Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The main pathophysiological feature characterizing multiple sclerosis (MS) is demyelination. However, the possibility of neural damage has recently been proposed as a mechanism in chronic disease. Experimental allergic encephalomyelitis (EAE) is the most widely used experimental model for MS. We investigated occurrences of microglial activation and astrocytosis in the spinal cord, choline acetyl-transferase (ChAT) and calcitonin gene-related peptide (CGRP) mRNA regulation in spinal motoneurones during EAE. EAE was induced in female Lewis rats by injecting guinea pig spinal cord tissue in complete Freund's adjuvant (CFA) to which heat-inactivated Mycobacterium had been added. Rats injected with CFA and uninjected rats were used as controls. ChAT and CGRP mRNAs were studied by in situ hybridization in the lumbar spinal cord and a computerized grain counting procedure was used for quantification. No differences in ChAT mRNA level were found between control and CFA-injected rats. ChAT mRNA level was strongly reduced in EAE 14 days after immunization and then recovered (29 days after immunization). CGRP mRNA increased 14 days after immunization, and then recovered to control level. Extensive long-lasting gliosis developed in the spinal cord and around motoneurones and a transient expression of p75LNGFR in motoneurones was also found. These data suggest that during EAE, gliosis induces distress in spinal cord neurones involving the synthesis enzyme for the main transmitter.
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PMID:Spinal motoneurone distress during experimental allergic encephalomyelitis. 1548 28

The active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], suppresses disease development in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). However, complete disease prevention only occurs with doses that dramatically elevate serum calcium levels, thus limiting the usefulness of 1,25(OH)(2)D(3) as a potential MS therapeutic agent. Because calcitonin (CT) is believed to be released by hypercalcemia and has been shown to be anti-inflammatory, we examined whether suppression of EAE by 1,25(OH)(2)D(3) could be mediated either in part or entirely by CT. Continuous administration of pharmacological doses of CT did not prevent EAE. However, a combination of CT and a subtherapeutic dose of 1,25(OH)(2)D(3) additively suppressed EAE without causing hypercalcemia. Moreover, CT decreased the dose of 1,25(OH)(2)D(3) required for disease suppression. Our results suggest that CT may be a significant factor but cannot account entirely for 1,25(OH)(2)D(3)-mediated suppression of EAE.
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PMID:Enhancement of 1,25-dihydroxyvitamin D3-mediated suppression of experimental autoimmune encephalomyelitis by calcitonin. 1928 78

The active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), can suppress disease in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. Calcium appears to be a critical component of 1,25(OH)(2)D(3)-mediated suppression of EAE, as complete disease prevention only occurs with a concomitant increase in serum calcium levels. Calcitonin (CT) is a peptide hormone released in response to acute increases in serum calcium, which led us to explore its importance in 1,25(OH)(2)D(3)-mediated suppression of EAE. Previously, we discovered that co-administration of pharmacological doses of CT enhanced the suppressive effect of 1,25(OH)(2)D(3) on EAE, suggesting CT may play a role in 1,25(OH)(2)D(3)-mediated suppression of EAE. To determine the importance of CT in EAE we have utilized a mouse strain in which the gene encoding CT and its alternative splice product, calcitonin gene related peptide-alpha (CGRP), have been deleted. Deletion of the CT/CGRP gene had no effect on EAE progression. Furthermore, treatment with 1,25(OH)(2)D(3) suppressed EAE in CT/CGRP knock-out mice equal to that in wild type mice. Therefore, we conclude that CT is not necessary for 1,25(OH)(2)D(3)-mediated suppression of EAE.
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PMID:The calcitonin/calcitonin gene related peptide-alpha gene is not required for 1alpha,25-dihydroxyvitamin D3-mediated suppression of experimental autoimmune encephalomyelitis. 1956 74

We recently demonstrated that SA13353 [1-[2-(1-adamantyl)ethyl]-1-pentyl-3-[3-(4-pyridyl)propyl]urea], a novel transient receptor potential vanilloid 1 (TRPV1) agonist, inhibits TNF-alpha production through the activation of capsaicin-sensitive afferent neurons. In the present study, we investigated the effects of SA13353 on lipopolysaccharide (LPS)-induced cytokine production and a murine model of experimental autoimmune encephalomyelitis (EAE). SA13353 inhibited LPS-induced TNF-alpha and interleukin (IL)-1beta production while augmenting IL-10 production in mice. It also inhibited TNF-alpha and IL-1beta mRNA expression, and increased IL-10 mRNA expression in LPS-treated murine liver. These effects were not observed in TRPV1 KO and sensory denervated mice. Capsaicin and SA13353 increased serum neuropeptide levels, and calcitonin gene-related peptide fragment 8-37 (CGRP(8)(-)(37)), a CGRP antagonist, partially blocked the inhibitory effects of capsaicin and SA13353 on LPS-induced TNF-alpha production. These results suggest that the TPPV1 agonistic effects inhibit TNF-alpha production, at least partially, via neuropeptide release. SA13353 did not directly affect LPS-induced cytokine production in vitro using RAW264.7 macrophages, which do not express TRPV1. Therefore, we consider SA13353 to be a good tool for the investigation of the value of TRPV1 agonists for the treatment of chronic inflammation. In a murine EAE model, SA13353 attenuated clinical signs and histopathological changes. SA13353 attenuated cytokine levels, including TNF-alpha, IL-1beta, IL-12p40, IL-17, and interferon (IFN)-gamma, after proteolipid protein (PLP) immunization. In addition, SA13353 attenuated the increase of IL-17-producing cells. These results suggest that TRPV1 agonists may act as anti-inflammatory and immunomodulatory agents in vivo in certain inflammatory diseases.
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PMID:Transient receptor potential vanilloid 1 agonists as candidates for anti-inflammatory and immunomodulatory agents. 1987 65

Activation states of immune cells (among them, the so-called pro- or anti-inflammatory states) influence the pathogenesis of multiple sclerosis (MS). The neuropeptide calcitonin gene-related peptide (CGRP) can exert a pro- or anti-inflammatory role in a context-dependent manner. In mice CGRP was found to attenuate the development of experimental autoimmune encephalomyelitis (EAE, a common MS animal model). We analyzed CGRP effects on the expression of cytokines and markers of activation states, as well as its intracellular cascade, following intrathecal administration during EAE immunization. Real Time quantitative-PCR (RT-PCR) showed that IL-1beta and IL-6 (associated to a pro-inflammatory state in EAE), but also Ym1 (also known as Chil3), Arg1 and CD163 (associated to an anti-inflammatory state in EAE) were decreased in the encephalon (devoid of cerebellum). In the cerebellum itself, IL-1beta and Ym1 were decreased. TNF-alpha (associated to a pro-inflammatory state in EAE), but also IL-10 (associated to another type of anti-inflammatory state) and BDNF were unchanged in these two regions. No changes were detected in the spinal cord. Additional tendencies toward a change (as revealed by RT-PCR) were again decreases: IL-10 in the encephalon and Arg1 in the spinal cord. CGRP decreased percentage of Ym1+/CD68+ immunoreactive cells and cell density of infiltrates in the cervical spinal cord pia mater. Instead, Ym1 in the underlying parenchyma and at thoracic and lumbar levels, as well as Arg1, were unchanged. In cultured microglia the neuropeptide decreased Ym1, but not Arg1, immunoreactivity. Inducible NOS (iNOS) was unchanged in spinal cord microglia and astrocytes. The neuropeptide increased the activation of ERK1/2 in the astrocytes of the spinal cord and in culture, but did not influence the activation of ERK1/2 or p38 in the spinal cord microglia. Finally, in areas adjacent to infiltration sites CGRP-treated microglia showed a larger ramification radius. In conclusion, CGRP-induced EAE amelioration was associated to a concomitant, context-dependent decrease in the expression of markers belonging to both pro- or anti-inflammatory activation states of immune cells. It can be hypothesized that CGRP-induced EAE attenuation is obtained through a novel mechanism that promotes down-regulation of immune cell activation that facilitates the establishment of a beneficial environment in EAE provided possibly also by other factors.
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PMID:Calcitonin gene-related peptide decreases IL-1beta, IL-6 as well as Ym1, Arg1, CD163 expression in a brain tissue context-dependent manner while ameliorating experimental autoimmune encephalomyelitis. 3019 40