Engineering Lipusu with lysophosphatidylcholine for improved tumor cellular uptake and anticancer efficacy.

Liposomes have been developed as drug delivery carriers to enhance the antitumor efficiency of therapeutic agents. Lipusu® (Lip), a paclitaxel (PTX) liposome, has been widely used in the treatment of breast cancer. Compared with PTX, Lip could change the biodistribution and reduce the systemic toxicity. However, there was no positive effect on the entry of PTX into tumor cells, and thus the therapeutic effect was not significantly improved. Therefore, it is meaningful to engineer Lip for improving tumor cellular uptake efficiency. Here, lysophosphatidylcholine (LPC)-engineered Lip (LPC-Lip) was constructed via inserting single chain lipid tails into liposomal lipid bilayers, which was realized by simple incubation. Compared with Lip, the better cellular uptake of liposomes modified with LPC resulted in enhanced cytotoxic activity of LPC-Lip in 4T1 cells. Furthermore, stronger tumor growth inhibition was observed in LPC-Lip treated 4T1 tumor-bearing mice without significant side effects. In conclusion, by modulating the lipid composition of Lip, the antitumor efficacy can be improved, and LPC engineered Lip may serve as a promising formulation of PTX for future cancer therapy.

Preserving Brain LPC-DHA by Plasma Supplementation Attenuates Brain Injury after Cardiac Arrest.

OBJECTIVE: Cardiac arrest (CA) is a major health burden with brain damage being a significant contributor to mortality. We found lysophosphatidylcholine (LPC), including a species containing docosahexaenoic acid (LPC-DHA), was significantly decreased in plasma post-CA, supplementation of which significantly improved neurological outcomes. The aim of this study is to understand the protective role of LPC-DHA supplementation on the brain post-CA. METHODS: We first evaluated associations between the plasma level of LPC-DHA and neurological injury and outcomes of human patients with CA. We then utilized a rat CA model and cell cultures to investigate therapeutic and mechanistic aspects of plasma LPC-DHA supplementation. RESULTS: We found that decreased plasma LPC-DHA was strongly associated with neurological outcomes and disappearance of the difference between gray and white matter in the brain after CA in human patients. In rats, the decreased plasma LPC-DHA was associated with decreased levels of brain LPC-DHA after CA, and supplementing plasma LPC-DHA normalized brain levels of LPC-DHA and alleviated neuronal cell death, activation of astrocytes, and expression of various inflammatory and mitochondrial dynamics genes. We also observed deceased severity of metabolic alterations with LPC-DHA supplementation using untargeted metabolomics analysis. Furthermore, LPC treatment showed a similar protective effect for neurons and astrocytes in mixed primary brain cell cultures. INTERPRETATION: The observed neuroprotection accompanied with normalized brain LPC-DHA level by plasma supplementation implicate the importance of preventing the decrease of brain LPC-DHA post-CA for attenuating brain injury. Furthermore, the data supports the causative role of decreased plasma LPC-DHA for brain damage after CA. ANN NEUROL 2022;91:389-403.

Impact of the immune response modification by lysophosphatidylcholine in the efficacy of antibiotic therapy of experimental models of peritoneal sepsis and pneumonia by Pseudomonas aeruginosa: LPC therapeutic effect in combined therapy.

INTRODUCTION: Immune response stimulation may be an adjuvant to antimicrobial treatment. Here, we evaluated the impact of immune response modification by lysophosphatidylcholine (LPC), combined with imipenem or ceftazidime, in murine models of peritoneal sepsis (PS) and pneumonia induced by Pseudomonas aeruginosa. METHODS: The imipenem and ceftazidime-susceptible strain (Pa39) and imipenem and ceftazidime-resistant strain (Pa238) were used. Ceftazidime pharmacokinetic and pharmacodynamic parameters were determined. The therapeutic efficacy and TNF-α and IL-10 levels were determined in murine models of PS and pneumonia induced by Pa39 and Pa238 and treated with LPC, imipenem or ceftazidime, alone or in combination. RESULTS: In the PS model, LPC+ceftazidime reduced spleen and lung Pa238 concentrations (-3.45 and -3.56log10CFU/g; P<0.05) to a greater extent than ceftazidime monotherapy, while LPC+imipenem maintained the imipenem efficacy (-1.66 and -1.45log10CFU/g; P>0.05). In the pneumonia model, LPC+ceftazidime or LPC+imipenem reduced the lung Pa238 concentrations (-2.37log10CFU/g, P=0.1, or -1.35log10CFU/g, P=0.75). For Pa39, no statistically significant difference was observed in the PS and pneumonia models between combined therapy and monotherapy. Moreover, LPC+imipenem and LPC+ceftazidime significantly decreased and increased the TNF-α and IL-10 levels, respectively, in comparison with the untreated controls and monotherapies. CONCLUSIONS: These results demonstrate the impact of immune response modification by LPC plus antibiotics on the prognosis of infections induced by ceftazidime-resistant P. aeruginosa.

Stearoyl lysophosphatidylcholine inhibits LPS-induced extracellular release of HMGB1 through the G2A/calcium/CaMKKß/AMPK pathway.

Stearoyl lysophosphatidylcholine (sLPC) has protective effects against several lethal sepsis models, even after induction of sepsis, which is associated with sLPC-mediated inhibition of high mobility group box 1 (HMGB1) release. This study investigated the mechanism by which sLPC inhibits lipopolysaccharide (LPS)-induced extracellular secretion of HMGB1 after the onset of sepsis. sLPC increased AMPK phosphorylation and the binding of AMPK to calcium/calmodulin-dependent protein kinase kinase ß (CaMKKß), one of the upstream signals of AMPK. Inhibition of CaMKKß activity decreased sLPC-mediated inhibition of HMGB1 release, and sLPC increased the concentration of intracellular calcium. Blocking of the macrophage G protein-coupled receptor G2A (G2A) suppressed AMPK phosphorylation, suppressed increases in the intracellular levels of calcium, and prevented the inhibition of HMGB1 release by sLPC. In particular, when macrophages were incubated with sLPC even after LPS treatment, sLPC increased the phosphorylation of AMPK and the binding of CaMKKß and AMPK, and suppressed the secretion of HMGB1. In addition, sLPC administered 1 h before or 4 h after establishment of sepsis significantly diminished circulating HMGB1 levels in mice. sLPC inhibited LPS-induced extracellular release of HMGB1 through the activation of the G2A/calcium/CaMKKß/AMPK pathway. These findings suggest that sLPC may be a potential anti-inflammatory agent for acute inflammatory conditions such as sepsis.

Dietary lysophosphatidylcholine-EPA enriches both EPA and DHA in the brain: potential treatment for depression.

EPA and DHA protect against multiple metabolic and neurologic disorders. Although DHA appears more effective for neuroinflammatory conditions, EPA is more beneficial for depression. However, the brain contains negligible amounts of EPA, and dietary supplements fail to increase it appreciably. We tested the hypothesis that this failure is due to absorption of EPA as triacylglycerol, whereas the transporter at the blood-brain barrier requires EPA as lysophosphatidylcholine (LPC). We compared tissue uptake in normal mice gavaged with equal amounts (3.3 µmol/day) of either LPC-EPA or free EPA (surrogate for current supplements) for 15 days and also measured target gene expression. Compared with the no-EPA control, LPC-EPA increased brain EPA >100-fold (from 0.03 to 4 µmol/g); free EPA had little effect. Furthermore, LPC-EPA, but not free EPA, increased brain DHA 2-fold. Free EPA increased EPA in adipose tissue, and both supplements increased EPA and DHA in the liver and heart. Only LPC-EPA increased EPA and DHA in the retina, and expression of brain-derived neurotrophic factor, cyclic AMP response element binding protein, and 5-hydroxy tryptamine (serotonin) receptor 1A in the brain. These novel results show that brain EPA can be increased through diet. Because LPC-EPA increased both EPA and DHA in the brain, it may help in the treatment of depression as well as neuroinflammatory diseases, such as Alzheimer's disease.

Drug induced exocytosis of glycogen in Pompe disease.

Pompe disease is caused by a deficiency in the lysosomal enzyme α-glucosidase, and this leads to glycogen accumulation in the autolysosomes of patient cells. Glycogen storage material is exocytosed at a basal rate in cultured Pompe cells, with one study showing up to 80% is released under specific culture conditions. Critically, exocytosis induction may reduce glycogen storage in Pompe patients, providing the basis for a therapeutic strategy whereby stored glycogen is redirected to an extracellular location and subsequently degraded by circulating amylases. The focus of the current study was to identify compounds capable of inducing rapid glycogen exocytosis in cultured Pompe cells. Here, calcimycin, lysophosphatidylcholine and α-l-iduronidase each significantly increased glycogen exocytosis compared to vehicle-treated controls. The most effective compound, calcimycin, induced exocytosis through a Ca2+-dependent mechanism, although was unable to release a pool of vesicular glycogen larger than the calcimycin-induced exocytic pore. There was reduced glycogen release from Pompe compared to unaffected cells, primarily due to increased granule size in Pompe cells. Drug induced exocytosis therefore shows promise as a therapeutic approach for Pompe patients but strategies are required to enhance the release of large molecular weight glycogen granules.

Efficacy of Lysophosphatidylcholine in Combination with Antimicrobial Agents against Acinetobacter baumannii in Experimental Murine Peritoneal Sepsis and Pneumonia Models.

Immune response stimulation to prevent infection progression may be an adjuvant to antimicrobial treatment. Lysophosphatidylcholine (LPC) is an immunomodulator involved in immune cell recruitment and activation. In this study, we aimed to evaluate the efficacy of LPC in combination with colistin, tigecycline, or imipenem in experimental murine models of peritoneal sepsis and pneumonia. We used Acinetobacter baumannii strain Ab9, which is susceptible to colistin, tigecycline, and imipenem, and multidrug-resistant strain Ab186, which is susceptible to colistin and resistant to tigecycline and imipenem. Pharmacokinetic and pharmacodynamic parameters for colistin, tigecycline, and imipenem and the 100% minimal lethal dose (MLD100) were determined for both strains. The therapeutic efficacies of LPC, colistin (60 mg/kg of body weight/day), tigecycline (10 mg/kg/day), and imipenem (180 mg/kg/day), alone or in combination, were assessed against Ab9 and Ab186 at the MLD100 in murine peritoneal sepsis and pneumonia models. The levels of pro- and anti-inflammatory cytokines, i.e., tumor necrosis factor alpha (TNF-α) and interleukin-10 (IL-10), were determined by enzyme-linked immunosorbent assay (ELISA) for the same experimental models after inoculating mice with the MLD of both strains. LPC in combination with colistin, tigecycline, or imipenem markedly enhanced the bacterial clearance of Ab9 and Ab186 from the spleen and lungs and reduced bacteremia and mouse mortality rates (P < 0.05) compared with those for colistin, tigecycline, and imipenem monotherapies. Moreover, at 4 h post-bacterial infection, Ab9 induced higher TNF-α and lower IL-10 levels than those with Ab186 (4 µg/ml versus 3 µg/ml [P < 0.05] and 2 µg/ml versus 3.4 µg/ml [P < 0.05], respectively). LPC treatment combined with colistin, tigecycline, or imipenem modestly reduced the severity of infection by A. baumannii strains with different resistance phenotypes compared to LPC monotherapy in both experimental models.

Use of adjuvants in the treatment of Acinetobacter baumannii.

The current antibiotic crisis to treat infections by Acinetobacter baumannii is linked with the increase of antimicrobial resistance and the lack of development of new antimicrobial drugs. For this reason, new alternatives for the treatment and control of infections by A. baumannii are necessary. Several studies have reported the effect of adjuvants to restore the efficacy of existing antimicrobial agents. Herein, we analyzed the main results on the development of adjuvant drugs, as monotherapy or in combination therapy with existing antimicrobial agents, which have shown promising results in vitro and in vivo. However, caution is needed and further extensive in vivo studies have to be performed to confirm the potential use of these adjuvants as true therapeutic alternatives.

Choline Supplementation With a Structured Lipid in Children With Cystic Fibrosis: A Randomized Placebo-Controlled Trial.

BACKGROUND: Choline depletion is seen in cystic fibrosis (CF) and pancreatic insufficiency in spite of enzyme treatment and may result in liver, fatty acid, and muscle abnormalities. This study evaluated the efficacy and safety of an easily absorbed choline-rich structured lipid (LYM-X-SORB™ [LXS]) to improve choline status. METHODS: Children with CF and pancreatic insufficiency were randomized to LXS or placebo in a 12-month double blind trial. Dietary choline intake, plasma cholines, plasma and fecal phospholipids, coefficient of fat absorption, pulmonary function, growth status, body composition, and safety measures were assessed. Magnetic resonance spectroscopy for calf muscle choline and liver fat were assessed in a subgroup and compared with a healthy comparison group matched for age, sex, and body size. RESULTS: A total of 110 subjects were enrolled (age 10.4 ±â€Š3.0 years). Baseline dietary choline, 88% recommended, increased 3-fold in the LXS group. Plasma choline, betaine, and dimethylglycine increased in the LXS but not placebo (P = 0.007). Plasma lysophosphatidylcholine and phosphatidylcholine increased, and fecal phosphatidylcholine/phosphatidylethanolamine ratio decreased (P ≤ 0.05) in LXS only, accompanied by a 6% coefficient of fat absorption increase (P = 0.001). Children with CF had higher liver fat than healthy children and depleted calf muscle choline at baseline. Muscle choline concentration increased in LXS and was associated with improvement in plasma choline status. No relevant changes in safety measures were evident. CONCLUSIONS: LXS had improved choline intake, plasma choline status, and muscle choline stores compared with placebo group. The choline-rich supplement was safe, accepted by participants, and improved choline status in children with CF.

Vinyl sulfone analogs of lysophosphatidylcholine irreversibly inhibit autotaxin and prevent angiogenesis in melanoma.

Autotaxin (ATX) is an enzyme discovered in the conditioned medium of cultured melanoma cells and identified as a protein that strongly stimulates motility. This unique ectonucleotide pyrophosphatase and phosphodiesterase facilitates the removal of a choline headgroup from lysophosphatidylcholine (LPC) to yield lysophosphatidic acid (LPA), which is a potent lipid stimulator of tumorigenesis. Thus, ATX has received renewed attention because it has a prominent role in malignant progression with significant translational potential. Specifically, we sought to develop active site-targeted irreversible inhibitors as anti-cancer agents. Herein we describe the synthesis and biological activity of an LPC-mimetic electrophilic affinity label that targets the active site of ATX, which has a critical threonine residue that acts as a nucleophile in the lysophospholipase D reaction to liberate choline. We synthesized a set of quaternary ammonium derivative-containing vinyl sulfone analogs of LPC that function as irreversible inhibitors of ATX and inactivate the enzyme. The analogs were tested in cell viability assays using multiple cancer cell lines. The IC50 values ranged from 6.74 to 0.39 µM, consistent with a Ki of 3.50 µM for inhibition of ATX by the C16H33 vinyl sulfone analog CVS-16 (10b). A phenyl vinyl sulfone control compound, PVS-16, lacking the choline-like quaternary ammonium mimicking head group moiety, had little effect on cell viability and did not inhibit ATX. Most importantly, CVS-16 (10b) significantly inhibited melanoma progression in an in vivo tumor model by preventing angiogenesis. Taken together, this suggests that CVS-16 (10b) is a potent and irreversible ATX inhibitor with significant biological activity both in vitro and in vivo.

Therapeutic efficacy of lysophosphatidylcholine in severe infections caused by Acinetobacter baumannii.

Due to the significant increase in antimicrobial resistance of Acinetobacter baumannii, immune system stimulation to block infection progression may be a therapeutic adjuvant to antimicrobial treatment. Lysophosphatidylcholine (LPC), a major component of phospholipids in eukaryotic cells, is involved in immune cell recruitment and modulation. The aim of this study was to show if LPC could be useful for treating infections caused by A. baumannii. A. baumannii ATCC 17978 was used in this study. Levels of serum LPC and levels of the inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), IL-1ß, and IL-10 were determined by spectrophotometric assay and enzyme-linked immunosorbent assay (ELISA), respectively, using a murine peritoneal sepsis model in which mice were inoculated with 5.3 log CFU/ml of A. baumannii. The therapeutic efficacy of LPC against A. baumannii in murine peritoneal sepsis and pneumonia models was assessed for 48 h after bacterial infection. At early time points in the murine model of peritoneal sepsis caused by A. baumannii, LPC was depleted and was associated with an increase of inflammatory cytokine release. Preemptive therapy with LPC in murine peritoneal sepsis and pneumonia models markedly enhanced spleen and lung bacterial clearance and reduced the numbers of positive blood cultures and the mouse mortality rates. Moreover, treatment with LPC reduced proinflammatory cytokine production. These data demonstrate that LPC is efficacious as a preemptive treatment in experimental models of peritoneal sepsis and pneumonia caused by A. baumannii.

Docosahexaenoic- and eicosapentaenoic acid-bound lysophospholipids are more effective in suppressing angiogenesis than conjugated docosahexaenoic acid.

Suppression of leukemia, colon cancer, myeloma, and fibrosarcoma to some extent by omega 3 fatty acid bound phospholipids has been reported in the last two decade. However, the anti-angiogenic activity of those phospholipids is still not known. Four kinds of marine phospholipid molecular species i.e. starfish EPA bound diacyl phospholipid (EPA-PC), EPA bound monoacyl phospholipid (EPA-LPC) which was prepare via Lipozyme RMIM mediated partial hydrolysis of EPA-PC, squid DHA bound diacyl phospholipid (DHA-PC), and DHA bound monoacyl phospholipid (DHA-LPC) which was also prepare via Lipozyme RMIM mediated partial hydrolysis of DHA-PC, were subjected to antiangiogenic activity assay by using a piece of rat main artery and a human umbilical cord vein endothelial cell. The lengths of micro vein generated from those tissues after incubation with the above four kinds of phospholipid molecular species were measured and compared. EPA-LPC and DHA-LPC showed strong antiangiogenic activity on the rat main artery tissue, while on the human umbilical cord vein endothelial cells, 100 µM of EPA-LPC in the culture medium, exhibited the most effective suppression on angiogenesis, followed by 100 µM of DHA-LPC. It was concluded that EPA-LPC obtained via Lipozyme RMIM mediated partial hydrolysis of EPA-PC is the most effective omega 3 phospholipid on anti-angiogenesis.

Brain-targeting form of docosahexaenoic acid for experimental stroke treatment: MRI evaluation and anti-oxidant impact.

Epidemiologic studies report cardiovascular protection conferred by omega-3 fatty acids, in particular docosahexaenoic acid (DHA). However, few experimental studies have addressed its potential in acute stroke treatment. The present study used multimodal MRI to assess in vivo the neuroprotection conferred by DHA and by a brain-targeting form of DHA-containing lysophosphatidylcholine (AceDoPC) in experimental stroke. Rats underwent intraluminal middle cerebral artery occlusion (MCAO) and were treated at reperfusion by intravenous injection of i) saline, ii) plasma from donor rats, iii) DHA or iv) AceDoPC, both solubilized in plasma. Twenty-four hours after reperfusion, animals underwent behavioral tests and were sacrificed. Multiparametric MRI (MRA, DWI, PWI, T2-WI) was performed at H0, during occlusion, and at H24, before sacrifice. Brain tissue was used for assay of F(2)-isoprostanes as lipid peroxidation markers. Initial lesion size and PWI/DWI mismatch were comparable in the four groups. Between H0 and H24, lesion size increased in the saline group (mean ± s.d.: +18% ± 20%), was stable in the plasma group (-3% ± 29%), and decreased in the DHA (-17% ± 15%, P=0.001 compared to saline) and AceDoPC (-34% ± 27%, P=0.001 compared to saline) groups. Neuroscores in the AceDoPC group tended to be lower than in the other groups (P=0.07). Treatments (pooled DHA and AceDoPC groups) significantly decreased lipid peroxidation as compared to controls (pooled saline and vehicle) (P=0.03). MRI-based assessment demonstrated the neuroprotective effect of DHA in the MCAO model. Results further highlighted the therapeutic potential of engineered brain-targeting forms of omega-3 fatty acids for acute stroke treatment.

Lysophosphatidylcholine reduces the organ injury and dysfunction in rodent models of gram-negative and gram-positive shock.

1. Lysophosphatidylcholine (LPC) modulates the inflammatory response and reduces mortality in animal models of sepsis. Here, we investigate the effects of LPC from synthetic (sLPC) and natural, soy bean derived LPC, (nLPC) sources on the organ injury/dysfunction caused by systemic administration of lipopolysaccharide (LPS) or peptidoglycan (PepG) and lipoteichoic acid (LTA). 2. Rats were subjected to (i) endotoxaemia (LPS 6 mg kg(-1) i.v.) and treated with sLPC (1-100 mg kg(-1)), (ii) endotoxaemia and treated with nLPC (10 mg kg(-1)) or (iii) gram-positive shock (PepG 10 mg kg(-1) and LTA 3 mg kg(-1) i.v.) and treated with sLPC (10 mg kg(-1)). 3. Endotoxaemia or gram-positive shock for 6 h resulted in increases in serum makers of renal dysfunction and liver, pancreatic and neuromuscular injury. 4. Administration of sLPC, at 1 or 2 h after LPS, dose dependently (1-10 mg kg(-1)) reduced the organ injury/dysfunction. High doses of sLPC (30 and 100 mg kg(-1)) were shown to be detrimental in endotoxaemia. sLPC also afforded protection against the organ injury/dysfunction caused by gram-positive shock. nLPC was found to be protective in endotoxaemic animals. 5. The beneficial effects of sLPC were associated with an attenuation in circulating levels of interleukin-1beta (IL-1beta). 6. In conclusion, LPC dose and time dependently reduces the organ injury and circulating IL-1beta levels caused by gram-negative or gram-positive shock in the rat. Thus, we speculate that appropriate doses of LPC may be useful in reducing the degree of organ injury and dysfunction associated with shock of various aetiologies.

Suppression of HMGB1 release by stearoyl lysophosphatidylcholine:an additional mechanism for its therapeutic effects in experimental sepsis.

Stearoyl lysophosphatidylcholine (LPC) has recently been proven protective against lethal sepsis by stimulating neutrophils to eliminate invading pathogens through an H2O2-dependent mechanism. Here, we demonstrate that stearoyl LPC, but not caproyl LPC, significantly attenuates circulating high-mobility group box 1 (HMGB1) levels in endotoxemia and sepsis by suppressing endotoxin-induced HMGB1 release from macrophages/monocytes. Neutralizing antibodies against G2A, a potential cell surface receptor for LPC, partially abrogated stearoyl LPC-mediated suppression of HMGB1 release. Thus, stearoyl LPC confers protection against lethal experimental sepsis partly by facilitating the elimination of the invading pathogens and partly by inhibiting endotoxin-induced release of a late proinflammatory cytokine, HMGB1.

Inhibition of osteoclast differentiation and bone resorption by a novel lysophosphatidylcholine derivative, SCOH.

Osteoclasts are multinucleated cells formed by multiple steps of cell differentiation from progenitor cells of hematopoietic origin. Intervention in osteoclast differentiation is considered as an effective therapeutic approach to the treatment for bone diseases involving osteoclasts. In this study, we found that the organic compound (S)-1-lyso-2-stearoylamino-2-deoxy-sn-glycero-3-phosphatidylcholine (SCOH) inhibited osteoclast differentiation. The inhibitory effect of SCOH was observed in mouse bone marrow cell cultures supported either by coculturing with osteoblasts or by adding macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappaB ligand (RANKL). M-CSF and RANKL activate the ERK, Akt, and NF-kappaB signal transduction pathways, and SCOH suppressed this activation. SCOH also inhibited the bone resorptive activity of differentiated osteoclasts. It attenuated bone resorption, actin ring formation, and survival of mature osteoclasts. Reduced activation of Akt and NF-kappaB and decreased induction of XIAP were observed in mature osteoclasts treated with SCOH. Thus, this novel phosphatidylcholine derivative may be useful for treating bone-resorption diseases.

Therapeutic effects of lysophosphatidylcholine in experimental sepsis.

Sepsis represents a major cause of death in intensive care units. Here we show that administration of lysophosphatidylcholine (LPC), an endogenous lysophospholipid, protected mice against lethality after cecal ligation and puncture (CLP) or intraperitoneal injection of Escherichia coli. In vivo treatment with LPC markedly enhanced clearance of intraperitoneal bacteria and blocked CLP-induced deactivation of neutrophils. In vitro, LPC increased bactericidal activity of neutrophils, but not macrophages, by enhancing H(2)O(2) production in neutrophils that ingested E. coli. Incubation with an antibody to the LPC receptor, G2A, inhibited LPC-induced protection from CLP lethality and inhibited the effects of LPC in neutrophils. G2A-specific antibody also blocked the inhibitory effects of LPC on certain actions of lipopolysaccharides (LPS), including lethality and the release of tumor necrosis factor-alpha (TNF-alpha) from neutrophils. These results suggest that LPC can effectively prevent and treat sepsis and microbial infections.

Immunoregulation and drug treatment in chronic relapsing experimental allergic encephalomyelitis in the Lewis rat.

Chronic relapsing experimental allergic encephalomyelitis (CR.EAE) was induced by immunizing Lewis rats with total guinea-pig spinal cord (GPSC) tissue emulsified in enriched complete Freund's adjuvant (CFA). The proliferative responses of draining inguinal and popliteal lymph node cells to GP.MBP, purified protein derivative (PPD) and concanavalin A (ConA) appeared significantly modulated according to the clinical state of the animals. Responses appeared significantly decreased in both lymphoid compartments during the recovery periods compared with that during relapses. Therapeutic treatment of CR.EAE with cyclosporin and different lysolecithin derivatives, such as ET-18-OCH3, SRI 62-843 and MLS 266-337, starting at the spontaneous remission of the first disease bout, could suppress the manifestation of further relapses. Whereas cyclosporin only delayed the onset of the disease relapse until discontinuation of treatment, all lysolecithins showed a curative effect in most animals. Plasma corticosterone levels measured at different time points in placebo, cyclosporin and MLS 266-377-treated rats showed a strong correlation with the clinical state of the animals. High corticosterone levels were detected during stages of acute paralysis, whereas a decrease to normal levels was noted during each recovery phase.