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)

The dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) is caused by point mutations in the neuroserpin gene. We have shown a correlation between the predicted effect of the mutation and the number of intracerebral inclusions, and an inverse relationship with the age of onset of disease. Our previous work has shown that the intraneuronal inclusions in FENIB result from the sequential interaction between the reactive centre loop of one neuroserpin molecule with beta-sheet A of the next. We show here that neuroserpin Portland (Ser52Arg), which causes a severe form of FENIB, also forms loop-sheet polymers but at a faster rate, in keeping with the more severe clinical phenotype. The Portland mutant has a normal unfolding transition in urea and a normal melting temperature but is inactive as a proteinase inhibitor. This results in part from the reactive loop being in a less accessible conformation to bind to the target enzyme, tissue plasminogen activator. These results, with those of the CD analysis, are in keeping with the reactive centre loop of neuroserpin Portland being partially inserted into beta-sheet A to adopt a conformation similar to an intermediate on the polymerization pathway. Our data provide an explanation for the number of inclusions and the severity of dementia in FENIB associated with neuroserpin Portland. Moreover the inactivity of the mutant may result in uncontrolled activity of tissue plasminogen activator, and so explain the epileptic seizures seen in individuals with more severe forms of the disease.
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PMID:Neuroserpin Portland (Ser52Arg) is trapped as an inactive intermediate that rapidly forms polymers: implications for the epilepsy seen in the dementia FENIB. 1615 19

Temporal lobe epilepsy (TLE) is the most common form of epilepsy, affecting approximately 1-2% of the population. Seizure events resulting from TLE are characterized by aberrant hippocampal mossy fiber sprouting and plastic responses that affect brain function. Seizure susceptibility is modulated by the enzyme tissue plasminogen activator (tPA), the normal physiological role of which includes promotion of synaptic reorganization in the mossy fiber pathway by initiating a proteolytic cascade that cleaves extracellular matrix components and influences neurite extension. tPA is concentrated at and selectively secreted from growth cones during excitatory events. However, the mechanisms underlying tPA release during seizure-induced synaptogenesis are not well understood. We examine here potential roles for the signaling enzyme phospholipase D1 (PLD1), which promotes regulated exocytosis in non-CNS cell types, and which we previously demonstrated increases in expression in hippocampal neurons during seizure-induced mossy fiber sprouting. We now show that overexpression of wild-type PLD1 in cultured neurons promotes tPA release and tPA-dependent neurite extension, whereas overexpression of an inactive PLD1 allele or pharmacological inhibition of PLD1 inhibits tPA release. Similarly, viral delivery of wild-type PLD1 into the hippocampus facilitates tPA secretion and mossy fiber sprouting in a seizure-inducing model, whereas the inactive PLD1 allele inhibits tPA release and elicits blunted and abnormal mossy fiber extension similar to that observed for tPA-/- mice. Together, these findings secretion and thus mossy fiber extension in the setting of elevated suggest that PLD1 functions endogenously to regulate tPA-/- neuronal stimulation, such as that seen in TLE.
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PMID:Phospholipase D1-promoted release of tissue plasminogen activator facilitates neurite outgrowth. 1571 16

In this report, we provide direct demonstration that the neurotrophin nerve growth factor (NGF) is released in the extracellular space in an activity-dependent manner in its precursor form (proNGF) and that it is in this compartment that its maturation and degradation takes place because of the coordinated release and the action of proenzymes and enzyme regulators. This converting protease cascade and its endogenous regulators (including tissue plasminogen activator, plasminogen, neuroserpin, precursor matrix metalloproteinase 9, and tissue inhibitor metalloproteinase 1) are colocalized in neurons of the cerebral cortex and released upon neuronal stimulation. We also provide evidence that this mechanism operates in in vivo conditions, as the CNS application of inhibitors of converting and degrading enzymes lead to dramatic alterations in the tissue levels of either precursor NGF or mature NGF. Pathological alterations of this cascade in the CNS might cause or contribute to a lack of proper neuronal trophic support in conditions such as cerebral ischemia, seizure and Alzheimer's disease or, conversely, to excessive local production of neurotrophins as reported in inflammatory arthritis pain.
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PMID:Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. 1661 25

Seizures during thrombolytic therapy for ischemic stroke have not previously been described as a favorable prognostic sign. We report three patients with severe stroke (NIH Stroke Scale [NIHSS] score 15 to 20) who experienced a seizure during tissue plasminogen activator (tPA) infusion. While initially raising alarm about possible hemorrhage, the seizures heralded dramatic recovery (an immediate 15-point NIHSS score improvement after tPA; NIHSS score 0 or 1 at 24 hours). We propose that the seizures during thrombolysis may indicate cortical reperfusion and/or hyperperfusion due to early recanalization of an acutely occluded intracranial artery.
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PMID:Seizures during stroke thrombolysis heralding dramatic neurologic recovery. 1764 39

Medically refractory seizures cause inflammation and neurodegeneration. Seizure initiation thresholds have been linked in mice to the serine protease tissue plasminogen activator (tPA); mice lacking tPA exhibit resistance to seizure induction, and the ensuing inflammation and neurodegeneration are similarly suppressed. Seizure foci in humans can be examined using PET employing 2-deoxy-2[(18)F]fluoro-d-glucose ((18)FDG) as a tracer to visualize metabolic dysfunction. However, there currently exist no such methods in mice to correlate measures of brain activation with behavior. Using a novel method for small animal PET data analysis, we examine patterns of (18)FDG uptake in wild-type and tPA(-/-) mice and find that they correlate with the severity of drug-induced seizure initiation. Furthermore, we report unexpected activations that may underlie the tPA modulation of seizure susceptibility. The methods described here should be applicable to other mouse models of human neurological disease.
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PMID:A novel approach for imaging brain-behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator. 1770 26

Reperfusion injury has been well described in medical literature; cerebral reperfusion injury is commonly seen in association with vascular surgical procedures such as carotid endarterectomies and stent placement procedures. Cerebral reperfusion injury can manifest as blood-brain barrier breakdown, cortical irritability, and epileptic seizures. Seizures induced by cerebral reperfusion have not been documented or reported after thrombolytic therapy for acute ischemic stroke. We report a patient who received intravenous recombinant tissue plasminogen activator within 3 hours of stroke symptom onset and developed the new-onset symptom of continuous, primary motor seizure activity within 20 minutes of recombinant tissue plasminogen activator administration. These epileptic seizures originated in the same area as the acute brain ischemia and occurred during the anticipated period of cerebral reperfusion. In this article we describe a case report and then discuss the pathophysiology and mechanisms that may underlie reperfusion epileptic seizures as a manifestation of cerebral reperfusion injury.
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PMID:Reperfusion seizures: a manifestation of cerebral reperfusion injury after administration of recombinant tissue plasminogen activator for acute ischemic stroke. 1803 46

Venous thrombosis (VT) is a rare condition in childhood, being usually associated with congenital predisposition or acquired risk factors. The incidence of VT among children with cancer is between 1 and 36%. The highest incidence is among children with acute lymphoblastic leukaemia, followed by those with lymphoma and solid tumours. Malignancy and/or chemotherapy complications are considered as triggering factors. We report a case of a 15-year-old girl with non-Hodgkin lymphoma who developed generalized seizures during chemotherapy. Head computed tomography revealed right transverse and sagittal sinus thrombosis. Anticoagulation treatment using heparin as well as thrombolytic treatment with recombinant human tissue plasminogen activator (rhtPA) were introduced. The immediate application of rhtPA resulted in recanalisation of initially involved vessels which led to recovery with no neurological deficits. The reported case of severe venous thrombosis suggests that systemic treatment with rhtPA is effective and safe in children with cerebral venous sinus thrombosis.
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PMID:[Venous sinus thrombosis which occurred during treatment of a 15-years old girl with t cell non-Hodgkin lymphoma - case report]. 1953 30

A growing body of evidence demonstrates the involvement of plasminogen activators (PAs) in a number of physiologic and pathologic events in the CNS. Induction of both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) has been observed in different experimental models of epilepsy and tPA has been implicated in the mechanisms underlying seizure activity. We investigated the expression and the cellular distribution of tPA and uPA in several epileptogenic pathologies, including hippocampal sclerosis (HS; n=6), and developmental glioneuronal lesions, such as focal cortical dysplasia (FCD, n=6), cortical tubers in patients with the tuberous sclerosis complex (TSC; n=6) and in gangliogliomas (GG; n=6), using immuno-cytochemical, western blot and real-time quantitative PCR analysis. TPA and uPA immunostaining showed increased expression within the epileptogenic lesions compared to control specimens in both glial and neuronal cells (hippocampal neurons in HS and dysplastic neurons in FCD, TSC and GG specimens). Confocal laser scanning microscopy confirmed expression of both proteins in astrocytes and microglia, as well as in microvascular endothelium. Immunoblot demonstrated also up-regulation of the uPA receptor (uPAR; P<0.05). Increased expression of tPA, uPA, uPAR and tissue PA inhibitor type mRNA levels was also detected by PCR analysis in different epileptogenic pathologies (P<0.05). Our data support the role of PA system components in different human focal epileptogenic pathologies, which may critically influence neuronal activity, inflammatory response, as well as contributing to the complex remodeling of the neuronal networks occurring in epileptogenic lesions.
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PMID:Tissue plasminogen activator and urokinase plasminogen activator in human epileptogenic pathologies. 2021 43

Cerebral hyperperfusion and reperfusion injuries are not infrequently encountered following in reperfusion of ischemic or hypoperfused brain. Mechanism of injury could be related to tissue plasminogen activator toxicity, oxidative stress, and hyperperfusion due to impaired cerebral autoregulation in already maximally dilated cerebral vasculature and compromised cerebral hemodynamic reserve. Reperfusion injury can present as headaches and seizures in mild forms and as subarachnoid hemorrhage, intracranial hemorrhage, cerebral edema, and encephalopathy in its most severe manifestation. Prevention and identifying those at risk of hyperperfusion syndromes are the best strategy. Active treatment includes basic neurocritical care with reduction of blood pressure to a reperfused brain and timely neuroprotection and cerebral edema control measures are the mainstay of its management approach.
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PMID:Neurocritical care of a reperfused brain. 2104 86

We conducted a study to assess pharmacokinetics of high-dose tranexamic acid for 24 h after administration of the drug in patients undergoing cardiac surgery with cardiopulmonary bypass. High-dose tranexamic acid involved a bolus of 30 mg.kg(-1) infused over 15 min followed by a 16 mg.kg(-1) .h(-1) infusion until chest closure with a 2 mg.kg(-1) load within the pump prime. Tranexamic acid followed first-order kinetics best described using a two-compartment model, with a total body clearance that approximated the glomerular filtration rate. Mean plasma tranexamic acid concentrations during the intra-operative period and in the first 6 postoperative hours were consistently higher than the suggested threshold to achieve 100% inhibition and 80% inhibition of tissue plasminogen activator. With recent studies implicating high-dose tranexamic acid as a possible aetiology of postoperative seizures following cardiac surgery, the minimum effective yet safe dose of tranexamic acid in high-risk cardiac surgery needs to be refined.
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PMID:Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass. 2282 64


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