inhibitors significantly exceeded their mild or no effect on normal astrocytes in control, which supports the therapeutic potential of these compounds against gliomas.

Glioblastoma (GBM) is the most common primary brain tumor. Tumor hypoxia is a pivotal factor responsible for the progression of this malignant glioma, and its resistance to radiation and chemotherapy. Thus, improved tumor tissue oxygenation may promote greater sensitivity to anticancer treatment. Protein kinase D1 (PKD1) protects cells from oxidative stress, and its abnormal activity serves an important role in multiple malignancies. The present study examined the effects of various oxygen conditions on the cytotoxic potential of the novel isothiourea derivate N,N'‑dimethyl‑S‑(2,3,4,5,6‑pentabromobenzyl)‑​isothiouronium bromide (ZKK‑3) against the T98G GBM cell line. ZKK‑3 was applied at concentrations of 10, 25 and 50 µM, and cells were maintained under conditions of normoxia, anoxia, hypoxia, hyperbaric oxygen (HBO), hypoxia/hypoxia and hypoxia/HBO. The proliferation and viability of neoplastic cells, and protein expression levels of hypoxia‑inducible factor 1α (HIF‑1α), PKD1, phosphorylated (p)PKD1 (Ser 916) and pPKD1 (Ser 744/748) kinases were evaluated. Oxygen deficiency, particularly regarding hypoxia, could diminish the cytotoxic effect of ZKK‑3 at 25 and 50 µM and improve T98G cell survival compared with normoxia. HBO significantly reduced cell proliferation and increased T98G cell sensitivity to ZKK‑3 when compared with normoxia. HIF‑1α expression levels were increased under hypoxia compared with normoxia and decreased under HBO compared with hypoxia/hypoxia at 0, 10 and 50 µM ZKK‑3, suggesting that HBO improved oxygenation of the cells. ZKK‑3 exhibited inhibitory activity against pPKD1 (Ser 916) kinase; however, the examined oxygen conditions did not appear to significantly influence the expression of this phosphorylated form in cells treated with the tested compound. Regarding pPKD1 (Ser 744/748), a significant difference in expression was observed only for cells treated with 10 µM ZKK‑3 and hypoxia/hypoxia compared with normoxia. However, there were significant differences in the expression levels of both phosphorylated forms of PKD1 under different oxygen conditions in the controls. In conclusion, the combination of isothiourea derivatives and hyperbaric oxygenation appears to be a promising therapeutic approach for malignant glioma treatment.

BACKGROUND/AIM Tumours of astroglial origin are the most common primary brain malignancy characterized by infiltrative growth and resistance to standard antitumour therapy. Glioma progression is thought to be related to various intracellular signal transduction pathways that involve the activation of protein kinases. Protein kinases play important roles in cell differentiation, proliferation, and survival. Recently, novel, specific inhibitors of constitutively active serine/threonine kinases and structurally similar isothiourea derivatives were suggested to induce apoptosis and inhibit proliferation in several types of human cancer cells. MATERIALS AND METHODS In this study, we examined the cytotoxic and proapoptotic activities of selected modified pentabromobenzyl isothioureas (ZKKs) in an adult human glioblastoma (T98G) and a subependymal giant cell astrocytoma cell (SEGA) line. We evaluated cell proliferation, viability, and apoptosis. RESULTS Two pentabromobenzyl isothiourea bromide derivatives, ZKK-13 and N,N,N'-trimethyl-ZKK1 (TRIM), exhibited the most potent cytotoxic and proapoptotic efficacies against human glioma-derived cells, even at a very low concentration (1 μM). ZKK-13 (25-50 μM) inhibited cell growth by approximately 80-90% in 24 and 48 h of treatment. We showed that selected ZKKs exerted antiproliferative activity against astroglial neoplastic cells of both low- and high-grade tumour malignancy classes. No synergistic effects were detected when ZKKs were combined with serine/threonine kinase inhibitors. CONCLUSION Our findings indicated that modified ZKKs show promise for the treatment of glioma-derived brain tumours.