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Fragile X syndrome (FXS) is a monogenic disorder characterized by intellectual disability and behavioral challenges. It is caused by aberrant methylation of the fragile X mental retardation 1 (FMR1) gene. Given the failure of clinical trials in FXS and growing evidence of a role of metabotropic glutamate subtype 5 receptors (mGluR5) in the pathophysiology of the disorder, we investigated mGluR5 function in FMR1 Knockout (FMR1-KO) mice and age- and sex-matched control mice using longitudinal positron emission tomography (PET) imaging to better understand the disorder. The studies were repeated at four time points to examine age- and disease-induced changes in mGluR5 availability using 3-fluoro-[18F]5-(2-pyridinylethynyl)benzonitrile ([18F]FPEB). We found that the binding potential (BP) of [18F]FPEB was significantly lower in the KO mice in mGluR5-implicated brain areas including striatum, cortex, hippocampus, thalamus, and olfactory bulb. The BP also changed with age, regardless of disorder status, increasing in early adulthood in male but not in female mice before decreasing later in both sexes. The difference in mGluR5 availability between the FMR1-KO and control mice and the change in BP in the KO mice as a function of age and sex illustrate the nature of the disorder and its progression, providing mechanistic insights for treatment design.

AIM: To investigate the suppression of aquaporin-4 (AQP4) synthesis through intracerebroventricular (i.c.v.) injection of antisense oligonucleotide after focal cortical contusion injury in mice. MATERIAL and METHODS: This study used 12-week-old female Swiss albino mice (weight, 20–25 g) to create a focal cortical contusion model by the weight-drop method (35 g blunt weight, 70 cm height) onto the parietal cortex after craniectomy. The sham group underwent craniectomy without trauma. In the control group, weight was dropped onto the parietal cortex immediately after i.c.v. injection of Dulbecco’s Modified Eagle Medium after craniectomy. In addition, 1 nM of aquaporin-4 (AQP4) antisense oligonucleotide (ASO) was injected via the i.c.v. route immediately after trauma (0 hour) and 4 hours after trauma. All animals underwent magnetic resonance (MR) imaging and were sacrificed at 24 hours. The brain–water content was determined using the wet/dry weight method. RESULTS: In the sham group, the average percentage of the brain–water content was 77.75% compared with the control group with 79.87%, and the difference was significant (p=0.017). The average was 78.81% and significantly reduced in the therapy group compared with the control group (p=0.026) at 0 hour. In the 4-hour treatment group, the average of 79.11% was not significant (p=0.39). MR imaging findings also showed a substantial reduction in brain edema in the 0-h treatment group. However, the 4-h treatment results, when compared with the control trauma group, did not show a significant difference. CONCLUSION: This study demonstrated that AQP4-ASO therapy, when administered early after diffuse traumatic brain injury, leads to a significant reduction in brain edema. © 2022, The Korean Society of Clothing and Textiles. All rights reserved.

Receptor-interacting protein kinase-1 (RIPK1) is a master regulator of cell death and inflammation, and mediates programmed necrosis (necroptosis) via mixed-lineage kinase like (MLKL) protein. Prior studies in experimental intracerebral hemorrhage (ICH) implicated RIPK1 in the pathogenesis of neuronal death and cognitive outcome, but the relevant cell types involved and potential role of necroptosis remain unexplored. In mice subjected to autologous blood ICH, early RIPK1 activation was observed in neurons, endothelium and pericytes, but not in astrocytes. MLKL activation was detected in astrocytes and neurons but not endothelium or pericytes. Compared with WT controls, RIPK1 kinase-dead ( RIPK1D138N/D138N) mice had reduced brain edema (24 h) and blood-brain barrier (BBB) permeability (24 h, 30 d), and improved postinjury rotarod performance. Mice deficient in MLKL ( Mlkl-/-) had reduced neuronal death (24 h) and BBB permeability at 24 h but not 30d, and improved post-injury rotarod performance vs. WT. The data support a central role for RIPK1 in the pathogenesis of ICH, including cell death, edema, BBB permeability, and motor deficits. These effects may be mediated in part through the activation of MLKL-dependent necroptosis in neurons. The data support development of RIPK1 kinase inhibitors as therapeutic agents for human ICH.

Important differences in the biology of focal and diffuse traumatic brain injury (TBI) subtypes may result in unique pathophysiological responses to shared molecular mechanisms. Interleukin-1 (IL-1) signaling has been tested as a potential therapeutic target in preclinical models of cerebral contusion and diffuse TBI, and in a phase II clinical trial, but no published studies have examined IL-1 signaling in an impact/acceleration closed head injury (CHI) model. We hypothesized that genetic deletion of IL-1 receptor-1 (IL-1R1 KO) would be beneficial in focal (contusion) and CHI in mice. Wild type and IL-1R1 KO mice were subjected to controlled cortical impact (CCI), or to CHI. CCI produced brain leukocyte infiltration, HMGB1 translocation and release, edema, cell death, and cognitive deficits. CHI induced peak rotational acceleration of 9.7 × 10(5) ± 8.1 × 10(4) rad/s(2), delayed time to righting reflex, and robust Morris water maze deficits without deficits in tests of anxiety, locomotion, sensorimotor function, or depression. CHI produced no discernable acute plasmalemma damage or cell death, blood-brain barrier permeability to IgG, or brain edema and only a modest increase in brain leukocyte infiltration at 72 h. In both models, mature (17 kDa) interleukin-1 beta (IL-1β) was induced by 24 h in CD31+ endothelial cells isolated from injured brain but was not induced in CD11b(+) cells in either model. High mobility group box protein-1 was released from injured brain cells in CCI but not CHI. Surprisingly, cognitive outcome in mice with global deletion of IL-1R1 was improved in CHI, but worse after CCI without affecting lesion size, edema, or infiltration of CD11b(+)/CD45(+) leukocytes in CCI. IL-1R1 may induce unique biological responses, beneficial or detrimental to cognitive outcome, after TBI depending on the pathoanatomical subtype. Brain endothelium is a hitherto unrecognized source of mature IL-1β in both models.

Adeno-associated virus (AAV)-based gene therapy is gaining popularity owing to its excellent safety profile and effective therapeutic outcomes in a number of diseases. Intravenous (IV) injection of AAV into the tail vein, facial vein and retro-orbital (RO) venous sinus have all been useful strategies to infuse the viral vector systemically. However, tail vein injection is technically challenging in juvenile mice, and injection at young ages (≤ postnatal day-(P)21) is essentially impossible. The temporal or facial vein is localized anterior to the ear bud and is markedly visible in the first couple of days postnatally. However, this method is age-dependent and requires a dissecting microscope. Retro-orbital injection (ROI), on the other hand, is suitable for all murine ages, including newborn and older mice, and is relatively less stressful to animals compared to tail vein injection. Although many reports have shown ROI as an effective route of AAV delivery, herein we aim to highlight and summarize the methods and benefits of ROI. To capture the full spectrum of transduction efficiency mediated by ROI, we transduced the editing-dependent reporter mice (Ai9 Cre reporter mice) with the AAV9 vector, which targets a wide range of peripheral tissues with exceptional brain tropism. We also provide a comprehensive description of the ROI technique to facilitate viral vector administration without complications.

Repetitive closed head injury (rCHI) is commonly encountered in young athletes engaged in contact and collision sports. Traumatic brain injury (TBI) including rCHI has been reported to be an important risk factor for several tauopathies in studies of adult humans and animals. However, the link between rCHI and the progression of tau pathology in adolescents remains to be elucidated. We evaluated whether rCHI can trigger the initial acceleration of pathological tau in adolescent mice and impact the long-term outcomes post-injury. To this end, we subjected adolescent transgenic mice expressing the P301S tau mutation to mild rCHI and assessed tau hyperphosphorylation, tangle formation, markers of neuroinflammation, and behavioral deficits at 40 days post rCHI. We report that rCHI did not accelerate tau pathology and did not worsen behavioral outcomes compared to control mice. However, rCHI induced cortical and hippocampal microgliosis and corpus callosum astrocytosis in P301S mice by 40 days post-injury. In contrast, we did not find significant microgliosis or astrocytosis after rCHI in age-matched WT mice or sham-injured P301S mice. Our data suggest that neuroinflammation precedes the development of Tau pathology in this rCHI model of adolescent repetitive mild TBI.

The lack of techniques to trace brain cell behavior in vivo hampers the ability to monitor status of cells in a living brain. Extracellular vesicles (EVs), nanosized membrane-surrounded vesicles, released by virtually all brain cells might be able to report their status in easily accessible biofluids, such as blood. EVs communicate among tissues using lipids, saccharides, proteins, and nucleic acid cargo that reflect the state and composition of their source cells. Currently, identifying the origin of brain-derived EVs has been challenging, as they consist of a rare population diluted in an overwhelming number of blood and peripheral tissue-derived EVs. Here, we developed a sensitive platform to select out pre-labelled brain-derived EVs in blood as a platform to study the molecular fingerprints of brain cells. This proof-of-principle study used a transducible construct tagging tetraspanin (TSN) CD63, a membrane-spanning hallmark of EVs equipped with affinity, bioluminescent, and fluorescent tags to increase detection sensitivity and robustness in capture of EVs secreted from pre-labelled cells into biofluids. Our platform enables unprecedented efficient isolation of neural EVs from the blood. These EVs derived from pre-labelled mouse brain cells or engrafted human neuronal progenitor cells (hNPCs) were submitted to multiplex analyses, including transcript and protein levels, in compliance with the multibiomolecule EV carriers. Overall, our novel strategy to track brain-derived EVs in a complex biofluid opens up new avenues to study EVs released from pre-labelled cells in near and distal compartments into the biofluid source.

Background/Aims: Decreasing levels of aromatase and seladin-1 could be one of the molecular mechanisms of Alzheimer’s disease (AD). Aromatase is an enzyme that catalyzes estrogen biosynthesis from androgen precursors, and seladin-1 is an enzyme that converts desmosterol to cholesterol, which is the precursor of all hormones. Verifying the potential relationship between these proteins and accordingly determining new therapeutic targets constitute the aims of this study. Methods: Changes in protein levels were compared in vitro in aromatase and seladin-1 inhibitor-administered human neuroblastoma (SH-SY5Y) cells in vivo in intracerebroventricular (icv) aromatase or seladin-1 inhibitor-administered rats, as well as in transgenic AD mice in which the genes encoding these proteins were knocked out. Results and Conclusions: In the cell cultures, we observed that seladin-1 protein levels increased after aromatase enzyme inhibition. The hippocampal aromatase protein levels decreased following chronic seladin-1 inhibition in icv inhibitor-administered rats; however, the aromatase levels in the dentate gyrus of seladin-1 knockout (SelKO) AD male mice increased. These findings indicate a partial relationship between these proteins and their roles in AD pathology.

BackgroundLeptomeningeal disease (LMD) occurs when cells from primary tumors metastasize to the cerebrospinal fluid (CSF) space leading to multifocal neurological deficits. LMD has an overall prevalence of ~5% in cancer patients, but is most commonly observed in breast, lung and melanoma patients. With improved therapies emerging for several primary tumor types, the incidence of LMD is rising, and with treatment options limited to radiotherapy and chemotherapy, the median survival of LMD patients remains poor at 3–6 months. Thus, there is high unmet medical need for development of effective therapeutic strategies for LMD.The STING (Stimulator of Interferon Genes) pathway has been shown to play a critical role in activating anti-tumor immunity through initiation of a tumor antigen-specific T cell response. exoSTING is an engineered extracellular vesicle exogenously loaded with a CDN (cyclic dinucleotide) STING agonist. We have previously demonstrated that it enhances the potency of the CDN, preferentially activates antigen presenting cells in the tumor microenvironment and increases CNS retention of the drug without systemic inflammatory cytokine stimulation. Histological data in LMD is scarce, however high levels of inhibitory macrophages and low T cell infiltration have recently been described, providing support for the therapeutic potential of exoSTING in LMD.MethodsA mouse model of LMD was generated by intracerebral inoculation of B16F10-Luc melanoma cells and was used to assess the efficacy of intracranial administration of exoSTING.ResultsTumor growth was monitored by bioluminescence imaging during course of each study, with rapid loss of signal post treatment observed in exoSTING treated groups compared to steady tumor growth in vehicle treated groups. Animals within vehicle treated groups demonstrated survival less than 30 days, whereas exoSTING treated mice survived 50+ days with a high complete response rate (over 85%), confirmed by ex vivo histopathological analysis. Peripheral immunological responses were demonstrated by lack of tumor growth following flank rechallenge in exoSTING treated mice. Strong anti-tumor response and tumor-specific immune activation in the absence of systemic inflammation was demonstrated. The presentation will summaries the immunological changes in the tumor microenvironment following exoSTING administration.ConclusionsexoSTING, which previously showed strong efficacy against primary melanoma in mouse models, has been demonstrated in this study to also suppress tumor growth and improve survival in the LMD context. Our study supports the therapeutic rationale for using exoSTING for the treatment of LMD.

Background and Purpose— Recent studies using cultured cells and rodent intracerebral hemorrhage (ICH) models have implicated RIPK1 (receptor interacting protein kinase-1) as a driver of programmed necrosis and secondary injury based on use of chemical inhibitors. However, these inhibitors have off-target effects and cannot be used alone to prove a role for RIPK1. The aim of the current study was to examine the effect of genetic inhibition of the kinase domain of RIPK1 in a mouse ICH model. Methods— We subjected 2 lines of mice with RIPK1 point mutations of the kinase domain (K45A and D138N), rendering them kinase inactive, to autologous blood ICH and measured acute cell death and functional outcome. Results— Compared with wild-type controls, RIPK1 K45A/K45A and RIPK1 D138N/D138N had significantly less cells with plasmalemma permeability, less acute neuronal cell death, less weight loss and more rapid weight gain to baseline, and improved performance in a Morris water maze paradigm after autologous blood ICH. In addition, mice systemically administered GSK′963, a potent, specific, brain penetrant small molecule RIPK1 inhibitor, had reduced acute neuronal death at 24 hours after ICH. Conclusions— The data show that the kinase domain of RIPK1 is a disease driver of ICH, mediating both acute cell death and functional outcome, and support development of RIPK1 inhibitors as therapeutic agents for human ICH.

Cortical spreading depolarization (SD) is the electrophysiological event underlying migraine aura, and a critical contributor to secondary damage after brain injury. Experimental models of SD have been used for decades in migraine and brain injury research; however, they are highly invasive and often cause primary tissue injury, diminishing their translational value. Here we present a non-invasive method to trigger SDs using light-induced depolarization in transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP). Focal illumination (470 nm, 1–10 mW) through intact skull using an optical fiber evokes power-dependent steady extracellular potential shifts and local elevations of extracellular [K(+)] that culminate in an SD when power exceeds a threshold. Using the model, we show that homozygous mice are significantly more susceptible to SD (i.e., lower light thresholds) than heterozygous ChR2 mice. Moreover, we show SD susceptibility differs significantly among cortical divisions (motor, whisker barrel, sensory, visual, in decreasing order of susceptibility), which correlates with relative channelrhodopsin-2 expression. Furthermore, the NMDA receptor antagonist MK-801 blocks the transition to SD without diminishing extracellular potential shifts. Altogether, our data show that the optogenetic SD model is highly suitable for examining physiological or pharmacological modulation of SD in acute and longitudinal studies.

Malignant gliomas are highly lethal. Delivering chemotherapeutic drugs to the brain in sufficient concentration is the major limitation in their treatment due to the blood-brain barrier (BBB). Drug delivery systems may overcome this limitation and can improve the transportation through the BBB. Paclitaxel is an antimicrotubule agent with effective anticancer activity but limited BBB permeability. R-Flurbiprofen is a nonsteroidal antienflammatory drug and has potential anticancer activity. Accordingly, we designed an approach combining R-flurbiprofen and paclitaxel and positively-charged chitosan-modified poly-lactide-co-glycolic acid (PLGA) nanoparticles (NPs) and to transport them to glioma tissue. NPs were characterized and, cytotoxicity and cellular uptake studies were carried out in vitro. The in vivo efficacy of the combination and formulations were evaluated using a rat RG2 glioma tumor model. Polyethylene glycol (PEG) modified and chitosan-coated PLGA NPs demonstrated efficient cytotoxic activity and were internalized by the tumor cells in RG2 cell culture. In vivo studies showed that the chitosan-coated and PEGylated NPs loaded with paclitaxel and R-flurbiprofen exhibited significantly higher therapeutic activity against glioma. In conclusion, PLGA NPs can efficiently carry their payloads to glioma tissue and the combined use of anticancer and anti-inflammatory drugs may exert additional anti-tumor activity.

Although growth factors and anti-apoptotic peptides have been shown to be neuroprotective in stroke models, translation of these experimental findings to clinic is hampered by limited penetration of peptides to the brain. Here, we show that a large peptide like the basic fibroblast growth factor (bFGF) and a small peptide inhibitor of caspase-3 (z-DEVD-FMK) can effectively be transported to the brain after systemic administration by incorporating these peptides to brain-targeted nanoparticles (NPs). Chitosan NPs were loaded with peptides and then functionalized by conjugating with antibodies directed against the transferrin receptor-1 on brain endothelia to induce receptor-mediated transcytosis across the blood—brain barrier (BBB). Pre-ischemic systemic administration of bFGF- or z-DEVD-FMK-loaded NPs significantly decreased the infarct volume after 2-hour middle cerebral artery occlusion and 22-hour reperfusion in mice. Co-administration of bFGF- or z-DEVD-FMK-loaded NPs reduced the infarct volume further and provided a 3-hour therapeutic window. bFGF-loaded NPs were histologically detected in the brain parenchyma and also restored ischemia-induced Akt dephosphorylation. The neuroprotection was not observed when receptor-mediated transcytosis was inhibited with imatinib or when bFGF-loaded NPs were not conjugated with the targeting antibody, which enables them to cross the BBB. Nanoparticles targeted to brain are promising drug carriers to transport large as well as small BBB-impermeable therapeutics for neuroprotection against stroke Turgay Dalkara’s work is supported by the Turkish Academy of Sciences. This study is supported by The Scientific and Technological Research Council of Turkey (TUBITAK, Project Number: 109S017) SI

Under pathological conditions such as brain trauma, subarachnoid hemorrhage and stroke, cortical spreading depression (CSD) or peri-infarct depolarizations contribute to brain damage in animal models of neurological disorders as well as in human neurological diseases. CSD causes transient megachannel opening on the neuronal membrane, which may compromise neuronal survival under pathological conditions. Poloxamer-188 (P-188) and citicoline are neuroprotectants with membrane sealing properties. The aim of this study is to investigate the effect of P-188 and citicoline on the neuronal megachannel opening induced by CSD in the mouse brain. We have monitored megachannel opening with propidium iodide, a membrane impermeable fluorescent dye and, demonstrate that P-188 and citicoline strikingly decreased CSD-induced neuronal PI influx in cortex and hippocampal dentate gyrus. Therefore, these agents may be providing neuroprotection by blocking megachannel opening, which may be related to their membrane sealing action and warrant further investigation for treatment of traumatic brain injury and ischemic stroke.

Objectives We aimed to develop lipid–polyethylene glycol (PEG)–polymer hybrid nanoparticles, which have high affinity to tumour tissue with active ingredient, a new generation antineoplastic drug, farnesylthiosalicylic acid (FTA) for treatment of glioblastoma. Method Farnesylthiosalicylic acid-loaded poly(lactic-co-glycolic acid)-1,2 distearoyl-glycerol-3-phospho-ethanolamine-N [methoxy (PEG)-2000] ammonium salt (PLGA-DSPE-PEG) with or without 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) hybrid nanoparticles has been prepared and evaluated for in-vitro characterization. Cytotoxicity of FTA-loaded nanoparticles along with its efficacy on rat glioma-2 (RG2) cells was also evaluated both in vitro (in comparison with non-malignant cell line, L929) and in vivo. Key findings Scanning electron microscopy studies showed that all formulations prepared had smooth surface and spherical in shape. FTA and FTA-loaded nanoparticles have cytotoxic activity against RG2 glioma cell lines in cell culture studies, which further increases with addition of DOTAP. Magnetic resonance imaging and histopathologic evaluation on RG2 tumour cells in rat glioma model (49 female Wistar rats, 250–300 g) comparing intravenous and intratumoral injections of the drug have been performed and FTA-loaded nanoparticles reduced tumour size significantly in in-vivo studies, with higher efficiency of intratumoral administration than intravenous route. Conclusion Farnesylthiosalicylic acid-loaded PLGA-DSPE-PEG-DOTAP hybrid nanoparticles are proven to be effective against glioblastoma in both in-vitro and in-vivo experiments.

New drug delivery systems are highly needed in research and clinical area to effectively treat gliomas by reaching a high antineoplastic drug concentration at the target site without damaging healthy tissues. Intranasal (IN) administration, an alternative route for non-invasive drug delivery to the brain, bypasses the blood-brainbarrier (BBB) and eliminates systemic side effects. This study evaluated the antitumor efficacy of farnesylthiosalicylic acid (FTA) loaded (lipid-cationic) lipid-PEG-PLGA hybrid nanoparticles (HNPs) after IN application in rats. FTA loaded HNPs were prepared, characterized and evaluated for cytotoxicity. Rat glioma 2 (RG2) cells were implanted unilaterally into the right striatum of female Wistar rats. 10 days later, glioma bearing rats received either no treatment, or 5 repeated doses of 500 mu M freshly prepared FTA loaded HNPs via IN or intravenous (IV) application. Pre-treatment and post-treatment tumor sizes were determined with MRI. After a treatment period of 5 days, IN applied FTA loaded HNPs achieved a significant decrease of 55.7% in tumor area, equal to IV applied FTA loaded HNPs. Herewith, we showed the potential utility of IN application of FTA loaded HNPs as a non-invasive approach in glioblastoma treatment.

The initial phase in the development of a migraine is still poorly understood. Here, we describe a previously unknown signaling pathway between stressed neurons and trigeminal afferents during cortical spreading depression (CSD), the putative cause of migraine aura and headache. CSD caused neuronal Pannexin1 (Panx1) megachannel opening and caspase-1 activation followed by high-mobility group box 1 (HMGB1) release from neurons and nuclear factor κB activation in astrocytes. Suppression of this cascade abolished CSD-induced trigeminovascular activation, dural mast cell degranulation, and headache. CSD-induced neuronal megachannel opening may promote sustained activation of trigeminal afferents via parenchymal inflammatory cascades reaching glia limitans. This pathway may function to alarm an organism with headache when neurons are stressed.

Epidermal growth factor (EGF) and its receptor (EGFR) have been shown to play a significant role in the pathogenesis of glioblastoma. In our study, the EGFR was stimulated with EGF in human U138 glioblastoma cells. We show that the activated mitogen-activated protein kinase (MAPK)extracellular-signal-regulated kinases (ERK) 1/2 pathway phosphorylated the E twenty-six (ETS)-like transcription factor 1 (Elk-1) mainly at serine 383 residue. Mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, UO126 and ERK inhibitor II, FR180204 blocked the Elk-1 phosphorylation and activation. The phosphatidylinositide-3-OH kinase (PI3K)/Akt pathway was also involved in the Elk-1 activation. Activation of the Elk-1 led to an increased survival and a proliferative response with the EGF stimulation in the U138 glioblastoma cells. Knocking-down the Elk-1 using an RNA interference technique caused a decrease in survival of the unstimulated U138 glioblastoma cells and also decreased the proliferative response to the EGF stimulation. The Elk-1 transcription factor was important for the survival and proliferation of U138 glioblastoma cells upon the stimulation of EGFR with EGF. The MAPK/ERK1/2 and PI3K/Akt pathways regulated this response via activation of the Elk-1 transcription factor. The Elk-1 may be one of the convergence points for pathways located downstream of EGFR in glioblastoma cells. Utilization of the Elk-1 as a therapeutic target may lead to a novel strategy in treatment of glioblastoma. (C) 2011 Elsevier Ltd. All rights reserved.

Alpha-synuclein oligomerization and aggregation are considered to have a role in the pathogenesis of neurodegenerative diseases. However, despite numerous in vitro studies, the impact of aggregates in the intact brain is unclear. In vitro, oxidative/nitrative stress and acidity induce alpha-synuclein oligomerization. These conditions favoring alpha-synuclein fibrillization are present in the ischemic brain, which may serve as an in vivo model to study alpha-synuclein aggregation. In this study, we show that 30-minute proximal middle cerebral artery (MCA) occlusion and 72 hours reperfusion induce oligomerization of wild-type alpha-synuclein in the ischemic mouse brain. The nonamyloidogenic isoform beta-synuclein did not form oligomers. Alpha-synuclein aggregates were confined to neurons and colocalized with ubiquitin immunoreactivity. We also found that 30 minutes proximal MCA occlusion and 24 hours reperfusion induced larger infarcts in C57BL/6(Thy1)-h[A30P]alphaSYN transgenic mice, which have an increased tendency to form synuclein fibrils. Trangenics also developed more selective neuronal necrosis when subjected to 20 minutes distal MCA occlusion and 72 hours reperfusion. Enhanced 3-nitrotyrosine immunoreactivity in transgenic mice suggests that oxidative/nitrative stress may be one of the mechanisms mediating aggregate toxicity. Thus, the increased vulnerability of transgenic mice to ischemia suggests that alpha-synuclein aggregates not only form during ischemia but also negatively impact neuronal survival, supporting the idea that alpha-synuclein misfolding may be neurotoxic. Journal of Cerebral Blood Flow & Metabolism (2011) 31, 913-923; doi:10.1038/jcbfm.2010.170; published online 29 September 2010

Asli Kurne1, Rana Karabudak1, Gul Yalcin-Cakmakli1, Yasemin Gursoy-Ozdemir1, Pinar Aydin3, Ayse Ilksen-Colpak1, Sevda Lule2, Tulay Kansu11Department of Neurology, 2Institute of Neurological Sciences and Psychiatry, Faculty of Medicine, Hacettepe University, Ankara, Turkey; 3Special Eye Clinic, Ankara, TurkeyBackground and aim: Optic neuritis (ON) can be recurrent, with unilateral or bilateral presentation. Diagnosis of recurrent cases may be challenging. In this study long-term follow-up of recurrent and/or bilateral ON patients is reported in an effort to guide differential diagnosis and treatment.Methods: The study included 474 optic neuropathy patients. Of these, 70 patients with recurrent unilateral or bilateral, and nonrecurrent bilateral ON were assessed. The characteristics of each ON attack, laboratory and magnetic resonance imaging (MRI) findings, associated diseases and response to treatment were noted for each patient. Most of the patients were reevaluated in the outpatient clinic. Seven patients were investigated for neuromyelitis optica (NMO)-immunoglobulin G (IgG) seropositivity.Results: Forty-seven patients had recurrent unilateral ON and 23 had bilateral ON. Mean follow-up was 7.55 years. Final diagnoses for recurrent unilateral group were multiple sclerosis (MS) (n = 29), chronic relapsing inflammatory optic neuritis (CRION) (n = 11), NMO (n = 4), or autoimmune thyroid disease (n = 3); and for bilateral ON group, MS (n = 4), vasculitis (n = 13), postinfectious ON (n = 4), and sarcoidosis (n = 2). Three patients were positive for NMO antibodies.Conclusion: Based on the data collected, we conclude when recurrent ON causes moderate to severe visual loss in the absence of cranial MRI findings typical of MS, other diagnoses should be considered, including NMO.Keywords: optic neuritis, recurrent, bilateral, multiple sclerosis, neuromyelitis optica

Global ischemia after cardiac arrest, intraoperative hypoxia/hypotension, and hemorrhagic shock causes brain injury resulting in severe neurological and neurobehavioral deficits. Neurodegeneration can be prevented by local aromatase expression, and estrogen synthesis can be neuroprotective in ischemia/reperfusion. Therefore, aromatase, the enzyme that transforms androgens to estrogens, may be a potential target for the study of reperfusion injury after brain ischemia. We investigated the expression of aromatase and C/EBPβ using western blotting in rat hippocampus after transient global ischemia plus hypotension. Immunohistochemical analysis was performed for aromatase. After 10 min of ischemia, aromatase and C/EBPβ expression in cytosolic extracts were observed after 10 min and 24 h of reperfusion. The expression of both proteins was similar in control and damaged tissues. Immunoblot analysis demonstrated that the highest aromatase expression appeared in damaged hippocampi after 1 week and was gradually reduced after 2–10 weeks. C/EBPβ expression increased at 1 week in nuclear extracts of damaged hippocampi. The aromatase inhibitor megestrol acetate (20 mg/kg/day) suppressed aromatase and nuclear C/EBPβ levels in ischemic hippocampi. Our findings indicate that ischemia as well as chronic neurodegenerative processes leads to an increase in cytoplasmic aromatase and nuclear C/EBPβ. Thus, it is possible to hypothesize an interaction between this enzyme gene and transcription factor.

Eine kortikale Spreading Depression (CSD) – eine sich uber die Gehirnoberflache ausbreitende Depolarisationswelle von Neuronen und Gliazellen – wird mit der Entstehung von Migrane-Kopfschmerzen, v. a. der Migrane mit Aura, in Zusammenhang gebracht. Wie genau aber die Vorgange in dieser anfanglichen Phase der Schmerzentstehung ablaufen, ist bisher nicht klar. Hulya Karatas und Mitarbeiter schlagen eine Moglichkeit vor.