Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase-2 (COX-2), a rate-limiting enzyme converting arachidonic acid to prostaglandins and a key player in neuroinflammation, has been implicated in the pathogenesis of neurodegenerative diseases such as multiple sclerosis, Parkinson's and Alzheimer's diseases, and in traumatic brain injury- and ischemia-induced neuronal damage, and epileptogenesis. Accumulated information suggests that the contribution of COX-2 to neuropathology is associated with its involvement in synaptic modification. Inhibition or elevation of COX-2 has been shown to suppress or enhance excitatory glutamatergic neurotransmission and long-term potentiation (LTP). These events are mainly mediated via PGE(2), the predominant reaction product of COX-2, and the PGE(2) subtype 2 receptor (EP(2))-protein kinase A pathway. Recent evidence shows that endogenous cannabinoids are substrates for COX-2 and can be oxygenated by COX-2 to form new classes of prostaglandins (prostaglandin glycerol esters and prostaglandin ethanolamides). These COX-2 oxidative metabolites of endocannabinoids, as novel signaling mediators, modulate synaptic transmission and plasticity and cause neurodegeneration. The actions of these COX-2 metabolites are likely mediated by mitogen-activated protein kinase (MAPK) and inositol 1,4,5-trisphosphate (IP(3)) signal transduction pathways. These discoveries suggest that the contributions of COX-2 to neurotransmission and brain malfunction result not only from its conversion of arachidonic acid to classic prostaglandins but also from its oxidative metabolism of endocannabinoids to novel prostaglandins. Thus, elucidation of COX-2 in synaptic signaling may provide a mechanistic basis for designing new drugs aimed at preventing, treating or alleviating neuroinflammation-associated neurological disorders.
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PMID:Cyclooxygenase-2 in synaptic signaling. 1853 67

The naturally occurring antioxidant lipoic acid (LA) was first described as an essential cofactor for the conversion of pyruvate to Acetyl-CoA, a critical step in respiration. LA is now recognized as a compound that has many biological functions. Along with its reduced form dihydrolipoic acid (DHLA), LA reduces and recycles cellular antioxidants such as glutathione, and chelates zinc, copper and other transition metal ions in addition to heavy metals. LA can also act as a scavenger of reactive oxygen and nitrogen species. By acting as an insulin mimetic agent, LA stimulates glucose uptake in many different cell types and can also modulate insulin signaling. The p38 and ERK MAP kinase pathways, AKT and NFkappaB are all regulated by LA. In addition, LA activates the prostaglandin EP2 and EP4 receptors to stimulate the production of the small molecule cyclic adenosine 5' monophosphate (cAMP). These diverse actions suggest that LA may be therapeutically effective in treating oxidative stress associated diseases. This review discusses the known biochemical properties of LA, its antioxidant properties, its ability to modulate signal transduction pathways, and the recent progress made in the utilization of LA as a therapeutic alternative for multiple sclerosis, Alzheimer's disease and diabetic neuropathy.
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PMID:Lipoic acid: a novel therapeutic approach for multiple sclerosis and other chronic inflammatory diseases of the CNS. 1853 99

Inflammatory cell trafficking into the brain complicates several neurological disorders including multiple sclerosis. Normally, reliable brain functioning is maintained and controlled by the blood-brain barrier (BBB), which is essential to restrict the entry of potentially harmful molecules and cells from the blood into the brain. The BBB is a selective barrier formed by dedicated brain endothelial cells and dependent on the presence of intracellular tight junctions. In multiple sclerosis, a severe dysfunction of the BBB is observed, which is key to monocyte infiltration and inflammation in the brain. Proteolytic activity has been associated with these inflammatory processes in the brain. Our studies in plasma of rats indicated that the extracellular protease tissue-type plasminogen activator (tPA) correlates with the clinical signs of experimental allergic encephalomyelitis, a rat model of multiple sclerosis. In this study, we studied the function of the tPA during diapedesis of monocytes through a rat and human brain endothelial barrier. Monocyte-brain endothelial cell coculture experiments showed that monocytes induce the release of tPA by brain endothelial cells, which subsequently activates the signal transduction protein extracellular signal related kinase (ERK1/2), both involved in monocyte diapedesis. Importantly, live imaging and immunoblot analyses of rat brain endothelial cells revealed that tPA and ERK1/2 control the breakdown of the tight junction protein occludin. These studies identify tPA as a novel and relevant pathological mediator of neuroinflammation and provide a potential mechanism for this.
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PMID:Tissue-type plasminogen activator is a regulator of monocyte diapedesis through the brain endothelial barrier. 1871 30

The endocannabinoid system represents a novel therapeutic target for autoimmune and chronic inflammatory diseases. IL-12 and IL-23 are functionally related heterodimeric cytokines that play a crucial role in the pathogenesis of multiple sclerosis (MS). In the present study we investigated the effects of the endocannabinoid anandamide (AEA) on the inducible expression of the biologically active cytokines IL-12p70 and IL-23, and their forming subunits, in activated microglial cells. We also studied the signalling pathways involved in the regulation of IL-12p70/IL-23 expression and addressed the possible interactions of AEA with these pathways. Here, we show that AEA was capable to inhibit the production of biologically active IL-12p70 and IL-23, and their subunits, by activated human and murine microglial cultures. Treatment of activated microglial cells with inhibitors of several mitogen-activated protein kinase (MAPK) reveals that AEA acts through the ERK1/2 and JNK pathways to down-regulate IL-12p70 and IL-23. These effects were partially mediated by CB2 receptor activation. Together, our results provide the first demonstration of a role of AEA in inhibiting IL-12p70/IL-23 axis in human and murine microglial cells via the CB2 receptor and suggest that the pharmacological manipulation of the endocannabinoid system is a potential tool for treating brain inflammatory and autoimmune diseases, like MS.
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PMID:A role for CB2 receptors in anandamide signalling pathways involved in the regulation of IL-12 and IL-23 in microglial cells. 1884 18

Sexual dimorphism of white matter has not been considered important, the assumption being that sex hormones are not essential for glial development. We recently showed exogenous hormones in vivo differentially regulate in male and female rodents the life span of oligodendrocytes (Olgs) and amount of myelin (Cerghet et al. [2006] J. Neurosci. 26:1439-1447). To determine which hormones regulate male and female Olg development, we prepared enriched Olg cultures grown in serum-free medium with estrogen (E2), progesterone (P2), and dihydrotestosterone (DHT) or their combinations. P2 significantly increased the number of Olgs in both sexes, but more so in females; E2 had minor effects on Olg numbers; and DHT reduced Olgs numbers in both sexes, but more so in females. Combinations of hormones affected Olg numbers differently from single hormones. The change in Olg numbers was due to changes not in proliferation but rather in survival. P2 increased pAKT by many-fold, but MAPK levels were unchanged, indicating that activation of the Akt pathway by P2 is sufficient to regulate Olg differentiation. DHT reduced pAkt in both sexes but differentially increased pMAPK in males and decreased it in females. Stressing Olgs reveals that both sexes are protected by P2, but females are slightly better protected than males. Females always showed greater differences than males regarding changes in Olg numbers and in signaling molecules. Given the greater fluctuation of neurosteroids in women than in men and the higher incidence of multiple sclerosis (MS) in women, these sexually dimorphic differences may contribute to differences in male and female MS lesions.
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PMID:Sexual dimorphism of oligodendrocytes is mediated by differential regulation of signaling pathways. 1908 4

Monocyte chemoattractant protein-1 (MCP-1, CCL2) is a well-defined chemokine implicated in the pathology of various neurodegenerative diseases and brain injuries, such as Alzheimer's disease, multiple sclerosis, stroke, and traumatic injury. We investigated the effect of the activation of P2 purinoceptors on MCP-1 production in rat corticostriatal slice cultures. Treatment with adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS), a hydrolysis-resistant adenosine triphosphate (ATP) analog, induced MCP-1 production in astrocytes. The induction was in a concentration-dependent manner and was antagonized by a P2 purinoceptor antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid. The inhibition of an extracellular signal-regulated kinase (ERK) pathway by PD98059 and U0126 significantly suppressed ATPgammaS-induced MCP-1 mRNA expression and protein production, while inhibition of c-Jun N-terminal kinase by SP600125 resulted in the partial suppression. Conversely, SB203580, a p38 mitogen-activated protein (MAP) kinase inhibitor, significantly enhanced ATPgammaS-induced MCP-1 production. Similar effects of ERK and p38 MAP kinase inhibitors on MCP-1 production were observed in the slices stimulated by ATP and BzATP. These results demonstrate that astrocytic MCP-1 production induced by P2 purinoceptor stimulation is reciprocally regulated by ERK and p38 MAP kinases in the organotypic slice cultures.
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PMID:Reciprocal regulation of ATPgammaS-induced monocyte chemoattractant protein-1 production by ERK and p38 MAP kinases in rat corticostriatal slice cultures. 1912 10

Intravenous (i.v.) administration of encephalitogenic peptide can effectively prevent experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis; however, the underlying cellular and molecular mechanisms are not fully understood. In this study, we induced i.v. tolerance to EAE by administration of MOG(35-55) peptide and determined the effect of this approach on intracellular signaling pathways of the IL-23/IL-17 system, which is essential for the pathogenesis of MS/EAE. In tolerized mice, phosphorylation of JAK/STAT-1, -4, ERK1/2 and NF-kappaBp65 were significantly reduced in splenocytes and the central nervous system. MOG i.v. treatment led to significantly lower production of IL-17, and administration of exogenous IL-17 slightly broke immune tolerance, which was associated with reduced activation of STAT4 and NF-kappaB. Suppressed phosphorylation of these pathway molecules was primarily evident in CD11b(+) and small numbers of CD4(+), CD8(+) and CD11c(+) cells. More importantly, adoptive transfer of CD11b(+) splenocytes of tolerized mice effectively delayed onset and reduced clinical severity of actively induced EAE. This study correlates MOG i.v. tolerance with modulation of Jak/STAT signaling pathways and investigates novel therapeutic avenues for the treatment of EAE/MS.
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PMID:MOG(35-55) i.v suppresses experimental autoimmune encephalomyelitis partially through modulation of Th17 and JAK/STAT pathways. 1922 32

Autoimmunity affects a substantial fraction of our population. In patients with autoimmune disease, the immune system recognizes self-tissues as foreign. Common autoimmune diseases include rheumatoid arthritis, diabetes mellitus, lupus and multiple sclerosis. Though different target organs may be affected in different autoimmune diseases, aberrations in adaptive or innate immunity underlie all of these diseases. Abnormal functioning, differentiation and/or activation of T-cells, B-cells and myeloid cells have been documented in various autoimmune diseases. More recent studies have also detailed anomalous activation of various signaling axes including various MAPK, AKT, NF-kappaB, Bcl-2 family members, and JAK/STAT molecules in these cells, in the context of systemic autoimmunity. Among these, one molecular pathway that appears to be particularly attractive for therapeutic targeting is the PI3K/AKT/mTOR axis. In this review, we summarize how the AKT axis affects multiple molecular processes in autoimmune diseases and discuss the potential of targeting this axis in these diseases.
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PMID:The AKT axis as a therapeutic target in autoimmune diseases. 1951 64

The endocannabinoid system exhibits anti-inflammatory properties by regulating cytokine production. Anandamide (AEA) down-regulates proinflammatory cytokines in a viral model of multiple sclerosis (MS). However, little is known about the mechanisms by which AEA exerts these effects. Microglial cells are the main source of cytokines within the brain and the first barrier of defense against pathogens by acting as antigen presenting cells. IL-10 is a key physiological negative regulator of microglial activation. In this study we show that AEA enhances LPS/IFNgamma-induced IL-10 production in microglia by targeting CB(2) receptors through the activation of ERK1/2 and JNK MAPKs. AEA also inhibits NF-kappaB activation by interfering with the phosphorylation of IkappaBalpha, which may result in an increase of IL-10 production. Moreover, endogenously produced IL-10 negatively regulates IL-12 and IL-23 cytokines, which in its turn modify the pattern of expression of transcription factors involved in Th commitment of splenocytes. This suggests that by altering the cytokine network, AEA could indirectly modify the type of immune responses within the central nervous system (CNS). Accordingly, pharmacological modulation of AEA uptake and degradation might be a useful tool for treating neuroinflammatory diseases.
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PMID:Anandamide enhances IL-10 production in activated microglia by targeting CB(2) receptors: roles of ERK1/2, JNK, and NF-kappaB. 1956 60

Microglia are important in homeostasis and widely considered to have roles in the pathogenesis of conditions such as neuropathic pain and multiple sclerosis. The need to study microglia from the adult spinal cord is essential to further understand the role of these cells in disease pathology. Primary microglia are often prepared from brain tissues obtained from embryonic or perinatal age rodents and the process can take over a week to complete. The protocol in this study provides rapid isolation of microglia from adult spinal cord, allowing immediate availability for experimentation of both ex vivo and in vitro within a few hours. A purity of 99% with little or no neuronal or astrocytic contamination can be achieved. Between 70% and 85% of these adult microglia were in a relatively non-activated state. Functionally, these microglia respond to lipopolysaccharide incubation with increases in both phospho-p38 MAPK and OX42 immunostaining, as well as release of ATP, as compared to un-stimulated microglia. This technique provides a protocol to achieve rapid and efficient extraction of high purity, quiescent and functionally active microglia from adult mouse spinal cord, allowing greater study of adult spinal microglia in physiological and pathophysiological states.
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PMID:Rapid isolation and culture of primary microglia from adult mouse spinal cord. 1959 75


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