experimental autoimmune encephalomyelitis

Phenidone (1-phenyl-3-pyrazolidinone) is a dual inhibitor of cyclooxygenases and lipoxygenases that ameliorates rat paralysis in experimental autoimmune encephalomyelitis by suppressing its target enzymes[1]. The lipoxygenase inhibitor phenidone is a potent hypotensive agent in the spontaneously hypertensive rat[2].

Ex26 (S1P1-IN-Ex26) is a selective and potent sphingosine 1-phosphate receptor 1 (S1P1) antagonist that disrupts SR-B1-S1PR1 interactions and inhibits S1P-S1PR1 signaling. Ex26 is used in experimental autoimmune encephalomyelitis, atherosclerosis, and gastric cancer.

Bacoside A has a possible anticancer activity that could be inducing cell cycle arrest and apoptosis through Notch pathway in GBM in vitro. It exerts cytoprotective efficacy by attenuation of ROS generated through oxidative stress by an increase in the concentration of antioxidant enzymes and sustain membrane integrity which leads to restoring the damage caused by tBHP. Bacoside A can able to inhibit the progression of Experimental Autoimmune Encephalomyelitis (EAE) may be by the inhibition of inflammatory cytokines and chemokine evolved during active EAE. Bacoside A also has vasorelaxation.

ASP-4058 is a selective, safe, and orally active second-generation agonist of sphingosine phosphate receptors 1 and 5 (S1P1 and S1P5).ASP-4058 ameliorates experimental autoimmune encephalomyelitis in mice.

AMG-369 (AMG 247) is an S1P1 S1P5 dual agonist that delays the onset of experimental autoimmune encephalomyelitis in rats. encephalomyelitis in rats.

CP-456773 (MCC950 (CP-456773) and CRID3) is an effective and specific cytokine release inhibitor and NLRP3 inflammasome inhibitor. CP-456773 inhibits IL-1β secretion and caspase 1 processing. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced IL-1β production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis.

Luzindole (N-0774) is a selective melatonin receptor antagonist that inhibits experimental autoimmune encephalomyelitis and exhibits antidepressant-like activity. It preferentially targets MT2 (Mel1b) over MT1 (Mel1a), with Ki values of 10.2 nM for human MT2 and 158 nM for MT1.

NIBR-0213, a potent and selective S1P(1) antagonist, has efficacy in experimental autoimmune encephalomyelitis.

S1PL-IN-31 is a dual-function chemical compound acting as an inhibitor of sphingosine-1-phosphate (S1P) lyase with an IC50 value of 210 nM and as an antagonist of the Smoothened (Smo) receptor with an IC50 of 440 nM. Demonstrating therapeutic potential, this compound, at a dosage of 2 mg/kg per day, effectively mitigates cervical and thoracic lymphocyte infiltration and neuromuscular weakness in rats suffering from experimental autoimmune encephalomyelitis (EAE), a condition triggered by the MOG29-152 peptide from myelin oligodendrocyte glycoprotein. Additionally, it significantly decreases the total lymphocyte count, including reductions in subsets of CD4+ T cells, CD8+ T cells, and B cells. At a higher dosage of 100 mg/kg, S1PL-IN-31 elevates S1P levels within the heart and lymph nodes, while doses of 3 and 10 mg/kg per day notably lower heart rates in female rats, showcasing its multifaceted biological impacts and potential for clinical application.

Forphenicine is a bacterial metabolite that has been found in S. fulvoviridis and an inhibitor of alkaline phosphatase (IC50 = 0.036 µg/ml for the chicken intestine enzyme). It inhibits the growth of HL-60 leukemia cells when used at a concentration of 10 µM. Forphenicine (50 and 500 µg/animal) increases survival in a guinea pig model of experimental autoimmune encephalomyelitis (EAE).

BIO5192 hydrate is a selective and potent integrin α4β1 (VLA-4) inhibitor (Kd < 10 pM). The compound selectively binds to α4β1 (IC50 = 1.8 nM) over various other integrins and results in a 30-fold increase in mobilization of murine hematopoietic stem and progenitors (HSPCs) over basal levels[1][2].

γ-Fibrinogen377-395 TFA is an inhibitory peptide derived from fibrinogen, which also functions as a fibrinogen epitope. It effectively blocks microglial activation and impedes fibrin-Mac-1 interactions in vitro. Additionally, it exhibits in vivo efficacy by suppressing experimental autoimmune encephalomyelitis (EAE) in mice. This compound has applications in researching multiple sclerosis (MS) and other neuroinflammatory diseases linked to blood-brain barrier disruption and microglial activation [1].

MOG peptide (35-55), a myelin oligodendrocyte glycoprotein (MOG) fragment spanning amino acids 35 to 55, selectively stimulates CD4+ T cell expansion and induces experimental autoimmune encephalomyelitis (EAE) in animal models [1] [2] [3].

Isogarcinol is a natural polyisoprenylated benzophenone first isolated from plant species in the genus Garcinia. It has immunosuppressant actions, inhibiting the protein phosphatase calcineurin (IC50 = 36 μM) and suppressing the proliferation of T cells. Oral administration of isogarcinol in mice decreases delayed type hypersensitivity, prolongs graft survival in allogeneic skin transplants, suppresses inflammation in collagen-induced arthritis, and reduces clinical symptoms in experimental autoimmune encephalomyelitis. Isogarcinol inhibits the proliferation of HL-60 and PC-3 cancer cells (IC50s = 4 and 8 μg/ml, respectively) through cell cycle arrest and apoptosis.

CA 074 is a potent inhibitor of cathepsin B with a Ki value of 2 to 5 nM.CA 074 inhibits ischemic hippocampal neuronal death in primates and attenuates retinopathy and optic neuritis in experimental autoimmune encephalomyelitis induced by SJL/J mice.

SR12418 is a specific REV-ERB synthetic ligand that acts on REV-ERBα (IC50: 68 nM) and REV-ERBβ (IC50: 119 nM) and can be used to study experimental autoimmune encephalomyelitis (EAE) and colitis.

Spermidine-d6 is intended for use as an internal standard for the quantification of spermidine by GC- or LC-MS. Spermidine is an endogenous polyamine. It is formed from putrescine by spermidine synthase. Spermidine (25 µM) inhibits the activity of the human inward-rectifying potassium channel Kir2.3 in a patch-clamp assay. It induces autophagy in HeLa cells when used at a concentration of 100 µM and increases the lifespan of D. melanogaster, yeast, and C. elegans. Spermidine (30 mM in the drinking water) reduces demyelination of the optic nerve and disease severity in a mouse model of experimental autoimmune encephalomyelitis (EAE). It reduces increases in blood pressure, left ventricular posterior wall thickness, and heart weight in salt-sensitive Dahl rats fed a high-salt diet, a model of hypertension-induced congestive heart failure.4 Formulations containing spermidine have been used as dietary supplements.

JC-171, a selective inhibitor of the NLRP3 inflammasome, effectively inhibits LPS ATP-induced interleukin-1β (IL-1β) release from J774A.1 macrophages with an IC50 of 8.45 μM[1].

MOG (92–106), mouse, rat, is a biologically active peptide corresponding to the fragment of amino acids 92 to 106 in myelin oligodendrocyte glycoprotein (MOG) from mice and rats. Mice subjected to MOG (92–106)-induced experimental autoimmune encephalomyelitis show substantial B cell reactivity to secondary myelin antigens. Although this MOG fragment elicits only modest T cell responses, the resultant autoimmunity is profoundly severe. The peptide demonstrates encephalitogenic properties in various species, including SJL mice, DA rats, and rhesus monkeys.

J5 peptide, an MBP inhibitor, competitively inhibits the binding of MBP 85-99 to HLA-DR2, and mitigates PLP 139-151/MBP 85-99-induced experimental autoimmune encephalomyelitis (EAE) in mice. It is utilized in research pertaining to inflammatory and immune diseases [1].

ASP-4058 hydrochloride is a selective, orally active secondary agonist of sphingosine phosphate receptors 1 and 5 (S1P1 and S1P5). ASP-4058 hydrochloride is safe and improves experimental autoimmune encephalomyelitis in mice.

MOG (35-55), human, a constituent of central nervous system myelin, is distinguishable from mMOG (35-55) due to a proline-to-serine substitution at position 42. It possesses immunogenic properties and is partially cross-reactive with mMOG35–55. However, MOG (35-55), human does not induce encephalitogenic effects, and only elicits minimal clinical signs of EAE (experimental autoimmune encephalomyelitis) in comparison to the rodent peptide.

R 715, a bradykinin B1 receptor antagonist, inhibits contractions in isolated human umbilical cords that express bradykinin B1 receptors (pA2 = 8.49). When administered at doses of 200, 400, and 600 µg/kg, R 715 enhances latency to tail withdrawal in the tail-flick test for diabetic neuropathy mouse models induced by streptozotocin (STZ), signaling potential analgesic properties. Furthermore, at a 1 mg/kg per day dosage, it mitigates symptoms in a mouse model of experimental autoimmune encephalomyelitis (EAE) induced by MOG35-55 antigen peptide, such as reducing hind limb weakness and paralysis, improving gait symmetry, and decreasing spinal inflammation, neuron demyelination, and lesion monocyte invasion. Additionally, R 715 at 0.01 nmol/animal, administered intracerebroventricularly (i.c.v.), lowers mean arterial blood pressure and increases heart rate in spontaneously hypertensive rats, indicating cardiovascular effects.

6(5H)-Phenanthridinone is an inhibitor of poly(ADP-ribose) polymerase 1 (PARP1) and PARP2. It decreases radiation-induced PARP activity and proliferation of RDM4 murine lymphoma cells. 6(5H)-Phenanthridinone reduces NF-κB-induced transcription of the genes encoding TNF-α, IL-2, and IFN-γ in rat lymphocytes. In vivo, 6(5H)-phenanthridinone reduces spinal cord expression of inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, IL-2, and IFN-γ and reduces disease score in a rat model of experimental autoimmune encephalomyelitis (EAE). It also decreases serum levels of lactate dehydrogenase as well as hepatic lipid peroxidation, oxidative DNA damage, and PARP levels.

Potent and selective KV1.3 channel blocker (IC50 values are 0.0019 and 0.65 nM for KV1.3 and KV1.1, respectively). Inhibits CD4+ CCR7- T cell activation. Ameliorates rat experimental autoimmune encephalomyelitis, in a model for multiple sclerosis.

γ-Fibrinogen377-395 is a peptide derived from fibrinogen, functioning both as an inhibitory molecule and an epitope. It inhibits microglial activation, disrupts fibrin-Mac-1 interactions in vitro, and mitigates experimental autoimmune encephalomyelitis (EAE) in murine models in vivo. This compound is relevant for research into multiple sclerosis (MS) and other neuroinflammatory disorders characterized by blood-brain barrier compromise and microglial activation [1].

Myelin Basic Protein (1-11), an encephalitogenic epitope of MBP, facilitates the induction of experimental autoimmune encephalomyelitis (EAE) [1] [2].

[Leu144,Arg147]-PLP (139-151) is a mutated fragment of the myelin proteolipid protein (PLP), featuring substitutions of tryptophan to leucine and histidine to arginine at positions 144 and 147, respectively. Immunizing mice with this peptide (50 µg) mixed in complete Freund’s adjuvant (CFA) elevates IL-4 levels in the spleen. While it suppresses Th1 cell activation in vitro, it does not do so in vivo; instead, it promotes the development of regulatory T cells. Preimmunization with [Leu144, Arg147]-PLP (139-151) postpones the onset of experimental autoimmune encephalomyelitis (EAE) triggered by encephalitogenic peptides from PLP (178-191), myelin oligodendrocyte glycoprotein (MOG) (92-106), or myelin basic protein (MBP) in mice.

AKP-11 is a sphingosine-1-phosphate receptor 1 (S1P1) agonist with an EC50 of 0.047 μM for [35S]GTPγS binding to CHO-K1 cell membranes expressing human S1P1. It reduces S1P1 surface expression and enhances Akt and ERK phosphorylation in CHO cells with S1P1-HA at a 100 nM concentration. At doses of 1.3 and 3 mg/kg, AKP-11 lowers IFN-γ and IL-17 protein levels in the spinal cord and mitigates disease severity in a rat experimental autoimmune encephalomyelitis (EAE) model. Additionally, it decreases peripheral total lymphocyte and specific T cell subsets (CD4+, CD8+, and CD26L+ T cells) counts in both EAE rats and healthy controls at a 1.3 mg/kg dosage.

BMS-520 is a potent, selective S1P1 agonist that has shown impressive efficacy when administered orally in a rat model of arthritis and in a mouse model of experimental autoimmune encephalomyelitis (EAE) with multiple sclerosis.

PDMP is a ceramide analog first prepared in a search for inhibitors of glucosylceramide synthase. PDMP has two adjacent chiral centers (C1 and C2) allowing for the formation of four possible isomers. PDMP contains all four of these stereoisomers. PDMP inhibits glucosylceramide synthase by 90% when used at a concentration of 0.8 μM in MDCK cell homogenates, however, the ability to inhibit glucosylceramide synthase has been found to reside in the D-threo (1R,2R) enantiomer. The D-threo PDMP enantiomer is also responsible for inhibition of β-1,4-galactosyltransferase 6 and prevention of lactosylceramide synthesis, which is a promotor of neuroinflammation in mice during chronic experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. PDMP enhances curcumin-induced inhibition of proliferation, JNK activation, and Akt inhibition, as well as induction of apoptosis in WM-115 melanoma cells in vitro.

Cenerimod (ACT-334441) is an orally active, selective, and potent sphingosine 1-phosphate receptor (S1P1) agonist (EC50: 1 nM).Cenerimod inhibits multiple S1P isoforms and can be used to study murine experimental autoimmune encephalomyelitis (EAE) and murine scleroderma.

5J-4 is a potent a blocker of calcium release-activated calcium (CRAC) channel and store-operated calcium entry (SOCE). 5J-4 reduces the production of IL-17 and decreases the expression of RORα and RORγt.

D359-0396, an orally active NLRP3 inflammasome inhibitor, mitigates pyroptosis and reduces IL-1β release in macrophages by inhibiting the oligomerization of NLRP3, ASC, and the cleavage of GSDMD. The compound is effective in alleviating Experimental Autoimmune Encephalomyelitis (EAE) and enhances survival following septic shock in mice [1].

Spermidine trihydrochloride (4-Azaoctamethylenediamine trihydrochloride), a natural polyamine, is a novel autophagy inducer and negatively modulates N-methyl-d-aspartate (NMDA).

Spermidine (N-(3-Aminopropyl)-1,4-diaminobutane) inhibits NOS1 (nNOS). Spermidine binds and precipitates DNA and may be used for purification of DNA binding proteins. Spermidine activates PNK (polynucleotide kinase T4). Spermidine binds to and activates NMDA and has been shown to potentiate NMDA-induced currents in a concentration-dependent manner.