Cerebrospinal fluid and blood profiles of transfer RNA fragments show age, sex, and Parkinson's disease-related changes.

Transfer RNA fragments (tRFs) have recently been shown to be an important family of small regulatory RNAs with diverse functions. Recent reports have revealed modified tRF blood levels in a number of nervous system conditions including epilepsy, ischemic stroke, and neurodegenerative diseases, but little is known about tRF levels in the cerebrospinal fluid (CSF). To address this issue, we studied age, sex, and Parkinson's disease (PD) effects on the distributions of tRFs in the CSF and blood data of healthy controls and PD patients from the NIH and the Parkinson's Progression Markers Initiative (PPMI) small RNA-seq datasets. We discovered that long tRFs are expressed in higher levels in the CSF than in the blood. Furthermore, the CSF showed a pronounced age-associated decline in the level of tRFs cleaved from the 3'-end and anti-codon loop of the parental tRNA (3'-tRFs, i-tRFs), and more pronounced profile differences than the blood profiles between the sexes. In comparison, we observed moderate age-related elevation of blood 3'-tRF levels. In addition, distinct sets of tRFs in the CSF and in the blood segregated PD patients from controls. Finally, we found enrichment of tRFs predicted to target cholinergic mRNAs (Cholino-tRFs) among mitochondrial-originated tRFs, raising the possibility that the neurodegeneration-related mitochondrial impairment in PD patients may lead to deregulation of their cholinergic tone. Our findings demonstrate that the CSF and blood tRF profiles are distinct and that the CSF tRF profiles are modified in a sex-, age-, and disease-related manner, suggesting that they reflect the inter-individual cerebral differences and calling for incorporating this important subset of small RNA regulators into future studies.

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.

INTRODUCTION: Females with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in transfer RNS (tRNA) fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). METHODS: We analyzed small RNA-sequencing (RNA-Seq) data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation. RESULTS: NAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single-cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations. DISCUSSION: Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.

[FALSE POSITIVE 5-ALA INDUCED FLUORESCENCE OF HEMATOLOGICAL MALIGNANCIES, BENIGN TUMORS, INFECTIOUS AND INFLAMMATORY PATHOLOGIES PRESENTED AS BRAIN LESIONS - A CASE SERIES].

INTRODUCTION: The 5-aminolevulinic acid (5-ALA) fluorescence-guided resection is an essential part of the current state-of-the-art treatment of primary malignant brain tumors. Metabolized by tumor cells, creating Protoporphyrin-IX, which is fluorescent under UV light emitted from the microscope, 5-ALA facilitates visual distinction between the tumor and the normal brain tissue surrounding it, coloring it pink. This real-time diagnostic feature was shown to lead to more complete removal of the tumor and confers a survival benefit. Nevertheless, despite the high sensitivity and specificity that was described using this method, there are other pathological processes in which 5-ALA is being metabolized that fluoresce similarly to a malignant glial tumor.

Identification of vascular cues contributing to cancer cell stemness and function.

Glioblastoma stem cells (GSCs) reside close to blood vessels (BVs) but vascular cues contributing to GSC stemness and the nature of GSC-BVs cross talk are not fully understood. Here, we dissected vascular cues influencing GSC gene expression and function to perfusion-based vascular cues, as well as to those requiring direct GSC-endothelial cell (EC) contacts. In light of our previous finding that perivascular tumor cells are metabolically different from tumor cells residing further downstream, cancer cells residing within a narrow, < 60 µm wide perivascular niche were isolated and confirmed to possess a superior tumor-initiation potential compared with those residing further downstream. To circumvent reliance on marker expression, perivascular GSCs were isolated from the respective locales based on their relative state of quiescence. Combined use of these procedures uncovered a large number of previously unrecognized differentially expressed GSC genes. We show that the unique metabolic milieu of the perivascular niche dominated by the highly restricted zone of mTOR activity is conducive for acquisition of GSC properties, primarily in the regulation of genes implicated in cell cycle control. A complementary role of vascular cues including those requiring direct glioma/EC contacts was revealed using glioma/EC co-cultures. Outstanding in the group of glioma cells impacted by nearby ECs were multiple genes responsible for maintaining GSCs in an undifferentiated state, a large fraction of which also relied on Notch-mediated signaling. Glioma-EC communication was found to be bidirectional, evidenced by extensive Notch-mediated EC reprogramming by contacting tumor cells, primarily metabolic EC reprogramming.

Intraoperative neuromonitoring during resection of cranial meningiomas and its effect on the surgical workflow.

PURPOSE: Resection of meningiomas adjacent to the central sulcus entails a high rate of morbidity. Explored for intra-axial lesion resection, intraoperative neuromonitoring intraoperative neuromonitoring (IONM) has been shown to decrease neurological deficits. The use of IONM is relatively uncommon and is not considered routine practice in the removal of extra-axial lesions. We sought to characterize IONM's impact on the surgical workflow in supratentorial meningiomas. METHODS: We retrospectively analyzed a prospectively collected database, searching cases in which IONM was used for resection of meningioma between 2017 and 2020. We classified the IONM effect on surgical workflow into 5 distinct categories of workflow changes (WFC). RESULTS: Forty cases of meningiomas with IONM use were identified. In 1 case (class 1 WFC), the operation was stopped due to IONM input. In 5 cases (class 2 WFC), the tumor was incompletely resected due to input from the IONM. In 14 cases (35%), IONM leads to an alteration of the resection process (alteration of approach, class 3 WFC). In 4 cases (10%), anesthesia care was modified based on IONM input (class 4 WFC). In 16 cases, no changes were made (class 5 WFC). In all patients in whom a change was made (24 cases, WFC 1-4), only 8.3% suffered a temporary deficit, and there were no permanent deficits, whereas when no change was made, there were 18.75% temporary deficit and 6.25% permanent deficit. CONCLUSION: IONM has an impact during resection of meningiomas in eloquent areas and may guide the surgical technique, approach to tumor resection, and extent of resection.

Metastases to meningioma-review and meta-analysis.

PURPOSE: Meningiomas are a common tumor within the cranial cavity. They may be a target for metastatic spread of cancer elsewhere in the body. We analyzed all the data in the literature about tumor-to-meningioma metastasis (TTMM). METHODS: We performed a meta-analysis using the PRISMA checklist to locate all cases of TTMM in the PubMed and Medline databases. We collected patient and cancer parameters, meningioma parameters, and clinical factors. RESULTS: We located 124 articles, describing 152 cases of patients with TTMM. The mean (± SD) age of all patients was 62.21 ± 10.8 years, with even distribution above and below the mean. Of the cases, 65.9% were reported in women. The most common cancer origins of TTMM were breast and lung carcinoma, followed by kidney, prostate, and GI tract carcinoma. Cancer status is not a good marker of TTMM when managing a meningioma. In 36.69% of cases, TTMM was the presentation of an unknown cancer. In nearly 60% of the known cases, cancer was considered in remission for at least 1 year. Meningioma parameters are unhelpful when considering a TTMM. The distribution of meningioma location is similar to other series of meningioma reported in the literature. Meningioma grade is similar to meningiomas without TTMM. In 57.89%, the patient presented with a focal deficit. Presenting factors were seizures, elevated ICP, and others. Over 95% of cases were symptomatic at presentation. CONCLUSION: TTMM should be suspected in cases of meningioma in a patient with background cancer, regardless of meningioma parameters or cancer status.

Correction to: Serum microRNA is a biomarker for post-operative monitoring in glioma.

For the reference citation '[57]' in the second paragraph of the Results section of the original article there was no corresponding entry in the References section. It should have referred to the below mentioned article by Ebrahimkhani et al. (2018).

Serum microRNA is a biomarker for post-operative monitoring in glioma.

PURPOSE: A circulating biomarker has potential to provide more accurate information for glioma progression post treatment, however no such biomarker is currently available. We aimed to discover a microRNA serum biomarker for longitudinal monitoring of glioma patients. METHODS: A prospectively collected cohort of 91 glioma patients and 17 healthy controls underwent pre and post-operative serum miRNA profiling using Nanostring®. Differentially expressed miRNAs were discovered using a machine learning random forest analysis. Candidate miRNAs were then assessed by droplet digital PCR in 11 patients with multiple follow up samples and compared to tumor volume based on magnetic resonance imaging. RESULTS: A 9-gene miRNA signature was identified that could distinguish between glioma and healthy controls with 99.8% accuracy. Two miRNAs miR-223 and miR-320e, best demonstrated dynamic changes that correlated closely with tumor volume in LGG and GBM respectively. Importantly, miRNA levels did not increase in two cases of pseudo-progression, indicating the potential utility of this test in guiding treatment decisions. CONCLUSIONS: We identified a highly accurate 9-miRNA signature associated with glioma serum. Additionally, we observed dynamic changes in specific miRNAs correlating with tumor volume over long-term follow up. These results support a large prospective validation study of serum miRNA biomarkers in glioma.

The efficacy of lapatinib and nilotinib in combination with radiation therapy in a model of NF2 associated peripheral schwannoma.

Neurofibromatosis type 2 (NF2), a neurogenetic condition manifest by peripheral nerve sheath tumors (PNST) throughout the neuroaxis for which there are no approved therapies. In vitro and in vivo studies presented here examine agents targeting signaling pathways, angiogenesis, and DNA repair mechanisms. In vitro dose response assays demonstrated potent activity of lapatinib and nilotinib against the mouse schwannoma SC4 (Nf2 -/-) cell line. We then examined the efficacy of everolimus, nilotinib, lapatinib, bevacizumab and radiation (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 -/-) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748). Lapatinib, nilotinib and RT significantly reduced tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas bevacizumab and everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed nilotinib or lapatinib as single agents (nilotinib vs. nilotinib + RT, p = 0.0001; lapatinib versus lapatinib + RT, p < 0.0001) with no observed toxicity. There was no re-growth of tumors even 14 days after treatment was stopped. The combination of either lapatinib or nilotinib with RT resulted in greater delays in tumor growth rate than any modality alone. This data suggest that concurrent low dose RT and targeted therapy may have a role in addressing progressive PNST in patients with NF2.

Clinical and angioarchitectural factors influencing the endovascular approach to galenic dural arteriovenous fistulas in adults: case series and review of the literature.

BACKGROUND: Galenic dural arteriovenous fistulas (DAVF) are rare; however, they are the most frequent type of DAVF to manifest aggressive clinical behavior and usually represent a diagnostic and therapeutic challenge for clinicians. METHODS: We retrospectively reviewed clinical and imaging data of patients managed with neuroendovascular techniques for the treatment of galenic DAVFs from 2000 to 2016. We searched the 2000-2016 English-language literature for papers discussing neuroendovascular management of galenic DAVFs, with or without companion surgical procedures. RESULTS: Five patients were treated for galenic DAVFs during the study period (four males; mean age, 61 years). Three presented with progressive neurological deterioration due to venous congestion, two with acute intracranial hemorrhage. Three were treated by staged transarterial embolization procedures (three procedures in two, four procedures in one); two underwent a single transvenous embolization procedure. Four out of five fistulas were completely occluded. All patients improved clinically; the patient whose fistula was partially occluded remains angiographically stable at 2-year follow-up. Six reports describing 17 patients are reviewed. Embolization was performed via transvenous approach in 1/17 and transarterial approach in 16/17 with additional open surgery in 9/16. The trend toward the use of transarterial approaches is based primarily on advances on embolization techniques that allow better and more controllable penetration of the embolizing agents with improved clinical and angiographic results, as well as the technical complexity of the transvenous approach. CONCLUSIONS: Although transarterial embolization is the preferred endovascular route for the management of most galenic DAVFs, selected cases can be successfully treated by transvenous approach.

Spinal intradural microsurgery in a nascent neurosurgical department: Lessons learned from the first 25 cases.

BACKGROUND: Between 2017 and 2021, the newly established Department of Neurosurgery at Shaare Zedek Medical Center in Jerusalem, a high volume metropolitan hospital, operated on 25 intradural lesions in 24 patients (one patient had multiple tumors). In this retrospective study, we review results and lessons learned as experienced surgeons opened a new service line. METHODS: A multidisciplinary team was assembled and led by experienced neurosurgeons with skills in both microneurosurgery and complex spine care. Standard operative techniques were used. A chart review was done to assess complications and outcome. RESULTS: 25 lesions were reviewed in 24 patients (14 female; 10 male) between the ages of 11-82 years of age. In 14 cases, gross total resection (GTR) was achieved; 11 cases underwent partial resection. Of the 11 non-GTR cases, 3 were initially planned as biopsies. In one case, there was a significant neurologic decline directly related to surgery. In a separate case, there was iatrogenic instability, necessitating further treatment. CONCLUSIONS: We identify six lessons learned in a nascent neurosurgical department, noting that surgical excellence is of paramount importance, but that the surgeon must also expand his/her role from master technician to team leader. Both microsurgical expertise for neural anatomy and understanding of spinal biomechanics for osseous anatomy is mandatory for surgery of SIDT. This retrospective analysis of our case series demonstrates experienced neurosurgeons can successfully deploy a new service line for challenging cases to the benefit of the hospital and local community.

Knockout of the longevity gene Klotho perturbs aging and Alzheimer's disease-linked brain microRNAs and tRNA fragments.

Overexpression of the longevity gene Klotho prolongs lifespan, while its knockout shortens lifespan and impairs cognition via perturbation of myelination and synapse formation. However, comprehensive analysis of Klotho knockout effects on mammalian brain transcriptomics is lacking. Here, we report that Klotho knockout alters the levels of aging- and cognition related mRNAs, long non-coding RNAs, microRNAs and tRNA fragments. These include altered neuronal and glial regulators in murine models of aging and Alzheimer's disease and in human Alzheimer's disease post-mortem brains. We further demonstrate interaction of the knockout-elevated tRNA fragments with the spliceosome, possibly affecting RNA processing. Last, we present cell type-specific short RNA-seq datasets from FACS-sorted neurons and microglia of live human brain tissue demonstrating in-depth cell-type association of Klotho knockout-perturbed microRNAs. Together, our findings reveal multiple RNA transcripts in both neurons and glia from murine and human brain that are perturbed in Klotho deficiency and are aging- and neurodegeneration-related.

Lysine tRNA fragments and miR-194-5p co-regulate hepatic steatosis via ß-Klotho and perilipin 2.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) involves hepatic accumulation of intracellular lipid droplets via incompletely understood processes. Here, we report distinct and cooperative NAFLD roles of LysTTT-5'tRF transfer RNA fragments and microRNA miR-194-5p. METHODS: Combined use of diet induced obese mice with human-derived oleic acid-exposed Hep G2 cells revealed new NAFLD roles of LysTTT-5'tRF and miR-194-5p. RESULTS: Unlike lean animals, dietary-induced NAFLD mice showed concurrent hepatic decrease of both LysTTT-5'tRF and miR-194-5p levels, which were restored following miR-132 antisense oligonucleotide treatment which suppresses hepatic steatosis. Moreover, exposing human-derived Hep G2 cells to oleic acid for 7 days co-suppressed miR-194-5p and LysTTT-5'tRF levels while increasing lipid accumulation. Inversely, transfecting fattened cells with a synthetic LysTTT-5'tRF mimic elevated mRNA levels of the metabolic regulator ß-Klotho while decreasing triglyceride amounts by 30% within 24 h. In contradistinction, antisense suppression of miR-194-5p induced accumulation of its novel target, the NAFLD-implicated lipid droplet-coating PLIN2 protein. Further, two out of 15 steatosis-alleviating screened drug-repurposing compounds, Danazol and Latanoprost, elevated miR-194-5p or LysTTT-5'tRF levels. CONCLUSION: Our findings highlight the different yet complementary roles of miR-194-5p and LysTTT-5'tRF and offer new insights into the complex roles of small non-coding RNAs and the multiple pathways involved in NAFLD pathogenesis.

Sex-specific declines in cholinergic-targeting tRNA fragments in the nucleus accumbens in Alzheimer's disease.

Introduction: Females with Alzheimer's disease (AD) suffer accelerated dementia and loss of cholinergic neurons compared to males, but the underlying mechanisms are unknown. Seeking causal contributors to both these phenomena, we pursued changes in tRNA fragments (tRFs) targeting cholinergic transcripts (CholinotRFs). Methods: We analyzed small RNA-sequencing data from the nucleus accumbens (NAc) brain region which is enriched in cholinergic neurons, compared to hypothalamic or cortical tissues from AD brains; and explored small RNA expression in neuronal cell lines undergoing cholinergic differentiation. Results: NAc CholinotRFs of mitochondrial genome origin showed reduced levels that correlated with elevations in their predicted cholinergic-associated mRNA targets. Single cell RNA seq from AD temporal cortices showed altered sex-specific levels of cholinergic transcripts in diverse cell types; inversely, human-originated neuroblastoma cells under cholinergic differentiation presented sex-specific CholinotRF elevations. Discussion: Our findings support CholinotRFs contributions to cholinergic regulation, predicting their involvement in AD sex-specific cholinergic loss and dementia.

Knockout of the longevity gene Klotho perturbs aging- and Alzheimer's disease-linked brain microRNAs and tRNA fragments.

Overexpression of the longevity gene Klotho prolongs, while its knockout shortens lifespan and impairs cognition via altered fibroblast growth factor signaling that perturbs myelination and synapse formation; however, comprehensive analysis of Klotho's knockout consequences on mammalian brain transcriptomics is lacking. Here, we report the altered levels under Klotho knockout of 1059 long RNAs, 27 microRNAs (miRs) and 6 tRNA fragments (tRFs), reflecting effects upon aging and cognition. Perturbed transcripts included key neuronal and glial pathway regulators that are notably changed in murine models of aging and Alzheimer's Disease (AD) and in corresponding human post-mortem brain tissue. To seek cell type distributions of the affected short RNAs, we isolated and FACS-sorted neurons and microglia from live human brain tissue, yielding detailed cell type-specific short RNA-seq datasets. Together, our findings revealed multiple Klotho deficiency-perturbed aging- and neurodegeneration-related long and short RNA transcripts in both neurons and glia from murine and human brain.

Fusion of Preoperative and Postoperative Imaging May Predict the Diagnostic Yield of Stereotactic Needle Brain Biopsies.

BACKGROUND: Stereotactic needle brain biopsy is a commonly used neurosurgical procedure. However, up to 15% of biopsies result in undiagnostic pathology reports. Repeat biopsy or continued management without a diagnosis are often considered after undiagnostic biopsies. There have been no reports about the role of postoperative imaging in predicting the diagnostic yield of stereotactic biopsies. METHODS: We retrospectively assessed all stereotactic biopsies performed over an 11-year period. We performed fusion of immediate postoperative computed tomography (CT) with preoperative MRI, to document whether the air bubble in the postoperative CT was located within the targeted lesion. We then evaluated the association of this fusion-based accuracy assessment with the diagnostic yield of the biopsy. RESULTS: Fewer than 5% of biopsies did not have an air bubble on postoperative CT. A total of 226 biopsies were performed for 219 patients. In our sample, 213 of 226 biopsies were accurate (94.2% accuracy rate), and 203 of 226 biopsies gave a definitive diagnosis (89.8% diagnostic rate). In those cases where the fusion was accurate, the diagnostic rate was 93.9%. When the fusion was inaccurate, the diagnostic rate was only 23.1% (odds ratio 51.5, 95% confidence interval 12.6-210.44, P < 0.001). Of all patient, imaging, surgical, and admission parameters, the only parameter that correlated with diagnostic outcome of the biopsy was the fusion construct accuracy. CONCLUSIONS: Fusion of immediate postoperative CT with preoperative imaging is predictive of the diagnostic rate. In cases where the pathology report following a biopsy is not diagnostic, this fusion may be useful in making decisions regarding repeat biopsy or considering other diagnostic options.

Acquisition of Basic Micro-Neurosurgical Skills Using Cavitron Ultrasonic Aspirator in Low-Cost Readily Available Models: The Egg Model.

BACKGROUND: Attainment of micro-neurosurgical skills is a challenge in teaching hospitals throughout training. Models that mimic the workflow as well as haptics are time-consuming, expensive, and unsuitable to serve as a routine platform. Our objective was to present a model and a set of tasks, based on a hard-boiled egg, microscope, and a Cavitron ultrasonic aspirator (CUSA; Integra Lifesciences Corp., Tullamore, Ireland), which is cheap, easy to setup and can be used for training microsurgery and CUSA skills, required for removal of deep-seated tumors. METHODS: The goal was to remove the egg yolk from within a hard-boiled egg, representing an intrinsic brain tumor, surrounded by the egg's white, representing adjacent brain tissue, while preserving it. Assessment was based on the yolk's exposure, completeness of removal, and collateral damage and task completion duration, with repeated trials (n = 4), for validation purposes, for 6 operators with different experience levels. RESULTS: Improvement in overall score (mean of 47.5 ± 19 in the first trial vs. 80.0 ± 12 in the fourth trial, P < 0.01), and task duration completion (mean initial duration of 21:25 ± 4:52 minutes to 15:30 ± 5:17 minutes, P < 0.01) was observed. Parameters gradually improved on repeated attempts, and experience level of the operators correlated with scores. CONCLUSIONS: The egg model is an easy-to-handle, cheap model that enables the acquisition of basic micro-neurosurgical skills and basic workflow required for removing of intrinsic brain tumors. This study has validated and defined reproducible tasks that can be scored, correlated with performance. This model can be incorporated into a resident's routine and potentially provide an accessible training platform for neurosurgical trainees.

Acquisition of Basic Microsurgical Skills Using Low-Cost, Readily Available Models: The Orange Model.

BACKGROUND: Attainment of basic microsurgical skills in neurosurgery presents a departmental challenge worldwide. Models for teaching are either not readily available or expensive and are incompatible with a resident's busy schedule, requiring lengthy and proper setup. We present a model and a set of measurable tasks, based on a fruit (orange) that is cheap, easy to set up instantly when desired, and useful for training of basic microsurgical skills. METHODS: Basic microsurgical skills were identified, necessitating hand-eye coordination working with the microscope. The goal was to dissect an orange segment while preserving adjacent segments. Assessment was based on the number of side tears and task completion duration. The task was repeated in a sequential manner (n = 10), for validation purposes, for 3 operators at different seniority levels. RESULTS: An improvement in the number of side tears (mean of 12.66 ± 9.01 in the first trial vs. 4 ± 4.35 in the 10th trial, P < 0.01), as well as duration of time required for task completion (mean initial duration of 28:16 ± 19:00 minutes to a duration of 16:33 ± 10:50 minutes in the last attempt, P < 0.01), was observed. Daily practice scores and time gradually improved, and the seniority level of operators was correlated with scoring between individuals. CONCLUSIONS: The orange model is an easily accessible, cheap model that enables the acquisition of basic microneurosurgical skills. In this work, we validated and defined reproducible tasks that can be scored and tracked, correlated with operator's proficiency and experience. This model can be incorporated into a resident's workflow environment and provides a platform for attainment of elementary microsurgical skills for neurosurgical residents.

Captopril inhibits Matrix Metalloproteinase-2 and extends survival as a temozolomide adjuvant in an intracranial gliosarcoma model.

BACKGROUND: Captopril is a well-characterized, FDA-approved drug that has demonstrated promise as a repurposed oncology therapeutic. Captopril's known anti-cancer effects include inhibition of Matrix Metalloproteinase-2 (MMP-2), an endopeptidase which selectively breaks down the extracellular matrix to promote cell migration. MMP-2 is a known therapeutic target in gliomas, tumors with significant clinical need. Using an aggressive gliosarcoma model, we assessed captopril's effects on MMP-2 expression in vitro and in vivo as well as its efficacy as an adjuvant in combination therapy regimens in vivo. METHODS: Following captopril treatment, MMP-2 protein expression and migratory capabilities of 9 L gliosarcoma cells were assessed in vitro via western blots and scratch wound assays, respectively. Rats were intracranially implanted with 9 L gliosarcoma tumors, and survival was assessed in the following groups: control; captopril (30 mg/kg/day); temozolomide (TMZ) (50 mg/kg/day), and captopril+TMZ. In vivo experiments were accompanied by immunohistochemistry for MMP-2 from brain tissue. RESULTS: In vitro, captopril decreased MMP-2 protein expression and reduced migratory capacity in 9 L gliosarcoma cells. In a gliosarcoma animal model, captopril decreased MMP-2 protein expression and extended survival as a TMZ adjuvant relative to untreated controls, captopril monotherapy, and TMZ monotherapy groups (27.5 versus 14 (p < 0.001), 16 (p < 0.001), and 23 (p = 0.018) days, respectively). CONCLUSIONS: Captopril decreases gliosarcoma cell migration, which may be mediated by reduction in MMP-2 protein expression. Captopril provided a survival advantage as a TMZ adjuvant in a rat intracranial gliosarcoma model. Captopril may represent a promising potential adjuvant to TMZ therapy in gliosarcoma as a modulator of the MMP-2 pathway.