oxadiazoles and Neurodegenerative-Diseases

Multiple Sclerosis is an immune-mediated neurodegenerative disease. IL-23-mediated signaling and Th17 cells play critical roles in disease pathogenesis in murine models of disease and humans. Sphingosine 1 phosphate (S1P) regulates migration of several types of immune cells including Th17 cells. S1P analogues (fingolimod (FTY720) and Siponimod (BAF312)) have been approved and currently used for MS treatment. Immunomodulatory roles for FTY720 have been defined, however, how different S1P analogues impact human Th17 and Treg cell generation and cytokine production, and IL-23-mediated signaling have not yet been explored in detail. In the current study, we investigated the effects of S1P receptor 1 (S1P1) specific S1P analogue SEW2871, S1P1 and S1P5 specific BAF312, and non-selective FTY720 on human Th17 and Treg differentiation and IL-23-mediated signaling. All three S1P analogues directly inhibited Th17 cell differentiation ex vivo while increasing Treg differentiation from naive CD4 + T cells. All three S1P analogues suppressed IL-23-mediated STAT4, NF-kB and AKT activation. Lastly, all three S1P analogues also inhibited Dectin-1 expression by both mature and immature monocyte-derived dendritic cells (moDCs) and in turn curdlan-mediated production of IL-23p19, p40, IL-6 and IL-1β cytokines. Our results provide novel insight into the immunomodulatory roles of different S1P analogues on human Th17 and Treg cell biology.

Topics: Animals; Azetidines; Benzyl Compounds; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Interleukin-23; Lysophospholipids; Mice; Neurodegenerative Diseases; Oxadiazoles; Propylene Glycols; Receptors, Lysosphingolipid; Sphingosine; T-Lymphocytes, Regulatory; Th17 Cells; Thiophenes

Alzheimer's disease (AD) is the most common neurodegenerative disease whose patients suffered from cognitive impairments. In our study, a novel 1,2,4-Oxadiazole derivative wyc-7-20 was synthesized, which showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, β-amyloid (Aβ) clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected. The results demonstrated wyc-7-20 was potent in AD therapy.. The pathological complexity of AD increased difficulties in medical research. To explore a new potential medical treatment for AD, a novel 1,2,4-Oxadiazole derivative (wyc-7-20) was designed, synthesized to explore the application in this study.. Human neuroblastoma (SH-SY5Y) cells and human hepatocellular carcinoma (HepG2) cells were used to detect median lethal dose (LD50). H. wyc-7-20 showed low cytotoxicity and potent neuroprotective effect at the cellular level. Improved cognitive impairments, Aβ clearance, and tau pathological phenotypes were detected in transgenic animal models after wyc-7-20 treatment. Reversed expressions in AD-related genes were also detected.. wyc-7-20 was potent in AD therapy.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Disease Models, Animal; Humans; Hydrogen Peroxide; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroblastoma; Neurodegenerative Diseases; Neuroprotective Agents; Oxadiazoles; Reactive Oxygen Species; tau Proteins

Stemazole exerts potent pharmacological effects against neurodegenerative diseases and protective effects in stem cells. However, on the basis of the current understanding, the molecular mechanisms underlying the effects of stemazole in the treatment of Alzheimer's disease and Parkinson's disease have not been fully elucidated. In this study, a network pharmacology-based strategy integrating target prediction, network construction, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, and molecular docking was adopted to predict the targets of stemazole relevant to the treatment of neurodegenerative diseases and to further explore the involved pharmacological mechanisms. The majority of the predicted targets were highly involved in the mitogen-activated protein kinase (MAPK) signaling pathway. RAC-alpha serine/threonine-protein kinase (AKT1), caspase-3 (CASP3), caspase-8 (CASP8), mitogen-activated protein kinase 8 (MAPK8), and mitogen-activated protein kinase 14 (MAPK14) are the core targets regulated by stemazole and play a central role in its anti-apoptosis effects. This work provides a scientific basis for further elucidating the mechanism underlying the effects of stemazole in the treatment of neurodegenerative diseases.

Topics: Drug Evaluation, Preclinical; Gene Ontology; Humans; Hydrazines; MAP Kinase Signaling System; Molecular Docking Simulation; Molecular Targeted Therapy; Neurodegenerative Diseases; Oxadiazoles; Protein Interaction Maps

The decline in testosterone levels in men during normal aging increases risks of dysfunction and disease in androgen-responsive tissues, including brain. The use of testosterone therapy has the potential to increase the risks for developing prostate cancer and or accelerating its progression. To overcome this limitation, novel compounds termed "selective androgen receptor modulators" (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in select androgen-responsive tissues. The efficacy of SARMs in brain is largely unknown. In this study, we investigate the SARM RAD140 in cultured rat neurons and male rat brain for its ability to provide neuroprotection, an important neural action of endogenous androgens that is relevant to neural health and resilience to neurodegenerative diseases. In cultured hippocampal neurons, RAD140 was as effective as testosterone in reducing cell death induced by apoptotic insults. Mechanistically, RAD140 neuroprotection was dependent upon MAPK signaling, as evidenced by elevation of ERK phosphorylation and inhibition of protection by the MAPK kinase inhibitor U0126. Importantly, RAD140 was also neuroprotective in vivo using the rat kainate lesion model. In experiments with gonadectomized, adult male rats, RAD140 was shown to exhibit peripheral tissue-specific androgen action that largely spared prostate, neural efficacy as demonstrated by activation of androgenic gene regulation effects, and neuroprotection of hippocampal neurons against cell death caused by systemic administration of the excitotoxin kainate. These novel findings demonstrate initial preclinical efficacy of a SARM in neuroprotective actions relevant to Alzheimer's disease and related neurodegenerative diseases.

Topics: Acetanilides; Animals; Apoptosis; Cell Survival; Cells, Cultured; Female; Hippocampus; Hormone Antagonists; Kainic Acid; Male; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Nitriles; Oxadiazoles; Rats; Rats, Sprague-Dawley; Risk; Signal Transduction

Increased expression of CD11b, the beta-integrin marker of microglia, represents microglial activation during neurodegenerative inflammation. However, the molecular mechanism behind increased microglial CD11b expression is poorly understood. The present study was undertaken to explore the role of nitric oxide (NO) in the expression of CD11b in microglial cells. Bacterial lipopolysaccharide (LPS) induced the production of NO and increased the expression of CD11b in mouse BV-2 microglial cells and primary microglia. Either a scavenger of NO (PTIO) or an inhibitor of inducible nitric-oxide synthase (L-NIL) blocked this increase in microglial CD11b expression. Furthermore, co-microinjection of PTIO with LPS was also able to suppress LPS-mediated expression of CD11b and loss of dopaminergic neuronal fibers and neurotransmitters in striatum in vivo. Similarly, other inducers of NO production such as interferon-gamma, interleukin-1beta, human immunodeficiency virus type-1 gp120, and double-stranded RNA (poly(IC)) also increased the expression of CD11b in microglia through NO. The role of NO in the expression of CD11b was corroborated further by the expression of microglial CD11b by GSNO, an NO donor. Because NO transduces many intracellular signals via guanylate cyclase (GC), we investigated the role of GC, cyclic GMP (cGMP), and cGMP-activated protein kinase (PKG) in microglial expression of CD11b. Inhibition of LPS- and GSNO-mediated up-regulation of CD11b either by NS2028 (a specific inhibitor of GC) or by KT5823 and Rp-8-bromo-cGMP (specific inhibitors of PKG), and increase in CD11b expression either by 8-bromo-cGMP or by MY-5445 (a specific inhibitor of cGMP phosphodiesterase) alone suggest that NO increases microglial expression of CD11b via GC-cGMP-PKG. In addition, GSNO induced the activation of cAMP response element-binding protein (CREB) via PKG that was involved in the up-regulation of CD11b. This study illustrates a novel biological role of NO in regulating the expression of CD11b in microglia through GC-cGMP-PKG-CREB pathway that may participate in the pathogenesis of devastating neurodegenerative disorders.

Topics: Animals; CD11b Antigen; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Gene Expression Regulation; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Microglia; Neurodegenerative Diseases; Nitric Oxide; Oxadiazoles; Oxazines; Up-Regulation