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Medulloblastoma (MB) is a malignant pediatric brain tumor arising in the cerebellum. Although abnormal GABAergic receptor activation has been described in MB, studies have not yet elucidated the contribution of receptor-independent GABA metabolism to MB pathogenesis. We find primary MB tumors globally display decreased expression of GABA transaminase (ABAT), the protein responsible for GABA metabolism, compared with normal cerebellum. However, less aggressive WNT and SHH subtypes express higher ABAT levels compared with metastatic G3 and G4 tumors. We show that elevated ABAT expression results in increased GABA catabolism, decreased tumor cell proliferation, and induction of metabolic and histone characteristics mirroring GABAergic neurons. Our studies suggest ABAT expression fluctuates depending on metabolite changes in the tumor microenvironment, with nutrient-poor conditions upregulating ABAT expression. We find metastatic MB cells require ABAT to maintain viability in the metabolite-scarce cerebrospinal fluid by using GABA as an energy source substitute, thereby facilitating leptomeningeal metastasis formation.

Previous studies indicate that conditional genetic deletion of phosphatase and tensin homolog (PTEN) in neonatal mice enhances the ability of axons to regenerate following spinal cord injury (SCI) in adults. Here, we assessed whether deleting PTEN in adult neurons post-SCI is also effective, and whether enhanced regenerative growth is accompanied by enhanced recovery of voluntary motor function. PTEN(loxP/loxP) mice received moderate contusion injuries at cervical level 5 (C5). One group received unilateral injections of adeno-associated virus expressing CRE (AAV-CRE) into the sensorimotor cortex; controls received a vector expressing green fluorescent protein (AAV-GFP) or injuries only (no vector injections). Forelimb function was tested for 14weeks post-SCI using a grip strength meter (GSM) and a hanging task. The corticospinal tract (CST) was traced by injecting mini-ruby BDA into the sensorimotor cortex. Forelimb gripping ability was severely impaired immediately post-SCI but recovered slowly over time. The extent of recovery was significantly greater in PTEN-deleted mice in comparison to either the AAV-GFP group or the injury only group. BDA tract tracing revealed significantly higher numbers of BDA-labeled axons in caudal segments in the PTEN-deleted group compared to control groups. In addition, in the PTEN-deleted group, there were exuberant collaterals extending from the main tract rostral to the lesion and into and around the scar tissue at the injury site. These results indicate that PTEN deletion in adult mice shortly post-SCI can enhance regenerative growth of CST axons and forelimb motor function recovery.

The importance of white matter (WM) injury to stroke pathology has been underestimated in experimental animal models and this may have contributed to the failure to translate potential therapeutics into the stroke clinic. Histone deacetylase (HDAC) inhibitors are neuroprotective and also promote neurogenesis. These properties make them ideal candidates for stroke therapy. In a pure WM tract (isolated mouse optic nerve), we show that pan- and class I-specific HDAC inhibitors, administered before or after a period of oxygen and glucose deprivation (OGD), promote functional recovery of axons and preserve WM cellular architecture. This protection correlates with the upregulation of an astrocyte glutamate transporter, delayed and reduced glutamate accumulation duringOGD,preservation of axonal mitochondria and oligodendrocytes, and maintenance of ATP levels. Interestingly, the expression of HDACs 1, 2, and 3 is localized to astrocytes, suggesting that changes in glial cell gene transcription and/or protein acetylation may confer protection to axons. Our findings suggest that a therapeutic opportunity exists for the use of HDAC inhibitors, targeting mitochondrial energy regulation and excitotoxicity in ischemic WM injury. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that glaucoma disrupts electrophysiological conduction properties and axon function in optic nerve as a function of intraocular pressure (IOP) levels and age in the DBA/2J mouse model of glaucoma. The amplitude and the integral of electrical signals evoked along the axons decreased considerably by 6 months of age as a function of increasing IOP levels. At young ages, raised IOP was directly associated with increased vulnerability to metabolic challenge. Changes in the physiological function of the optic nerves were accentuated with aging, leading to loss of compound action potential in an entire population of fibers: small, slow conducting axons. This loss was accompanied with loss of small fiber axon counts and declining metabolic reserve by demonstrating IOP-dependent ATP decrease in mouse optic nerves. These data shed light on a novel potential mechanism of glaucoma pathology whereby increased IOP and declining metabolic capacity lead to axon liability and eventually dysfunction and loss. [ABSTRACT FROM AUTHOR]

Objective: Spinal cord ischemia (SCI) remains one of the most devastating complications in both open and endovascular stent graft repair of thoracoabdominal aortic aneurysms. The endovascular aortic aneurysm repair (EVAR) can be either thoracic (TEVAR) when it targets the thoracic aortic aneurysm or fenestrated branched when repair involves the visceral and/or renal arteries. Even though EVAR interventions are less invasive than open repair, they are still associated with a significant risk of SCI. The current primary strategy to prevent SCI after TEVAR is to increase and/or maintain spinal cord perfusion pressure (blood flow) by increasing the mean arterial pressure while simultaneously draining CSF. Although the benefit of CSF drainage in EVAR procedures remains uncertain, it provides an opportunity to study the changes in cytokine and oxidative stress markers that may signal the pathophysiology of SCI following EVAR. The aim of this study was to evaluate the temporal relationship between stent deployment and CSF cytokine and oxidative stress marker levels as predictors of delayed SCI in patients undergoing an EVAR procedure., Methods: There were 16 EVAR cases across 15 patients enrolled in this study, with 1 patient undergoing the procedure twice 1 year apart. The levels of oxidative stress (8-hydroxy-2'-deoxyguanosine [8-OHdG], glial fibrillary acidic [GFAP], and lactic acid) and proinflammatory (tumor necrosis factor-alpha [TNF-α], interleukin (IL)-6, and IL-1β) and antiinflammatory (IL-4) markers were quantified at different time points between 0 and 48 hours after EVAR by enzyme-linked immunosorbent assay. The changes in protein levels of both oxidative stress and inflammatory markers were expressed as fold change from the time of the lumbar drain insertion prior to surgery., Results: Following the EVAR procedure, 8-OHdG resulted in the highest upregulation at later time points postoperatively (48 hours) and this increase was positively correlated with TNF-α level. The data also revealed that IL-6 peaked during the stent deployment intervention and this pattern of expression was positively correlated with the expression of lactic acid. No significant changes were noted in the expression levels of GFAP, lactic acid, and IL-1β., Conclusions: There appears to be a temporal relationship between lumbar CSF drainage and CSF cytokines and oxidative stress markers that may help 1) identify patients at risk for developing delayed SCI and 2) modify patient management to prevent the damage from delayed SCI.