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)

We used an antisense oligodeoxynucleotide (ODN) complementary to inducible nitric oxide synthase (iNOS) to inhibit experimental autoimmune encephalomyelitis (EAE) in female SJL/J mice, an animal model for multiple sclerosis. The antisense ODN was administered intraventricularly to mice daily for 10 days beginning at the time of adoptive transfer of myelin basic protein-specific T lymphocytes. The antisense ODN treatment significantly reduced the clinical score of EAE and blocked iNOS mRNA and protein synthesis, as well as iNOS enzyme activity within the central nervous system. The levels of nitric oxide and cyclic guanosine monophosphate were also significantly reduced by the antisense ODN treatment. Neither sense nor random ODN affected clinical EAE or iNOS expression. Moreover, the protein and enzyme activity level of constitutive neuronal nitric oxide synthase was not affected by the antisense ODN. Thus, we have shown that the iNOS antisense ODN specifically blocked iNOS expression and ameliorated the induction of EAE.
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PMID:Antisense knockdown of inducible nitric oxide synthase inhibits induction of experimental autoimmune encephalomyelitis in SJL/J mice. 951 Jan 51

Monoclonal antibody (Mab) 5D12 is a potent antagonist of the CD40-CD40L pathway. This cellular interaction has been validated in a large number of experimental animal models where dys-regulation of the immune system plays a role. Chimeric 5D12 (ch5D12) was constructed to reduce the potential immunogenicity and enhance the in vivo half-life when used in humans. ch5D12 is a molecularly engineered human IgG(4) antibody containing the variable domains of the heavy and light chains of the murine version of 5D12 (mu5D12). This new chimeric Mab was tested in a marmoset experimental autoimmune encephalomyelitis model and was shown to effectively prevent disease symptoms. The results of this in vivo evaluation supported clinical use of ch5D12 for immune targeted diseases. Therefore GMP material was prepared and a GLP-compliant tissue cross-reactivity study on human tissues (3 donors/37 tissues) and cynomolgus tissues (2 donors/37 tissues) was performed. ch5D12 stained on the surface of B cells and selected dendritic cells and no unexpected cross-reactivity was observed. The identical staining patterns in human and cynomolgus tissues justified the use of cynomolgus monkeys as a relevant model for humans. A GLP-compliant safety and tolerability evaluation for ch5D12 in cynomolgus monkeys was performed using the GMP produced material. Weekly administration of ch5D12 at two dose levels for 4 weeks was shown to be safe and without any side effects in all monkeys.
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PMID:Preclinical assessment of anti-CD40 Mab 5D12 in cynomolgus monkeys. 1197 92

Phosphodiesterases (PDEs) are involved in the regulation of intracellular levels of the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). These enzymes hydrolyse the cyclic nucleotides to the corresponding nucleoside 5'-monophosphates. Nine PDE subtypes have been identified; these differ in their substrate specificity and mode of activation. The type 4 PDE (PDE(4)) hydrolyses cAMP, is activated by elevated levels of cAMP, and is inhibited by rolipram. Inhibition of enzyme activity has been shown to modulate the activity of cells of the immune system. The production of tumour necrosis factor (TNF)(alpha) by activated monocytes and macrophages is inhibited, and cytokine secretion and proliferation of type 1 T helper cells are suppressed. Both immune cell activation and their concomitant induction of cytokine secretion are implicated in multiple sclerosis (MS), which is the major demyelinating disease of the central nervous system. Studies with the selective PDE(4) inhibitor rolipram in experimental autoimmune encephalomyelitis (an animal model of MS) in mice, rats and nonhuman primates have demonstrated the efficacy of the compound in this disease model, suggesting that PDE(4) inhibitors could ameliorate the clinical course of MS. Unfortunately, clinical trials with PDE(4) inhibitors revealed the major adverse effects of these drugs, namely nausea and vomiting. However, novel PDE(4) inhibitors, which target only a subpopulation of PDE(4) enzymes, may provoke fewer adverse effects. The efficacy of a PDE(4) inhibitor in MS still needs to be demonstrated in a well designed clinical trial.
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PMID:Phosphodiesterase type 4 inhibitors: potential in the treatment of multiple sclerosis? 1803 15

Bone marrow (BM) derived mesenchymal stem cells (MSC) differentiate into cells of the mesodermal lineage but also, under certain experimental circumstances, into cells of the neuronal and glial lineage. Their therapeutic translation has been significantly boosted by the demonstration that MSC display significant also anti-proliferative, anti-inflammatory and anti-apoptotic features. These properties have been exploited in the effective treatment of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis where the inhibition of the autoimmune response resulted in a significant neuroprotection. A significant rescue of neural cells has been achieved also when MSC were administered in experimental brain ischemia and in animals undergoing brain or spinal cord injury. In these experimental conditions BM-MSC therapeutic effects are likely to depend on paracrine mechanisms mediated by the release of growth factors, anti-apoptotic molecules and anti-inflammatory cytokines creating a favorable environment for the regeneration of neurons, remyelination and improvement of cerebral flow. For potential clinical application BM-MSC offer significant practical advantages over other types of stem cells since they can be obtained from the adult BM and can be easily cultured and expanded in vitro under GMP conditions displaying a very low risk of malignant transformation. This review discusses the targets and mechanisms of BM-MSC mediated neuroprotection.
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PMID:Neuroprotective features of mesenchymal stem cells. 2139 93