ABSTRACT
Background@#and Purpose Nelonemdaz (Neu2000) has both selective antagonism against 2B subunit of N-methyl-D-aspartate receptor and antioxidant activity. This drug provides sufficient evidence of neuroprotection in acute cerebral ischemia/reperfusion models. This phase III trial aims to determine this effect in patients.Design The Rescue on Reperfusion Damage in Cerebral Infarction by Nelonemdaz is a multicenter, double-blinded clinical trial. A total of 496 patients will be randomly assigned into the nelonemdaz (a total of 5,250 mg divided by 10 times for 5 days) and placebo groups. Patients will be included if they have an acute ischemic stroke (National Institutes of Health Stroke Scale score ≥8) caused by intracranial large vessel occlusion in the anterior circulation (Alberta Stroke Program Early CT Score ≥4), and if they are expected to undergo endovascular thrombectomy within 12 hours after stroke onset.Endpoints The primary endpoint is a favorable shift in the modified Rankin Scale (mRS) score at 90 days after the first dose of drug. The data will be analyzed by the Cochran–Mantel–Haenszel shift test. The secondary endpoints include functional independence (mRS 0–2) at 35 and 90 days, the favorable shift of mRS at 35 days, the proportion of mRS 0 at 35 and 90 days, and the occurrence rates of symptomatic intracranial hemorrhage within 7 days. @*Conclusion@#This trial will clarify the efficacy and safety of nelonemdaz in patients with acute ischemic stroke and endovascular thrombectomy. This study has been registered at ClinicalTrials. gov (NCT05041010).
ABSTRACT
Alzheimer's disease (AD) is a neurodegenerative disease that proceeds with the age-dependent neuronal loss, an irreversible event which causes severe cognitive and psychiatric devastations. In the present study, we investigated whether the compound, AAD-2004 [2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylaminobenzoic acid] which has anti-oxidant and anti-inflammatory properties, is beneficial for the brain of Tg-betaCTF99/B6 mice, a murine AD model that was recently developed to display age-dependent neuronal loss and neuritic atrophy in the brain. Administration of AAD-2004 in Tg-betaCTF99/B6 mice from 10 months to 18 months of age completely repressed the accumulation of lipid peroxidation in the brain. AAD-2004 markedly suppressed neuronal loss and neuritic atrophy, and partially reversed depleted expression of calbindin in the brain of Tg-beta-CTF99/B6. These results suggest that AAD-2004 affords neurodegeneration in the brain of AD mouse model.
Subject(s)
Animals , Mice , Alzheimer Disease , Aspirin , Atrophy , Brain , S100 Calcium Binding Protein G , Lipid Peroxidation , Neurodegenerative Diseases , NeuronsABSTRACT
The possibility that P2X7 receptor (P2X7R) expression in microglia would mediate neuronal damage via reactive oxygen species (ROS) production was examined in the APPswe/PS1dE9 mouse model of Alzheimer's disease (AD). P2X7R was predominantly expressed in CD11b-immunopositive microglia from 3 months of age before Abeta plaque formation. In addition, gp91phox, a catalytic subunit of NADPH oxidase, and ethidium fluorescence were detected in P2X7R-positive microglial cells of animals at 6 months of age, indicating that P2X7R-positive microglia could produce ROS. Postsynaptic density 95-positive dendrites showed significant damage in regions positive for P2X7R in the cerebral cortex of 6 month-old mice. Taken together, up-regulation of P2X7R activation and ROS production in microglia are parallel with Abeta increase and correlate with synaptotoxicity in AD.
Subject(s)
Animals , Mice , Aging , Alzheimer Disease/genetics , Amyloid beta-Peptides , CD11b Antigen/immunology , Blotting, Western , Cerebral Cortex/metabolism , Disease Models, Animal , Gene Expression , Mice, Transgenic , Microglia/metabolism , Neurons/metabolism , Plaque, Amyloid , Reactive Oxygen Species/metabolism , Receptors, Immunologic/analysis , Receptors, Purinergic P2X7/geneticsABSTRACT
Blood cells are transported into the brain and are thought to participate in neurodegenerative processes following hypoxic ischemic injury. We examined the possibility that transient forebrain ischemia (TFI) causes the blood-brain barrier (BBB) to become permeable to blood cells, possibly via dysfunction and degeneration of endothelial cells in rats. Extravasation of Evans blue and immunoglobulin G (IgG) was observed in the hippocampal CA1-2 areas within 8 h after TFI, and peaked at 48 h. This extravasation was accompanied by loss of tight junction proteins, occludin, and zonula occludens-1, and degeneration of endothelial cells in the CA1-2 areas. Iron overload and mitochondrial free radical production were evident in the microvessel endothelium of the hippocampus before endothelial cell damage occurred. Administration of deferoxamine (DFO), an iron chelator, or Neu2000, an antioxidant, blocked free radical production and endothelial cell degeneration. Our findings suggest that iron overload and iron-mediated free radical production cause loss of tight junction proteins and degeneration of endothelial cells, opening of the BBB after TFI.
Subject(s)
Animals , Male , Rats , Blood-Brain Barrier/metabolism , Capillary Permeability , Endothelial Cells/metabolism , Evans Blue/metabolism , Free Radicals/metabolism , Hippocampus/metabolism , Iron/metabolism , Ischemic Attack, Transient/pathology , Membrane Proteins/metabolism , Rats, Sprague-DawleyABSTRACT
The endoplasmic reticulum (ER) stress results from disrupted protein folding triggered by protein mutation or oxidation, reduced proteasome activity, and altered Ca2+ homeostasis. ER stress is accompanied by activation of the unfolded protein response (UPR) and cell death pathway. We examined if the UPR and cell death pathway would be activated in Alzheimer's disease (AD). RT-PCR experiments revealed increased splicing of X-box binding protein-1 (XBP-1), an UPR transcription factor, in AD compared with age-matched control. Among target genes of XBP-1, expression of protein disulfide isomerase (PDI), but not glucose-regulated protein 78 (GRP78), was increased in AD, suggesting disturbed activation of the UPR in AD. C/EBP homologous protein (CHOP), caspase-3, caspase-4, and caspase-12, downstream mediators of cell death pathway, were activated in AD. Neither the UPR nor cell death pathway was induced in aged Tg2576 mice, a transgenic mouse model of Alzheimer's disease that reveals both plaque pathology and some cognitive deficits. The present study suggests that disturbed induction of the UPR and activation of the pro-apoptotic proteins contribute to neuropathological process in AD irrespective of amyloid beta and senile plaque.
ABSTRACT
OBJECTIVES: For the past half century, lithium has been used for the acute and prophylactic treatment of bipolar disorder and recurrent depression. Recently, new pharmacological effects of Li+ have appeared, showing that Li+ can influence neuronal injury. We tested the effects of Li+ on free radical induced neuronal injury in primary murine cortical cell cultures. METHODS: Cortical cells were prepared from fetal mice (embryonic day 15) and exposed to 30 micrometer Fe2+ alone or with 5 mM Li+ or 5 mM Li+ alone for 24 hrs at Days in vitro (DIV) 14. Neuronal death was analyzed by measuring lactate dehydrogenase (LDH) release into media. The fluorescence of 2',7'-dichlorofluorescin (DCF) was measured in as a mean of estimating the formation of reactive oxygen species (ROS). RESULTS: Li+ alone does not produce neuronal injury itself but it potentiates Fe2+-induced neuronal injury through increasing the production of free radical. CONCLUSION: This study suggests that the effects of Li+ on neuronal survivorship may be injury type dependent and Li+ potentiate the free radical injury. Therefore in practice clinician should be cautious in using the lithium in the treatment of brain injured patients.
Subject(s)
Animals , Humans , Mice , Bipolar Disorder , Brain , Cell Culture Techniques , Depression , Fluorescence , L-Lactate Dehydrogenase , Lithium , Necrosis , Neurons , Reactive Oxygen Species , Survival RateABSTRACT
OBJECTIVES: We examined the effects of neurotrophins and insulin-like growth factors on cell death induced by haloperidol, a typical anti-psychotic agent. METHOD: Neocortices from 14- or 15-daysold fetal mice for neuron-glia co-cultures were used for this experiment. RESULT: Twenty-four hours treatment of mouse cortical cell cultures with 30 M haloperidol-induced wide spread neuronal apoptosis characterized by cell body shrinkage, DNA fragmentation and condensation. Concurrent treatment with growth factors, BDNF, NT4/5, IGF-I and IGF-II, protect the neurons from the haloperidol-induced neuronal apoptosis(HINA) in a dose dependent manner(10-100ng/ml). CONCLUSION: The present study suggests the possibility that haloperidol toxicity can be hampered with growth factors. Further study about the mechanism underlying the protective capacity of the growth factors on HINA may lead to the development of the new protective strategy for tardive dyskinesia.
Subject(s)
Animals , Mice , Apoptosis , Brain-Derived Neurotrophic Factor , Cell Culture Techniques , Cell Death , Coculture Techniques , DNA Fragmentation , Haloperidol , Insulin-Like Growth Factor I , Insulin-Like Growth Factor II , Intercellular Signaling Peptides and Proteins , Movement Disorders , Neocortex , Nerve Growth Factors , Neurons , SomatomedinsABSTRACT
OBJECTIVES: We examined the patterns of cell death induced by the 6-hydroxydopamine, a selective dopaminergic toxin that used to produce Parkinson's disease model. METHOD: Neocortices from 14- or 15-day-old fetal mice for neuron-glia co-cultures were used for this experiments. RESULTS: Cortical cell cultures exposed to 10-100 microM 6-hydroxydopamine for 24 hr under-went neuronal death without injuring glia. The degenerating neurons showed hallmark of apoptosis featuring cell body shrinkage, nuclear chromatin condensation and aggregation, nuclear membrane disintegration with intact plasma membrane, and prominent internucle- osomal DNA fragmentation. Neither the glutamate antagonists (10 microM MK-801 and 50 microM CNQX) nor antioxidants (trolox, 100 microM, N-acetyl-cysteine, 100 microM) prevented the 6-OHDA induced neuronal injury. The death was attenuated by addition of two different anti-apoptotic agents, 1 microgram/ml cycloheximide and caspase inhibitor (100 microM zVAD-fmk). CONCLUSION: These features suggest that 6-OHDA induced apoptotic type of neuronal death in cortical neuronal culture. Considering the protective effect of caspase inhibitors, a mechanism involving caspase cascade rather than oxidative stress is responsible for the 6-OHDA-induced neuronal apoptosis. In addition, our results showed that 6-OHDA-induced apoptosis is not confined to dopaminergic neurons and the primary cortical culture system so this system is suitable for the study of 6-OHDA-induced neuronal apoptosis.
Subject(s)
Animals , Mice , Antioxidants , Apoptosis , Caspase Inhibitors , Cell Culture Techniques , Cell Death , Cell Membrane , Chromatin , Coculture Techniques , Cycloheximide , Dizocilpine Maleate , DNA Fragmentation , Dopaminergic Neurons , Excitatory Amino Acid Antagonists , Neocortex , Neuroglia , Neurons , Nuclear Envelope , Oxidative Stress , Oxidopamine , Parkinson DiseaseABSTRACT
No abstract available.