Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Indirect evidence from in vitro studies implicates a functional role for matrix metalloproteinases (MMPs) in the central nervous system (CNS), including induction of neuronal migration during development and enhancement of neurite extension. Few reports have documented the expression of these enzymes in the brain, especially after injury in vivo. The objective of this study was to determine whether MMPs are expressed in various regional areas of rat brain after administration of the neurotoxin, kainic acid. Limbic motor seizures and neuronal degeneration were induced in Sprague-Dawley rats by systemic administration of kainate (10 mg/kg). Rats were subsequently divided into convulsive and non-convulsive groups, after observing their behaviour in response to the drug. Animals were killed 6, 12, 24, 72 and 168 h (7 days) after injection of kainate. Gelatinases were extracted from various brain regions and assayed by gelatin-substrate zymography. Levels of glial fibrillary acidic protein (GFAP) in corresponding regions were measured by ELISA. In the absence of treatment, MMP-2 and MMP-9 activities were expressed differentially in various brain regions with the highest levels in the hippocampus and the lowest in the cerebellum. In areas from convulsive rats, MMP-9 activity was markedly elevated at 6 h, and reached a maximum at 12 h after injection of kainate (8.1-fold hippocampus, 7.7-fold diencephalon, 7.2-fold striatum, 5.7-fold frontal cortex, 5.5-fold cerebellum, 2.6-fold midbrain). MMP-2 activity was induced more than two-fold in the hippocampus, diencephalon and striatum, to a lesser extent in the frontal cortex and midbrain, and was unchanged in the cerebellum, 72 h after injection. Neither MMP activity was altered in any brain region derived from non-convulsive rats. Treatment with the GABAA antagonist, bicuculline, resulted in increased levels of MMP-9, 12 h after drug administration, but no change in levels of MMP-2 up to 3 days following treatment. GFAP levels were induced 3 days after kainic acid injection in brain regions where MMP-2 was elevated. Nissl staining displayed the classical, regional neurodegeneration in kainate-treated animals that exhibited seizures. No obvious degeneration was detected in kainate-treated, non-convulsive rats or bicuculline-treated animals. These data demonstrate that MMP-9 and MMP-2 are differentially expressed with respect to time after kainic acid injection, and suggest that they are regulated by convulsion and/or neurodegenerative-associated mechanisms, respectively. Although similar in catalytic activity, MMP-9 and MMP-2 may play different roles in response to kainic acid-induced seizure and neuronal degeneration.
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PMID:Regional and differential expression of gelatinases in rat brain after systemic kainic acid or bicuculline administration. 982 49

Neurons of adult brain are able to remodel their synaptic connections in response to various stimuli. Modifications of the peridendritic environment, including the extracellular matrix, are likely to play a role during synapse remodeling. Proteolytic disassembly of ECM is a complex process using the regulated actions of specific extracellular proteinases. One of best-characterized families of matrix-modifying enzymes is the matrix metalloproteinase (MMP) family. Here, we describe changes in the expression and function of two well known MMPs, MMP-9 and MMP-2, in adult rat brain before and after systemic administration of the glutamate receptor agonist kainate. Kainate application results in enhanced synaptic transmission and seizures followed by selective tissue remodeling, primarily in hippocampal dentate gyrus. MMP-9 but not MMP-2 was highly expressed by neurons in normal adult rat brain. MMP-9 protein was localized in neuronal cell bodies and dendrites. Kainate upregulated the level of MMP-9 mRNA and protein within hours after drug administration. This was followed several hours later by MMP-9 enzymatic activation. Within hippocampus, MMP-9 mRNA and activity were increased selectively in dentate gyrus, including its dendritic layer. In addition, MMP-9 mRNA levels decreased in areas undergoing neuronal cell loss. This unique spatiotemporal pattern of MMP-9 expression suggests its involvement in activity-dependent remodeling of dendritic architecture with possible effects on synaptic physiology.
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PMID:Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus. 1182 21

Matrix metalloproteinase-9 has recently emerged as an important molecule in control of extracellular proteolysis in the synaptic plasticity. However, no synaptic targets for its enzymatic activity had been identified before. In this report, we show that beta-dystroglycan comprises such a neuronal activity-driven target for matrix metalloproteinase-9. This notion is based on the following observations. (i) Recombinant, autoactivating matrix metalloproteinase-9 produces limited proteolytic cleavage of beta-dystroglycan. (ii) In neuronal cultures, beta-dystroglycan proteolysis occurs in response to stimulation with either glutamate or bicuculline and is blocked by tissue inhibitor of metalloproteinases-1, a metalloproteinase inhibitor. (iii) Beta-dystroglycan degradation is also observed in the hippocampus in vivo in response to seizures but not in the matrix metalloproteinase-9 knock-out mice. (iv) Beta-dystroglycan cleavage correlates in time with increased matrix metalloproteinase-9 activity. (v) Finally, beta-dystroglycan and matrix metalloproteinase-9 colocalize in postsynaptic elements in the hippocampus. In conclusion, our data identify the beta-dystroglycan as a first matrix metalloproteinase-9 substrate digested in response to enhanced synaptic activity. This demonstration may help to understand the possible role of both proteins in neuronal functions, especially in synaptic plasticity, learning, and memory.
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PMID:Beta-dystroglycan as a target for MMP-9, in response to enhanced neuronal activity. 1742 29

Chronic alcohol drinking has been associated with the development of a number of abnormalities, including neuron-behavioral disorders, liver, pancreas, and heart-related diseases and inflammation and immune disorders. Because diverse mechanisms are involved in the development of these disorders, the commonly used receptor- or enzyme-specific drugs do not provide comprehensive protection against the adverse effects of alcoholism. This study describes possible therapeutic potency of puerarin (PU) from kudzu root, polyenylphosphatidylcholine from soy (SPCh), and curcumin (CU) from turmeric against alcohol's addiction-related and inflammatory-related abnormalities in alcohol-preferring P rats receiving free choice water and 15% ethanol in water. P-rats were fed once daily either the vehicle (for control) or different doses of PU, SPCh, CU, PU + SPCh, or PU + CU. The rats were divided in two groups: one received water alone, and the other free choice water and ethanol. Four rats from each group were fitted with electroencephalogram (EEG) electrodes for EEG recording. After 70 days of alcohol drinking, alcohol was withdrawn for 2 weeks, and the withdrawal symptoms were assessed. This study showed that alcohol drinking for 70 days (1) caused liver inflammation characterized by elevated tumor necrosis factor-alpha, interleukin-1beta, and matrix metalloproteinase-9 expression and (2) dysregulated lipopolysaccharide (LPS)-induced pleurisy. Alcohol withdrawal after 70 days of drinking generated severe withdrawal symptoms including seizure-type EEG activity. PU suppressed the addiction-mediated abnormalities but did not affect the inflammation-related abnormalities, while SPCh or CU suppressed only the inflammation-related abnormalities in alcohol-drinking rats subjected to LPS-induced pleurisy. A combination of PU with SPCh or CU suppressed both the addiction-related and inflammation-related abnormalities of alcohol drinking. Therefore, a mixture consisting of PU and either SPCh or CU may provide alternative therapy for alcohol-related disorders.
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PMID:Herbal mixtures consisting of puerarin and either polyenylphosphatidylcholine or curcumin provide comprehensive protection against alcohol-related disorders in P rats receiving free choice water and 15% ethanol in pure water. 1788 48

Prolonged febrile seizures may be followed by acute encephalopathy with neurological sequelae. To investigate the function of the blood-brain-barrier (BBB) in acute encephalopathy following prolonged febrile seizures with neurological sequelae (AEPFS), the concentrations of serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitors of metalloproteinases 1 (TIMP-1) were measured by ELISA in 10 children with AEPFS, 16 with prolonged febrile seizures without encephalopathy (PFS), 20 with simple febrile seizures (SFS), 23 with convulsive status epilepticus (CSE), and 18 with West syndrome. Serum MMP-9 levels in AEPFS and PFS patients were significantly higher than those in SPS and West syndrome patients and in controls, and those in CSE patients were significantly higher than in controls. Serum TIMP-1 levels in AEPFS patients were significantly lower than those in PFS, SFS, CSE and West syndrome patients and in controls. Serum MMP-9 levels and MMP-9/TIMP-1 ratios in AEPFS patients with motor paralysis were significantly higher than for those without motor paralysis. Our results suggest that prolonged seizures are related to high serum MMP-9 levels, and that an increased MMP-9/TIMP-1 ratio in AEPFS might induce dysfunction of the BBB. Furthermore, an imbalance of serum MMP-9 and TIMP-1 levels in patients with AEPFS may be associated with severe neurological sequelae.
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PMID:Roles of matrix metalloproteinase-9 and tissue inhibitors of metalloproteinases 1 in acute encephalopathy following prolonged febrile seizures. 1792 6

The phenomenon of dendritic transport and local translation of mRNA is considered to be one of the most fundamental mechanisms underlying long-term synaptic plasticity. Matrix metalloproteinase 9 (gelatinase B) (MMP-9) is a matrix metalloproteinase implicated in synaptic long-term potentiation and hippocampus-dependent memory. It was recently shown to be prominently up-regulated in the hippocampal dentate gyrus (DG) upon kainate-mediated seizures. Here, using a high resolution nonradioactive in situ hybridization at the light- and electron-microscopic levels, as well as subcellular fractionation, we provide evidence that in the rat hippocampus, MMP-9 mRNA is associated with dendrites and dendritic spines bearing asymmetric (excitatory) synapses. Moreover we observe that after kainate treatment the number of dendrites and synapses containing MMP-9 mRNA increases markedly. Our results indicate that we are observing the phenomenon of dendritic transport of seizure-induced MMP-9 mRNA.
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PMID:Synaptic localization of seizure-induced matrix metalloproteinase-9 mRNA. 1792 57

Temporal lobe epilepsy (TLE) is a devastating disease in which aberrant synaptic plasticity plays a major role. We identify matrix metalloproteinase (MMP) 9 as a novel synaptic enzyme and a key pathogenic factor in two animal models of TLE: kainate-evoked epilepsy and pentylenetetrazole (PTZ) kindling-induced epilepsy. Notably, we show that the sensitivity to PTZ epileptogenesis is decreased in MMP-9 knockout mice but is increased in a novel line of transgenic rats overexpressing MMP-9. Immunoelectron microscopy reveals that MMP-9 associates with hippocampal dendritic spines bearing asymmetrical (excitatory) synapses, where both the MMP-9 protein levels and enzymatic activity become strongly increased upon seizures. Further, we find that MMP-9 deficiency diminishes seizure-evoked pruning of dendritic spines and decreases aberrant synaptogenesis after mossy fiber sprouting. The latter observation provides a possible mechanistic basis for the effect of MMP-9 on epileptogenesis. Our work suggests that a synaptic pool of MMP-9 is critical for the sequence of events that underlie the development of seizures in animal models of TLE.
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PMID:Important role of matrix metalloproteinase 9 in epileptogenesis. 1833 22

Synaptic plasticity involves remodeling of extracellular matrix. This is mediated, in part, by enzymes of the matrix metalloproteinase (MMP) family, in particular by gelatinase MMP-9. Accordingly, there is a need of developing methods to visualize gelatinolytic activity at the level of individual synapses, especially in the context of neurotransmitters receptors. Here we present a high-resolution fluorescent in situ zymography (ISZ), performed in thin sections of the alcohol-fixed and polyester wax-embedded brain tissue of the rat (Rattus norvegicus), which is superior to the current ISZ protocols. The method allows visualization of structural details up to the resolution-limit of light microscopy, in conjunction with immunofluorescent labeling. We used this technique to visualize and quantify gelatinolytic activity at the synapses in control and seizure-affected rat brain. In particular, we demonstrated, for the first time, frequent colocalization of gelatinase(s) with synaptic N-methyl-D-aspartic acid (NMDA)- and AMPA-type glutamate receptors. We believe that our method represents a valuable tool to study extracellular proteolytic processes at the synapses, it could be used, as well, to investigate proteinase involvement in a range of physiological and pathological phenomena in the nervous system.
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PMID:High resolution in situ zymography reveals matrix metalloproteinase activity at glutamatergic synapses. 1858 50

Recent studies demonstrate that matrix metalloproteinase-9 (MMP-9) is closely involved in the pathogenesis of epilepsy. This study investigated the role of MMP-9 in hippocampal cell death after pilocarpine-induced status epilepticus (SE). We showed that MMP-9 expression and activity significantly increased and beta1-integrin levels decreased on day 3 after SE. beta1-integrin degradation was also observed in hippocampal ex vivo extracts incubated with recombinant active MMP-9. Treatment with a selective MMP-9 inhibitor attenuated MMP-9 up-regulation, beta1-integrin degradation, the reduction of ILK activity and Akt phosphorylation, and subsequent hippocampal damage after SE. However, co-treatment with anti-beta1-integrin antibody almost completely blocked the protective effects of the MMP-9 inhibitor on both integrin-mediated survival signaling and hippocampal cell death. Our study demonstrates that MMP-9 induces apoptotic hippocampal cell death by interrupting integrin-mediated survival signaling after SE and suggests that MMP-9 may be a promising target for a neuroprotective approach to preventing seizure-induced hippocampal damage.
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PMID:The role of MMP-9 in integrin-mediated hippocampal cell death after pilocarpine-induced status epilepticus. 1963 48

Epileptogenesis is defined as the process of developing epilepsy - a disorder characterized by recurrent seizures - following an initial insult. Neuronal death, aberrant synaptic plasticity and neuroinflammation play essential roles in epileptogenesis. An effective neuroprotective therapeutic agent should counteract one or, ideally, all the above-mentioned mechanisms. However, antiepileptic drugs obtainable nowadays can only suppress seizures, without antiepileptogenic effects. Matrix metalloproteinase-9 (MMP-9) is a member of matrix metalloproteinase (MMP) family that remodels the extracellular matrix. Recently, cumulative evidence indicates that MMP-9, a key participant in neuronal death, aberrant synaptic plasticity and neuroinflammation, is upregulated in experimental epilepsy models. Increased MMP-9 is also implicated in clinical epilepsy studies. Thus, we hypothesize that MMP-9 may be a novel therapeutic target for epilepsy and some agents, such as S24994, atorvastatin and minocycline, may be potential antiepileptogenic drugs.
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PMID:Matrix metalloproteinase-9 may be a potential therapeutic target in epilepsy. 2135 77


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