Unwinding of a cholesteric liquid crystal and bidirectional surface anchoring

We examine the influence of bidirectional anchoring on the unwinding of a planar cholesteric liquid crystal induced by the application of a magnetic field. We consider a liquid crystal layer confined between two plates with the helical axis perpendicular to the substrates. We fixed the director twist on one boundary and allow for bidirectional anchoring on the other by introducing a high-order surface potential. By minimizing the total free energy for the system, we investigate the untwisting of the cholesteric helix as the liquid crystal attempts to align with the magnetic field. The transitions between metastable states occur as a series of pitchjumps as the helix expels quarter or half-turn twists, depending on the relative sizes of the strength of the surface potential and the bidirectional anchoring. We show that secondary easy axis directions can play a significant role in the unwinding of the cholesteric in its transition towards a nematic, especially when the surface anchoring strength is large

Nelonemdaz for Patients with Acute Ischemic Stroke Undergoing Endovascular Reperfusion Therapy: A Randomized Phase II Trial

BACKGROUND: Nelonemdaz is a multitarget neuroprotectant that selectively blocks N-methyl-D-aspartate receptors and scavenges free radicals, as proven in preclinical ischemia-reperfusion studies. We aimed to evaluate the safety and efficacy of nelonemdaz in patients with acute ischemic stroke receiving endovascular reperfusion therapy. METHODS: This phase II randomized trial involved participants with large-artery occlusion in the anterior circulation at baseline who received endovascular reperfusion therapy <8 hours from symptom onset at 7 referral stroke centers in South Korea between October 29, 2016, and June 1, 2020. Two hundred thirteen patients were screened and 209 patients were randomly assigned at a 1:1:1 ratio using a computer-generated randomization system. Patients were divided into 3 groups based on the medication received-placebo, low-dose (2750 mg) nelonemdaz, and high-dose (5250 mg) nelonemdaz. The primary outcome was the proportion of patients with modified Rankin Scale scores of 0-2 at 12 weeks. RESULTS: Two hundred eight patients were assigned to the placebo (n=70), low-dose (n=71), and high-dose (n=67) groups. The groups had similar baseline characteristics. The primary outcome was achieved in 183 patients, and it did not differ among the groups (33/61 [54.1%], 40/65 [61.5%], and 36/57 [63.2%] patients; P=0.5578). The common odds ratio (90% CI) indicating a favorable shift in the modified Rankin Scale scores at 12 weeks was 1.55 (0.92-2.60) between the placebo and low-dose groups and 1.61 (0.94-2.76) between the placebo and high-dose groups. No serious adverse events were reported. CONCLUSIONS: The study arms showed no significant difference in the proportion of patients achieving modified Rankin Scale scores of 0-2 at 12 weeks. Nevertheless, nelonemdaz-treated patients showed a favorable tendency toward achieving these scores at 12 weeks, without serious adverse effects. Thus, a large-scale phase III trial is warranted. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02831088

Attenuation of oxidative neuronal necrosis by a dopamine D1 agonist in mouse cortical cell cultures.

Events which lead to an increase in intracellular free radicals induce necrotic cell death of cultured cortical neurons. In the present study, we report that treatment with 1 microM (+/-)-SKF-38393 hydrochloride, a selective D1 agonist, as well as 100 microM trolox, a lipophilic vitamin E analogue, significantly prevented oxidative-related necrotic cell death following exposure to 10 microM Fe2+ or 1 mM buthionine sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase. The neuroprotective effect of (+/-)-SKF-38393 hydrochloride was partially reversed by addition of (+/-)-SKF-83566 hydrochloride, a selective D1 antagonist. Quinelorane dihydrochloride, a selective D2 agonist, did not influence free radical neurotoxicity. Interestingly, inclusion of (+/-)-SKF-38393 hydrochloride or quinelorane dihydrochloride did not attenuate apoptotic cell death of cortical neurons deprived of serum. The present study provides evidence that (+/-)-SKF-38393 hydrochloride attenuates oxidative neuronal necrosis, which has unique therapeutic potential for the treatment of various neurodegenerative diseases linked to oxidative stress

Calcium-dependent prevention of neuronal apoptosis by lithium ion: essential role of phosphoinositide 3-kinase and phospholipase Cgamma.

We examined the possibility that the neuroprotective effects of Li+ would depend upon the patterns of neuronal death, apoptosis versus necrosis, and whether Ca2+ as well as phosphoinositide 3-kinase (PI3-K) would mediate the neuroprotective effect of Li+. Cortical neurons treated with Li+ showed marked increase in [Ca2+]i within 2 min. Addition of BAPTA-acetoxymethyl ester, a selective Ca2+ chelator, abrogated the antiapoptotic effect of Li+. PI3-K was activated rapidly within 1 min after exposure to Li+, which mediated Ca2+-dependent neuroprotective effects of Li+. Activated PI3-K seemed to increase [Ca2+]i via the phospholipase Cgamma (PLCgamma) pathway. Antiapoptosis action of Li+ was prevented in the presence of U-73122, a selective phospholipase C inhibitor, and was not observed in PLCgamma1-null fibroblasts. In contrast to antiapoptosis action, administration of Li+ did not prevent neuronal cell necrosis by excitotoxicity or free radicals. Li+ selectively prevents apoptosis by increasing [Ca2+]i through activation of PI3-K and PLCgamma pathways

Neurotoxic and neuroprotective actions of catecholamines in cortical neurons.

We examined the possibility that catecholamines (CA) could act as endogenous modulators of neuronal death. Exposure to high doses (>100 microM) of dopamine (DA) caused widespread neuronal death within 24 h in mouse cortical cell cultures and was accompanied by cell body shrinkage, aggregation and condensation of nuclear chromatin, and prominent internucleosomal DNA fragmentation. Epinephrine, but not norepinephrine (NE), was slightly toxic to neurons at doses higher than 1 mM. DA-induced death was attenuated by the addition of three different anti-apoptosis agents, 1 microgram/ml cycloheximide, 25 mM K(+), or 100 ng/ml brain-derived neurotrophic factor (BDNF). While treatment with 100 microM N-acetyl-l-cysteine attenuated DA neurotoxicity, neither the glutamate antagonists (10 microM MK-801 plus 50 microM CNQX) nor several antioxidants [trolox, 100 microM; Mn (III) tetrakis (4-benzoic acid) porphyrin chloride, 100 microM; Mn (III) tetrakis (1-methyl-4-pyridyl) prophyrin pentachloride, 100 microM; N-tert-butyl-alpha-phenylnitrone, 3 mM] prevented the CA-induced apoptosis. Interestingly, all CA at 1-30 microM attenuated free radical-mediated neuronal necrosis following exposure to 30 microM Fe(2+) or 200 microM H(2)O(2), which was insensitive to DA or NE antagonists. Like trolox, CA reduced levels of the stable free radical 1,1-diphenyl-2-picrylhydrazyl under cell-free conditions, raising the possibility that CA as an antioxidant protects neurons. We also found that the neuroprotective effect of CA prolonged the protective effects of BDNF against serum deprivation. The present findings suggest that CA induces apoptosis at high doses but prevents free radical-mediated neurotoxicity as an anti-oxidant without being coupled to the receptors

Phosphatidylinositol 3-kinase-mediated regulation of neuronal apoptosis and necrosis by insulin and IGF-I.

We examined effects of two insulin-like growth factors, insulin and insulin-like growth factor-I (IGF-I), against apoptosis, excitotoxicity, and free radical neurotoxicity in cortical cell cultures. Like IGF-I, insulin attenuated serum deprivation-induced neuronal apoptosis in a dose-dependent manner at 10-100 ng/mL. The anti-apoptosis effect of insulin against serum deprivation disappeared by addition of a broad protein kinase inhibitor, staurosporine, but not by calphostin C, a selective protein kinase C inhibitor. Addition of PD98059, a mitogen-activated protein kinase kinase (MAPKK) inhibitor, blocked insulin-induced activation of extracellular signal-regulated protein kinases (ERK1/2) without altering the neuroprotective effect of insulin. Cortical neurons underwent activation of phosphatidylinositol (PI) 3-kinase as early as 1 min after exposure to insulin. Inclusion of wortmannin or LY294002, selective inhibitors of PI 3-K, reversed the insulin effect against apoptosis. In contrast to the anti-apoptosis effect, neither insulin nor IGF-I protected excitotoxic neuronal necrosis following continuous exposure to 15 microM N-methyl-D-aspartate or 40 microM kainate for 24 h. Surprisingly, concurrent inclusion of 50 ng/mL insulin or IGF-I aggravated free radical-induced neuronal necrosis over 24 h following continuous exposure to 10 microM Fe2+ or 100 microM buthionine sulfoximine. Wortmannin or LY294002 also reversed this potentiation effect of insulin. These results suggest that insulin-like growth factors act as anti-apoptosis factor and pro-oxidant depending upon the activation of PI 3-kinase

대뇌 피질 신경세포 일차 배양에서 리튬의 FeCl₂에 의한 Free Radical Injury 증강 기전 연구

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 μM 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

Chronic cerebral hypoperfusion in a mouse model of Alzheimer's disease: an additional contributing factor of cognitive impairment

The purpose of the present study was to evaluate whether chronic cerebral hypoperfusion would affect cognitive status in an Alzheimer mouse model. Behavioral tests and histological evaluations were performed using female Tg2576 mice eight weeks after right common carotid artery occlusion (rCCAO), which is known to induce a type of vascular dementia without neuronal necrosis in nontransgenic mice. Positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) was utilized to evaluate metabolic status in the rCCAO-operated brain of nontransgenic mice. Escape latency from the Morris water maze test was not significantly different between rCCAO- and sham-operated mice. However, the learning curve was impaired in rCCAO-operated transgenic mice while it was preserved in sham-operated transgenic or rCCAO-operated nontransgenic mice. Histological examination revealed no evidence of cell death in the rCCAO-operated brains, and the extent of amyloid deposition was not different in rCCAO- and sham-operated mice. The brain of rCCAO-operated mice showed metabolic deficits in the ipsilateral parietal cortex through FDG-PET. In conclusion, further cognitive decline which is more comparable to typical Alzheimer's disease was induced by chronic cerebral hypoperfusion in an Alzheimer mouse model. This aggravation might be associated with hypometabolism via chronic cerebral hypoperfusion