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

Delta9-tetrahydrocannabinol (Delta9-THC), the major psychoactive component of marijuana, induces catalepsy-like immobilization and impairment of spatial memory in rats. Delta9-THC also induces aggressive behavior in isolated housing stress. These abnormal behaviors could be counteracted by SR141716A, a CB1 cannabinoid receptor antagonist. Also Delta9-THC inhibited release of glutamate in the dorsal hippocampus, but this inhibition could be antagonized by SR141716A in an in vivo microdialysis study. Moreover, NMDA and AMPA-type glutamate receptor enhancers improved the Delta9-THC-induced impairment of spatial memory. On the other hand, Delta9-THC markedly inhibited the neurodegeneration in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis and reduced the elevated glutamate level of cerebrospinal fluid induced by EAE. These therapeutic effects on EAE were reversed by SR141716A. Taken together, our results demonstrate that the inhibition of glutamate release via activation of the CB1-cannabinoid receptor is one mechanism involved in Delta9-THC-induced impairment of spatial memory, and the therapeutic effect of Delta9-THC on EAE, and a Delta9-THC analog might provide an effective treatment for psychosis and neurodegenerative diseases.
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PMID:New perspectives in the studies on endocannabinoid and cannabis: abnormal behaviors associate with CB1 cannabinoid receptor and development of therapeutic application. 1559 3

The authors provide an extensive review of new data related to the role of glutamate in CNS disorders, describing new aspects in glutamate and glutamatergic receptors-NMDA receptors, NR2B-selective antagonists, non-NMDA ionotropic glutamate receptors, N-acetylaspartylglutamate, and glutamate and glycine transporters. New findings in animal models and in human diseases-stroke, traumatic brain injury, Alzheimer's, Parkinson's and Huntington's diseases, tardive dyskinesia, ALS, olivopontcerebellar degeneration, AIDS, allergic encephalomyelitis, epilepsy, anxiety, depression, schizophrenia, liver disease, aminoglycoside antibiotic-induced hearing loss, hemiplegia, chronic pain and drug tolerance and abuse-are presented. Finally, the authors cite the progress achieved in the development of agents that interact with the glutamatergic system: NMDA channel blockers, competitive NMDA receptor antagonists, NR2B-selective antagonists, glutamate release inhibitors, glycineB antagonists, AMPA and kainate receptor antagonists, AMPA receptor-positive modulators and agents that act by modifying endogenous kynurenic acid metabolism.
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PMID:Glutamate in CNS disorders as a target for drug development: an update. 1561 69

Complement is implicated in the pathogenesis of inflammatory disorders of the central nervous system (CNS), like multiple sclerosis, Alzheimer's disease, and trauma. The anaphylatoxins C3a and C5a are thought to be the major contributors to complement-mediated inflammation in the CNS, likely mediating their effects via their ability to attract and activate leukocytes and common capacity to augment inflammation. For example, in experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, CNS-specific expression of C3a in C3a/GFAP transgenic mice renders them prone to massive cellular infiltration of the CNS and increases their mortality. In contrast, other studies have suggested that C3a can function in an anti-inflammatory fashion in the CNS, by inducing neurotrophin production and preventing NMDA-mediated neurotoxicity. To further investigate the seemingly paradoxical role of C3a in acute inflammation of the brain, we studied the pathogenesis of endotoxin shock in C3a/GFAP transgenic, C3a receptor-deficient (C3aR-/-) and C3a/GFAPxC3aR-/- mutant mice. Here we report that C3a/GFAP mice were significantly more resistant to endotoxin-induced lethality than wild-type and C3aR-/- mice. Surprisingly, C3a/GFAPxC3aR-/- hybrids were also significantly protected, indicating that C3a exerts its protective anti-inflammatory effect either directly or via an as yet unidentified non-canonical C3aR.
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PMID:C3a expressed in the central nervous system protects against LPS-induced shock. 1608 60

Generalized 1Hz, burst-and-slow-wave complexes were observed in a comatosed patient with acute disseminated encephalomyelitis (ADEM) when she showed extremely intractable, generalized convulsions and fragmented myoclonus in the whole body. Two types of short-latency SEPs were obtained separately during the burst and slow phase of the EEG (SEP-burst and SEP-slow, respectively), which showed a two fold greater amplitude of N20 in the former than in the latter. This suggests enhanced responsiveness to the peripheral stimuli during the burst phase as compared with the slow phase. CSF and serum were positive for autoantibodies to NMDA receptors. The "burst and slow complexes" reported here are considered to be an atypical EEG pattern of a generalized epileptic phenomenon.
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PMID:"Burst and slow complexes" in nonconvulsive epileptic status. 1656 28

There is accumulating and convincing evidence indicating a role for glutamate in the pathogenesis of the human demyelinating disease multiple sclerosis (MS). Studies in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, demonstrate that pharmacological inhibition of specific glutamate receptors suppresses neurological symptoms and prevents blood-brain barrier (BBB) breakdown. The mechanisms through which glutamate influences BBB function during EAE remain unclear. Glutamate triggers the production of nitric oxide and superoxide, which can lead to the formation of peroxynitrite (ONOO(-)). Recent studies have implicated ONOO(-) in the loss of neurovascular integrity during EAE. We propose that glutamate contributes to BBB breakdown via the actions of ONOO(-). The present investigation examined glutamate-induced ONOO(-) formation in the b.End3 brain-derived endothelial cell line. b.End3 cells were incubated with a concentration range of glutamate and ONOO(-) production was assessed over time. Results showed a concentration- and time-dependent increase in ONOO(-) levels in glutamate-treated cells that were suppressed by selective and non-selective inhibitors of ONOO(-)-mediated reactions. Specific activation of b.End3-associated NMDA receptors also resulted in a concentration-dependent increase in ONOO(-) production. The ability of b.End3 cells to respond to the presence of glutamate was confirmed through the detection of NMDA receptor immnuoreactivity in cell extracts. In addition, the use of the NMDA receptor antagonists MK-801 and memantine reduced glutamate-mediated ONOO(-) generation from b.End3 cells. The data reinforce the important relationship between glutamate and the NMDA receptor, positioned at neurovascular sites, which may be of particular relevance to the pathogenesis of demyelinating disease.
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PMID:Glutamate-stimulated peroxynitrite production in a brain-derived endothelial cell line is dependent on N-methyl-D-aspartate (NMDA) receptor activation. 1711 45

The experimental allergic encephalomyelitis (EAE) developed on the 11 - 12th day after inoculation of encephalitogenic mixture in 96% of female Wistar rats in the control group. In the majority of control rats, severe EAE with a long duration of action prevailed (average cumulative index, 25.6; average duration of illness, 15.8 days). A course of NMDA-antagonist memantine administration in a doze of 10 and 20 mg/kg prevented the development of EAE in 10% of rats. In rats with EAE (on the average, 12-13 days after the administration of encephalitogenic mixture) the drug slightly reduced the severity and duration of neurological disorder: the average cumulative index and duration of illness decreased by a factor of 1.4-1.5 in comparison to the control. The antagonist of NMDA and GluR1 AMPA receptors, IEM-1913, upon a course of administration in a doze of 0.1-1 mg/kg prevented the EAE development in 23-25% of rats. In the rats with EAE treated with IEM-1913 in the maximum doze (1 mg/kg), the EAE developed only after completion of the course of drug administration (on the 19-20th day), proceeded quickly (no more than 5 days), and in the easy form (average cumulative index. 8.3). High efficacy of IEM-1913 administration in rats with EAE is apparently connected with its neuroprotective and antiinflammatory action, which is related, on the one hand, to a combined block of NMDA and GluR1 AMPA of receptors in brain and, on the other hand, to a reduction of the permeability of BBB for encephalitogenic T-lymphocytes owing to the blockade of NMDA receptors in BBB.
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PMID:[Combined blockade of GluR1 AMPA and NMDA receptors effectively eliminates neurological disorders in rats with experimental allergic encephalomyelitis]. 1807 35

We compared preventive and therapeutic effects of memantine, a selective blocker of NMDA-receptors, and IEM-1966, a blocker of both NMDA- and GluR1 AMPA-receptors, on the model of acute experimental allergic encephalomyelitis. Memantine in high doses prevented the development of experimental allergic encephalomyelitis only in 10% rats, slightly (by 1.4-1.5 times) moderated the neurological disturbances, and shortened the duration of the disease. In far lower doses, IEM-1966 prevented the development of experimental allergic encephalomyelitis in 50% rats, while in the affected rats it decreased the severity of neurological disturbances and duration of the disease by 3-4 times. When applied during the clinical phase of the disease, IEM-1966 decreased the severity of neurological disturbances and duration of the disease by 2.0-2.5 times predominantly in rats with mild and moderate course of experimental allergic encephalomyelitis.
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PMID:Comparative study of preventive and therapeutic effects of IEM-1966 and memantine in rats with experimental allergic encephalomyelitis. 1839 84

Nitrosative stress has been implicated in the pathophysiology of several CNS disorders, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). We have recently shown that protein nitrosothiols (PrSNOs) accumulate in the brain of MS patients, and there is indirect evidence that PrSNO levels are also increased in EAE. In this study we sought to identify the major PrSNOs in the spinal cord of EAE animals prepared by active immunization of C57/BL6 mice with MOG(35-55) peptide. For this purpose, PrSNOs from control and EAE mice at various disease stages were derivatized with HPDP-biotin, and the biotinylated proteins were isolated with streptavidin-agarose. Proteins from total and streptavidin-bound fractions were then analyzed by Western blotting using antibodies against the major S-nitrosylated substrates of CNS tissue. With this approach we found that the proportion of S-nitrosylated neurofilament proteins, NMDA receptors, alpha/beta-tubulin, beta-actin, and GAPDH is increased in EAE. Other potential substrates either were not S-nitrosylated in vivo (HCN3, HSP-72, CRMP-2, gamma-actin, calbindin) or their S-nitrosylation levels were unaltered in EAE (Na/K ATPase, hexokinase, glycogen phosphorylase). We also discovered that neuronal specific enolase is the major S-nitrosylated protein in acute EAE. Given that S-nitrosylation affects protein function, it is likely that the observed changes are significant to the pathophysiology of inflammatory demyelination.
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PMID:Identification of major S-nitrosylated proteins in murine experimental autoimmune encephalomyelitis. 1940 5

Limbic encephalitis is a paraneoplastic syndrome that is often associated with small cell lung cancer (SCLC), breast cancer, testicular tumors, teratoma, Hodgkin's lymphoma and thymoma. The common clinical manifestations of limbic encephalitis are subacute onset, cognitive dysfunction, seizures and psychiatric symptoms. Paraneoplastic neurological disorders are considered to occur because of cytotoxic T cell responses and antibodies against target neuronal proteins that are usually expressed by an underlying tumor. The main intracellular antigens related to limbic encephalitis are Hu, Ma2, and less frequently CV2/CRMP5 and amphiphysin. The anti-Hu antibody, which is involved in cerebellar degeneration and extensive or multifocal encephalomyelitis such as limbic encephalitis is closely associated with a history of smoking and SCLC. The anti-Ma2 antibody is associated with encephalitis of the limbic system, hypothalamus and brain-stem. For this reason, some patients with limbic encephalitis have sleep disorders (including REM sleep abnormalities), severe hypokinesis and gaze palsy in addition to limbic dysfunction. In men aged less than 50 years, anti-Ma2 antibody encephalitis is almost always associated with testicular germ-cell tumors that are occasionally difficult to detect. In older men and women, the most common tumors are non-SCLC and breast cancer. Limbic encephalitis associated with cell-surface antigens (e.g., voltage-gated potassium channels, NMDA receptors) is mediated by antibodies and often improves after a reduction in the antibody titer and after tumor resection. Patients with antibodies against intracellular antigens, except for those with anti-Ma2 antibodies and testicular tumors, are less responsive. Early diagnosis and treatment with immunotherapy, tumor resection or both are important for improving or stabilizing the condition of limbic encephalitis.
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PMID:[Limbic encephalitis with antibodies against intracellular antigens]. 2042 Jan 74

Paraneoplastic neurological syndromes (PNSs) cover a wide range of diseases and involve both the central nervous system (CNS) and peripheral nervous system. Paraneoplastic encephalitis comprises several diseases such as paraneoplastic cerebellar degeneration (PCD), limbic encephalitis (LE), paraneoplastic encephalomyelitis (PEM), brainstem encephalitis, opsomyoclonus syndrome, in addition to other even less frequently occurring entities. LE was the first historically identified CNS PNS, and similarities between other temporal lobe diseases such as herpes encephalitis have been elucidated. In the past few decades several autoantibodies have been described in association with LE. These encompass the classical 'onconeuronal' antibodies (abs) such as Hu, Yo, Ri and others, and now additionally abs towards either ion channels or surface antigens. The clinical core findings in LE are various mental changes such as amnesia or confusion, often associated with seizures. Careful characterization of psychiatric manifestations and/or associated neurological signs can help to characterize the syndrome and type of ab. The treatment options in LE depend on the aetiology. In LE caused by onconeuronal abs, the treatment options are poor. In two types of abs associated with LE, abs against ion channels and surface antigens (e.g. NMDA), immunomodulatory treatments seem effective, making these types of LE treatable conditions. However, LE can also occur without being associated with cancer, in which case only immunomodulation is required. Despite effective treatments, some patients' residual deficits remain, and recurrences have also been described.
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PMID:Current approaches to the treatment of paraneoplastic encephalitis. 2176 74


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