Efficacy of LY233053, a competitive glutamate antagonist, in experimental central nervous system ischemia

1992 ◽  
Vol 76 (1) ◽  
pp. 106-110 ◽  
Author(s):  
Kenneth P. Madden ◽  
Wayne M. Clark ◽  
Abha Kochhar ◽  
Justin A. Zivin
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Side Effects ◽  
Excitatory Amino Acids ◽  
Neurological Damage ◽  
Content Type ◽  
Glutamate Antagonist ◽  
Fine Print

✓ Antagonists of excitatory amino acids appear to serve a neuroprotective role during ischemic conditions in a variety of in vivo and in vitro models. The usefulness of such agents in the clinical setting, however, may be limited by poor central nervous system (CNS) entry and intolerable side effects. The authors report high efficacy in reducing neurological damage and relatively limited side effects of LY233053, a novel competitive glutamate antagonist, in two models of experimental CNS ischemia in the rabbit.

Side effects of spasmolytic agents in the monkey

1973 ◽  
Vol 39 (5) ◽  
pp. 629-635 ◽  
Author(s):  
Albert N. Martins ◽  
John K. Wiley
Keyword(s):  
Central Nervous System ◽  
Cerebrospinal Fluid ◽  
Nervous System ◽  
Side Effects ◽  
System Function ◽  
Central Nervous System Function ◽  
Content Type ◽  
Spasmolytic Agents ◽  
Nervous System Function ◽  
Fine Print

✓ The authors report a study of the physiological and morphological responses of the rhesus monkey brain to intracisternal injections of two potentially useful spasmolytic agents, phenoxybenzamine and phentolamine. Central nervous system function remained unaffected by intracisternal injections of either drug in doses that were small but nevertheless sufficient to attain pharmacologically effective concentrations in the cerebrospinal fluid. Larger doses of phenoxybenzamine caused a chemical basilar meningitis. Phentolamine caused arterial hypotension without meningitis. It is concluded that intracisternal spasmolytic therapy deserves further experimental evaluation.

Gangliosides: the relevance of current research to neurosurgery

1991 ◽  
Vol 74 (4) ◽  
pp. 606-619 ◽  
Author(s):  
Frank A. Rodden ◽  
Herbert Wiegandt ◽  
Bernard L. Bauer
Keyword(s):  
Nervous System ◽  
Mammalian Cells ◽  
Human Subjects ◽  
Laboratory Animals ◽  
Trophic Effect ◽  
Content Type ◽  
Degree Of Malignancy ◽  
Fine Print

✓ Gangliosides are complex glycolipids found on the outer surface of most cell membranes: they are particularly concentrated in tissues of the nervous system. Gangliosides form part of the immunological identity of mammalian cells and are involved in a variety of cell-surface phenomena such as cell-substrate binding and receptor functions. In tumorous tissue, the ganglioside composition is altered, sometimes in direct proportion to the degree of malignancy. The literature on the glycosphingolipid composition and immunology of intracranial tumors is reviewed. Some gangliosides induce neuritogenesis and exhibit a trophic effect on nerve cells grown in vitro. In vivo, a particular ganglioside, GM1, reduces cerebral edema and accelerates recovery from injury (traumatic and ischemic) to the peripheral and central nervous systems of laboratory animals. Preliminary clinical studies have shown that treatment with gangliosides may have corresponding effects on lesions of the human peripheral nervous system. Gangliosides have not been tested in human subjects with brain injury.

Insulin and insulin-like growth factors in central nervous system tumors

1992 ◽  
Vol 77 (3) ◽  
pp. 445-450 ◽  
Author(s):  
Roberta P. Glick ◽  
Terry G. Unterman ◽  
Mary Van der Woude ◽  
Lisa Zollner Blaydes
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Growth Factor ◽  
Tumor Cell ◽  
Cns Tumors ◽  
Insulin Like Growth Factor ◽  
Content Type ◽  
Igf I ◽  
Fine Print

✓ The authors have previously reported the presence of insulin-like growth factor (IGF) receptors in central nervous system (CNS) tumors and the production of IGF's and their binding proteins by CNS tumors in situ. This study was designed to investigate whether CNS tumor cells are capable of autocrine secretion of IGF-I and IGF-II in vitro. Production of IGF's was studied by specific radioimmunoassay of tumor-cell-conditioned serum-free media from 34 CNS tumors: 12 gliomas, 12 meningiomas, and 10 miscellaneous tumors. Normal human serum and cerebrospinal fluid served as controls. Insulin-like growth factor I was detected in five of 12 meningiomas but in none of the gliomas studied. In contrast, IGF-II was detected in four of 12 gliomas and in six of 11 meningiomas studied. Four miscellaneous tumors produced IGF-I and/or IGF-II. These results suggest that CNS tumors differentially produce IGF-I and IGF-II in vitro. Preferential production of IGF's may be an important marker of the tumor-cell differentiation or malignancy and may be useful as a clinical diagnostic tool. These results add further support to the concept that IGF's may play a role in the regulation of the behavior of CNS tumors.

scholarly journals The Orotomide Olorofim Is Efficacious in an Experimental Model of Central Nervous System Coccidioidomycosis

2018 ◽  
Vol 62 (9) ◽  
Author(s):  
Nathan P. Wiederhold ◽  
Laura K. Najvar ◽  
Rosie Jaramillo ◽  
Marcos Olivo ◽  
Michael Birch ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Oral Therapy ◽  
Vehicle Control ◽  
Coccidioides Immitis ◽  
Central Nervous System Infections ◽  
Content Type ◽  
Highly Active

ABSTRACT Olorofim (formerly F901318) is an advanced analog of the orotomide class that inhibits fungal pyrimidine biosynthesis. We evaluated the in vitro and in vivo activities of olorofim against Coccidioides species. In vitro activity was assessed against 59 clinical Coccidioides isolates. Central nervous system infections were established in mice via intracranial inoculation with Coccidioides immitis arthroconidia. Oral therapy began 48 h postinoculation and consisted of vehicle control, olorofim daily doses of 20 mg/kg (6.67 mg/kg three times daily or 10 mg/kg twice daily) or 40 mg/kg (13.3 mg/kg three times daily or 20 mg/kg twice daily), or fluconazole (25 mg/kg twice daily). Treatment continued for 7 and 14 days in the fungal burden and survival arms, respectively. Fungal burdens were assessed by CFU counts in brains. Olorofim demonstrated potent in vitro activity (MIC range, ≤0.008 to 0.06 μg/ml). Survival was significantly enhanced in mice treated with olorofim. Reductions in brain tissue fungal burdens were also observed on day 9 in the olorofim-treated groups. Improvements in survival and reductions in fungal burdens also occurred with fluconazole. More frequent dosing of olorofim was associated with enhanced survival and greater reductions in fungal burdens. In the group treated with 13.3 mg/kg olorofim three times daily, fungal burdens remained low on day 30 (15 days after treatment was stopped), with undetectable levels in 7 of 10 mice. In contrast, fungal burdens rebounded in all other groups after therapy stopped. Olorofim was highly active in vitro and in vivo against Coccidioides. These results demonstrate that olorofim may have a role in the treatment of coccidioidomycosis.

scholarly journals INFLUENCE OF ANESTHESIA ON EXPERIMENTAL NEUROTROPIC VIRUS INFECTIONS

1946 ◽  
Vol 84 (4) ◽  
pp. 277-292 ◽  
Author(s):  
S. Edward Sulkin ◽  
Christine Zarafonetis ◽  
Andres Goth
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Diethyl Ether ◽  
Cervical Region ◽  
Virus Infections ◽  
Ether Anesthesia ◽  
Neurotropic Virus ◽  
Experimental Infections

Anesthesia with diethyl ether significantly alters the course and outcome of experimental infections with the equine encephalomyelitis virus (Eastern or Western type) or with the St. Louis encephalitis virus. No comparable effect is observed in experimental infections produced with rabies or poliomyelitis (Lansing) viruses. The neurotropic virus infections altered by ether anesthesia are those caused by viruses which are destroyed in vitro by this anesthetic, and those infections not affected by ether anesthesia are caused by viruses which apparently are not destroyed by ether in vitro. Another striking difference between these two groups of viruses is their pathogenesis in the animal host; those which are inhibited in vivo by ether anesthesia tend to infect cells of the cortex, basal ganglia, and only occasionally the cervical region of the cord. On the other hand, those which are not inhibited in vivo by ether anesthesia tend to involve cells of the lower central nervous system and in the case of rabies, peripheral nerves. This difference is of considerable importance in view of the fact that anesthetics affect cells of the lower central nervous system only in very high concentrations. It is obvious from the complexity of the problem that no clear-cut statement can be made at this point as to the mechanism of the observed effect of ether anesthesia in reducing the mortality rate in certain of the experimental neurotropic virus infections. Important possibilities include a direct specific effect of diethyl ether upon the virus and a less direct effect of the anesthetic upon the virus through its alteration of the metabolism of the host cell.

scholarly journals Astrocyte-Derived CCL2 is Associated with M1 Activation and Recruitment of Cultured Microglial Cells

2016 ◽  
Vol 38 (3) ◽  
pp. 859-870 ◽  
Author(s):  
Mingfeng He ◽  
Hongquan Dong ◽  
Yahui Huang ◽  
Shunmei Lu ◽  
Shu Zhang ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Microglial Activation ◽  
Culture Media ◽  
Microglial Cells ◽  
Migration Ability ◽  
Migration Assay ◽  
Tnf Α

Background/Aims: Microglia are an essential player in central nervous system inflammation. Recent studies have demonstrated that the astrocytic chemokine, CCL2, is associated with microglial activation in vivo. However, CCL2-induced microglial activation has not yet been studied in vitro. The purpose of the current study was to understand the role of astrocyte-derived CCL2 in microglial activation and to elucidate the underlying mechanism(s). Methods: Primary astrocytes were pre-treated with CCL2 siRNA and stimulated with TNF-α. The culture medium (CM) was collected and added to cultures of microglia, which were incubated with and without CCR2 inhibitor. Microglial cells were analyzed by quantitative RT-PCR to determine whether they polarized to the M1 or M2 state. Microglial migratory ability was assessed by transwell migration assay. Results: TNF-α stimulated the release of CCL2 from astrocytes, even if the culture media containing TNF-α was replaced with fresh media after 3 h. CM from TNF-α-stimulated astrocytes successfully induced microglial activation, which was ascertained by increased activation of M1 and enhanced migration ability. In contrast, CM from astrocytes pretreated with CCL2 siRNA showed no effect on microglial activation, compared to controls. Additionally, microglia pre-treated with RS102895, a CCR2 inhibitor, were resistant to activation by CM from TNF-α-stimulated astrocytes. Conclusion: This study demonstrates that the CCL2/CCR2 pathway of astrocyte-induced microglial activation is associated with M1 polarization and enhanced migration ability, indicating that this pathway could be a useful target to ameliorate inflammation in the central nervous system.

Antitumor effects of antiprogesterones on human meningioma cells in vitro and in vivo

1994 ◽  
Vol 80 (3) ◽  
pp. 527-534 ◽  
Author(s):  
Yasuhiro Matsuda ◽  
Keiichi Kawamoto ◽  
Katsuzo Kiya ◽  
Kaoru Kurisu ◽  
Kazuhiko Sugiyama ◽  
...  
Keyword(s):  
Marked Reduction ◽  
Tumor Volume ◽  
Collagen Gel ◽  
Antitumor Effects ◽  
Histological Changes ◽  
Content Type ◽  
The Relationship ◽  
Fine Print

✓ The presence of the progesterone receptor (PR) in meningioma tissue has been confirmed by previous investigations. Studies have shown that the antiprogesterone drug, mifepristone, is a potent agent that inhibits the growth of cultured meningioma cells and reduces the size of meningiomas in experimental animal models and humans. However, these studies have not fully examined the relationship between the antitumor effects of an antiprogesterone agent and the expression of the PR. The present study examined the antitumor effects of mifepristone and a new potent antiprogesterone agent, onapristone; a correlation between the antitumor effects of these antiprogesterones and the presence of PR's in meningiomas in vitro and in vivo was also investigated. Meningioma tissue surgically removed from 13 patients was used in this study. In the in vitro arm of the study, mifepristone and onapristone exhibited cytostatic and cytocidal effects against cultured meningioma cells, regardless of the presence or absence of PR's; however, three PR-negative meningiomas showed no response to any dose of mifepristone and/or onapristone. In the in vivo arm, meningioma cells, embedded in a collagen gel, were implanted into the renal capsules of nude mice. Antiprogesterone treatment resulted in a marked reduction of the tumor volume regardless of the presence or absence of PR's. No histological changes in the meningioma cells suggestive of necrosis or apoptosis were detected in any of the mice treated with antiprogesterones. These findings suggest that mifepristone and onapristone have an antitumor effect against meningioma cells via the PR's and/or another receptor, such as the glucocorticoid receptor.

scholarly journals Polo-Like Kinase 4 (PLK4) Is Overexpressed in Central Nervous System Neuroblastoma (CNS-NB)

2018 ◽  
Vol 5 (4) ◽  
pp. 96 ◽  
Author(s):  
Anders Bailey ◽  
Amreena Suri ◽  
Pauline Chou ◽  
Tatiana Pundy ◽  
Samantha Gadd ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Brain Tumors ◽  
Meta Analysis ◽  
P Value ◽  
Embryonal Tumors ◽  
Expression Levels ◽  
Embryonal Brain

Neuroblastoma (NB) is the most common extracranial solid tumor in pediatrics, with rare occurrences of primary and metastatic tumors in the central nervous system (CNS). We previously reported the overexpression of the polo-like kinase 4 (PLK4) in embryonal brain tumors. PLK4 has also been found to be overexpressed in a variety of peripheral adult tumors and recently in peripheral NB. Here, we investigated PLK4 expression in NBs of the CNS (CNS-NB) and validated our findings by performing a multi-platform transcriptomic meta-analysis using publicly available data. We evaluated the PLK4 expression by quantitative real-time PCR (qRT-PCR) on the CNS-NB samples and compared the relative expression levels among other embryonal and non-embryonal brain tumors. The relative PLK4 expression levels of the NB samples were found to be significantly higher than the non-embryonal brain tumors (p-value < 0.0001 in both our samples and in public databases). Here, we expand upon our previous work that detected PLK4 overexpression in pediatric embryonal tumors to include CNS-NB. As we previously reported, inhibiting PLK4 in embryonal tumors led to decreased tumor cell proliferation, survival, invasion and migration in vitro and tumor growth in vivo, and therefore PLK4 may be a potential new therapeutic approach to CNS-NB.

scholarly journals Neurons Are Host Cells for Mycobacterium tuberculosis

2014 ◽  
Vol 82 (5) ◽  
pp. 1880-1890 ◽  
Author(s):  
Philippa J. Randall ◽  
Nai-Jen Hsu ◽  
Dirk Lang ◽  
Susan Cooper ◽  
Boipelo Sebesho ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Mycobacterium Tuberculosis ◽  
Host Cells ◽  
Productive Infection ◽  
Target Cells ◽  
Dependent Manner ◽  
Content Type ◽  
The Central Nervous System

ABSTRACTMycobacterium tuberculosisinfection of the central nervous system is thought to be initiated once the bacilli have breached the blood brain barrier and are phagocytosed, primarily by microglial cells. In this study, the interactions ofM. tuberculosiswith neuronsin vitroandin vivowere investigated. The data obtained demonstrate that neurons can act as host cells forM. tuberculosis.M. tuberculosisbacilli were internalized by murine neuronal cultured cells in a time-dependent manner after exposure, with superior uptake by HT22 cells compared to Neuro-2a cells (17.7% versus 9.8%). Internalization ofM. tuberculosisbacilli by human SK-N-SH cultured neurons suggested the clinical relevance of the findings. Moreover, primary murine hippocampus-derived neuronal cultures could similarly internalizeM. tuberculosis. InternalizedM. tuberculosisbacilli represented a productive infection with retention of bacterial viability and replicative potential, increasing 2- to 4-fold within 48 h.M. tuberculosisbacillus infection of neurons was confirmedin vivoin the brains of C57BL/6 mice after intracerebral challenge. This study, therefore, demonstrates neurons as potential new target cells forM. tuberculosiswithin the central nervous system.

Teratomas of the central nervous system: treatment considerations based on 34 cases

1998 ◽  
Vol 89 (5) ◽  
pp. 728-737 ◽  
Author(s):  
Yutaka Sawamura ◽  
Tsutomu Kato ◽  
Jun Ikeda ◽  
Jun-ichi Murata ◽  
Mitsuhiro Tada ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Radiation Therapy ◽  
Adjuvant Therapy ◽  
Karnofsky Performance Scale ◽  
Content Type ◽  
Treatment Considerations ◽  
Low Incidence ◽  
A Prospective Study ◽  
Fine Print

Object. The optimum clinical management of central nervous system (CNS) teratomas, particularly postsurgical adjuvant therapy, is still unclear, partly as a result of the tumors' low incidence. In this study the authors analyze 34 cases of CNS teratomas so that they may adequately indicate management of these lesions. Methods. The median age of the 34 patients was 13 years. Twenty-seven patients treated between 1970 and 1991 were retrospectively reviewed. Four of these 27 patients died as a result of radical surgery; each of them had a teratoma involving the hypothalamus. After initial treatment, which included radiation therapy, 20 patients (48%) had died. In all seven cases of mature teratomas there was no recurrence. In two cases of immature teratomas in which there was complete surgical resection there was recurrence; however, salvage therapies were effective. Seven of eight patients with highly malignant teratomas died; for these patients salvage therapies, including repeated radiation and chemotherapy, failed. Seven patients who presented with CNS teratomas between 1992 and 1996 received adjuvant chemotherapy and radiation therapy according to a prospective study protocol. All seven patients were free from recurrence with a 70 to 100% Karnofsky Performance Scale score at a median follow-up period of 41 months. Patients with CNS teratomas rarely responded completely to chemotherapy or radiation therapy; an effective adjuvant therapy produced a partial response at best. Conclusions. Because teratomas show various responses to adjuvant therapy, a misdiagnosis of their histological subtype will lead to inadequate therapy. A diverse therapeutic protocol based on histological diagnosis is necessary to plan appropriate management. Treatment recommendations are discussed in detail in the article.

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