Sevda Lule

Repetitive mild traumatic brain injury during adolescence can induce neurological dysfunction through undefined mechanisms. Interleukin-1 (IL-1) contributes to experimental adult diffuse and contusion TBI models, and IL-1 antagonists have entered clinical trials for severe TBI in adults; however, no such data exist for adolescent TBI. We developed an adolescent mouse repetitive closed head injury (rCHI) model to test the role of IL-1 family members in post-injury neurological outcome. Compared to one CHI, three daily injuries (3HD) produced acute and chronic learning deficits and emergence of hyperactivity, without detectable gliosis, neurodegeneration, brain atrophy, and white matter loss at one year. Mature IL-1β and IL-18 were induced in brain endothelium in 3HD but not 1HD, three hit weekly, or sham animals. IL-1β processing was induced cell-autonomously in three-dimensional human endothelial cell cultures subjected to in vitro concussive trauma. Mice deficient in IL-1 receptor-1 or caspase-1 had improved post-injury Morris water maze performance. Repetitive mild CHI in adolescent mice may induce behavioral deficits in the absence of significant histopathology. The endothelium is a potential source of IL-1β and IL-18 in rCHI, and IL-1 family members may be therapeutic targets to reduce or prevent neurological dysfunction after repetitive mild TBI in adolescents.

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.

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.

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.

How Migraine Develops: Migraine is a common medical disorder. Unfortunately, how and why migraine headache is initiated is unclear. Karatas et al. (p. 1092 ) now describe a signaling pathway between stressed neurons and meningeal trigeminal afferents, which may explain how migraine headaches can be generated.

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 α-synuclein oligomerization. These conditions favoring α-synuclein fibrillization are present in the ischemic brain, which may serve as an in vivo model to study α-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 α-synuclein in the ischemic mouse brain. The nonamyloidogenic isoform β-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 α-synuclein aggregates not only form during ischemia but also negatively impact neuronal survival, supporting the idea that α-synuclein misfolding may be neurotoxic.