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)

Neuronal degeneration in the hippocampus, a region of the brain important for acquisition of memory in humans, occurs in various pathological conditions, including Alzheimer's disease, brain ischaemia and epilepsy. When neuronal activity is stimulated in the adult rat and mouse hippocampus, tissue plasminogen activator (tPA), a serine protease that converts inactive plasminogen to the active protease plasmin, is transcriptionally induced. The activity of tPA in neural tissue is correlated with neurite outgrowth, regeneration and migration, suggesting that it might be involved in neuronal plasticity. Here we show that tPA is produced primarily by microglia in the hippocampus. Using excitotoxins to induce neuronal cell loss, we demonstrate that tPA-deficient mice are resistant to neuronal degeneration. These mice are also less susceptible to pharmacologically induced seizures than wild-type mice. These findings identify a role for tPA in neuronal degeneration and seizure.
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PMID:Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. 756 88

BACKGROUND--Aortic thrombosis is more frequent since the use of umbilical artery catheters in neonatal intensive care units. Some drugs or surgery are proposed to prevent complications; experience with tissue plasminogen activator (tPA) is still limited. CASE REPORT NO 1--A neonate, weighing 2400 g, developed respiratory distress requiring insertion of a catheter into her umbilical artery at H12. Ultrasonography on day 3 showed aortic thrombosis extending to the right renal artery which was confirmed by angiography. tPA 0.1 mg/kg was administered through the catheter, followed by 0.3 mg/kg/h for 3 hours and heparin, 100 IU/kg/hour for 54 hours. Angiography, performed 18 hours later, showed complete disappearance of the thrombosis. CASE REPORT NO 2--A neonate, weighing 2520 g suffered at 12 hours of life from seizures, apnea and bradycardia which required insertion of a catheter into her umbilical artery. Cyanosis of the right leg with weakening of femoral pulsations, 14 hours later, lead to the diagnosis of aortic thrombosis which was confirmed by aortography. The patient was given tPA 0.1 mg/kg followed by 0.3 mg/kg/h for 3 hours and heparin 100 IU/kg/hour for 6 hours. Amplitude of femoral pulsations strikingly increased within 6 hours with the disappearance of cyanosis. CONCLUSION--These results suggest that tPA can be useful in neonates presenting with aortic thrombosis.
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PMID:[Use of tissue plasminogen activator in the treatment of aortic thrombosis in newborn infants]. 778 May 51

Human recombinant tissue plasminogen activator (tPA) may benefit ischemic stroke patients by dissolving clots. However, independent of thrombolysis, tPA may also have deleterious effects on neurons by promoting excitotoxicity. Zinc neurotoxicity has been shown to be an additional key mechanism in brain injuries. Hence, if tPA affects zinc neurotoxicity, this may provide additional insights into its effect on neuronal death. Independent of its proteolytic action, tPA markedly attenuated zinc-induced cell death in cortical culture, and, when injected into cerebrospinal fluid, also reduced kainate seizure-induced hippocampal neuronal death in adult rats.
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PMID:Nonproteolytic neuroprotection by human recombinant tissue plasminogen activator. 1021 88

Neuronal migration is a critical phase of brain development, where defects can lead to severe ataxia, mental retardation, and seizures. In the developing cerebellum, granule neurons turn on the gene for tissue plasminogen activator (tPA) as they begin their migration into the cerebellar molecular layer. Granule neurons both secrete tPA, an extracellular serine protease that converts the proenzyme plasminogen into the active protease plasmin, and bind tPA to their cell surface. In the nervous system, tPA activity is correlated with neurite outgrowth, neuronal migration, learning, and excitotoxic death. Here we show that compared with their normal counterparts, mice lacking the tPA gene (tPA(-/-)) have greater than 2-fold more migrating granule neurons in the cerebellar molecular layer during the most active phase of granule cell migration. A real-time analysis of granule cell migration in cerebellar slices of tPA(-/-) mice shows that granule neurons are migrating 51% as fast as granule neurons in slices from wild-type mice. These findings establish a direct role for tPA in facilitating neuronal migration, and they raise the possibility that late arriving neurons may have altered synaptic interactions.
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PMID:Neuronal migration is retarded in mice lacking the tissue plasminogen activator gene. 1057 Feb 8

Short seizure episodes are associated with remodeling of neuronal connections. One region where such reorganization occurs is the hippocampus, and in particular, the mossy fiber pathway. Using genetic and pharmacological approaches, we show here a critical role in vivo for tissue plasminogen activator (tPA), an extracellular protease that converts plasminogen to plasmin, to induce mossy fiber sprouting. We identify DSD-1-PG/phosphacan, an extracellular matrix component associated with neurite reorganization, as a physiological target of plasmin. Mice lacking tPA displayed decreased mossy fiber outgrowth and an aberrant band at the border of the supragranular region of the dentate gyrus that coincides with the deposition of unprocessed DSD-1-PG/phosphacan and excessive Timm-positive, mossy fiber termini. Plasminogen-deficient mice also exhibit the laminar band and DSD- 1-PG/phosphacan deposition, but mossy fiber outgrowth through the supragranular region is normal. These results demonstrate that tPA functions acutely, both through and independently of plasmin, to mediate mossy fiber reorganization.
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PMID:The tissue plasminogen activator (tPA)/plasmin extracellular proteolytic system regulates seizure-induced hippocampal mossy fiber outgrowth through a proteoglycan substrate. 1072 41

The ability of the rodent brain to support plasticity-related phenomena declines with increasing age. Here we investigated the extent to which old rats retain the capacity to initiate transcription for immediate early genes, particularly as it relates to brain plasticity, in response to a strong stimulus. The intraperitoneal administration of pentylenetetrazole (PTZ) to rats of various ages evoked tonic-clonic seizures. Using an RNA gel-blot and in situ hybridization analysis, we found that 1 hour after the onset of seizure, messenger RNA (mRNA) for tissue plasminogen activator (TPA) was increased approximately 3.7-fold in the hippocampi of 3-month-old rats. The levels of TPA mRNA in the hippocampi and cortices of 3-month-old rats returned to control levels by 3 hours after PTZ administration. The levels of TPA mRNA increased 2.5-fold in the hippocampi of 18-month-old rats and 1.8-fold in the brains of the 28-month-old-rats at 3 hours and returned to basal levels by 15 hours following PTZ treatment. Quantitatively similar increases were calculated for the cortex. At peak induction the transcripts were localized throughout the cortical layers of the 3-month-old rats, whereas the TPA mRNA expression was restricted to cortical layer V of the older rats. Our results suggest that although the aging brain retains the capacity to respond to chemically induced seizures, the induction of TPA mRNA is temporarily delayed and the levels are diminished with increasing age. Because TPA has been implicated in neuronal plasticity, this finding suggests that immediate early genes are important factors in the limited plasticity of the aging brain.
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PMID:Delayed and blunted induction of mRNA for tissue plasminogen activator in the brain of old rats following pentylenetetrazole-induced seizure activity. 1081 11

The protective blood-brain barrier normally allows diffusion of small molecules such as oxygen and carbon dioxide, and transport of essential nutrients, but excludes large proteins and other blood constituents from the interstitial space of the CNS. However, head trauma, stroke, status epilepticus and other pathological conditions can all compromise the integrity of this barrier, and allow blood proteins as large as albumin to gain access to the extracellular spaces that surround neurons and glia. Given their possible entry into brain tissue during cerebrovascular insult, the effects of blood-derived proteases such as thrombin, tissue plasminogen activator and plasmin in the CNS have come under increasing scrutiny. Evidence now supports a role for serine proteases in the sequence of events that can lead to glial scarring, edema, seizure and neuronal death.
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PMID:Serine proteases and brain damage - is there a link? 1126 39

The ability of the rodent brain to support plasticity-related phenomena declines with increasing age. A decreased coordination of genes implicated in brain plasticity may be one factor contributing to this decline. Synaptic rearrangement that occurs after seizure activity is regarded as a model of brain plasticity. In a rat model of seizure-related brain plasticity, we found that the induction of immediate-early genes, as exemplified by c-fos and tissue plasminogen activator (TPA) is not impaired in the aged rat brain. However, the aged rat brain responded more slowly to chemically induced seizure and the levels of c-fos and TPA mRNAs induction are decreased in the cortex and in the hippocampus of 30-month-old rats, as compared to the levels expressed by 3-month-old rats. In addition, at the peak induction the TPA transcripts were restricted to certain cortical layers of the older rats. Surprisingly, in applying the same experimental paradigm to late genes we found that there was a shift toward earlier times in the maximum expression of growth-related molecule, the microtubule-associated protein 1B (MAP1B) mRNA, which was very evident in 18-month-old rats. Aberrant immunolabeling of MAP1B occurred in cortical layer VI of the aged rats where, unlike in young rats, there was heavy staining of neuronal somata. These results suggest that (i) one consequence of aging, besides decreases in the levels of mRNA, is a progressive loss of coordination in gene activity following the administration of a stimulus; (ii) since c-fos, TPA and MAP1B have been implicated in neuronal plasticity, these findings could explain, in part, the limited plasticity of the aging brain.
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PMID:Brain plasticity: to what extent do aged animals retain the capacity to coordinate gene activity in response to acute challenges. 1111 3

The ability of the rodent brain to support plasticity-related phenomena declines with increasing age. A decreased coordination of genes implicated in brain plasticity may be one factor contributing to this decline. Synaptic rearrangement that occurs after seizure activity is regarded as a model of brain plasticity. In a rat model of seizure-related brain plasticity, we found that the induction of immediate-early genes, as exemplified by c-fos and tissue plasminogen activator ( tPA), is not impaired in the aged rat brain. However, the aged rat brain responded more slowly to chemically induced seizure, and the levels of c-fos and tPA mRNAs induction are decreased in the cortex and in the hippocampus of 30 month old rats, as compared to the levels expressed by 3 month old rats. In addition, at the peak induction, the TPA transcripts were restricted to certain cortical layers of the older rats. Surprisingly, in applying the same experimental paradigm to late genes, we found that there was a shift toward earlier times in the maximum expression of growth-related molecules, the microtubule-associated protein 1B (MAP1B) mRNA, which was very evident in 18 month old rats. Aberrant immunolabeling of MAP1B occurred in cortical layer VI of the aged rats where, unlike in young rats, there was heavy staining of neuronal somata. These results suggest that (1) one consequence of aging, besides decreases in the levels of mRNA, is a progressive loss of coordination in gene activity following the administration of a stimulus; (2) since c-fos, TPA and MAP1B have been implicated in neuronal plasticity, these findings could explain, in part, the limited plasticity of the aging brain.
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PMID:Dynamics of gene expression for immediate early- and late genes after seizure activity in aged rats. 1139 67

Kindled seizures are widely used as a model for epileptogenesis. Although the achievement of kindling criterion is known to require time to develop, the precise developmental period has not been identified. We now report that optimal achievement of the kindling criterion in the Sprague-Dawley rat is associated with a critical inter-stimulus interval of 24 to 26 days. We show that highly efficient kindling can be achieved with only two subconvulsive doses of pentylenetetrazole so long as they are given 25 days apart. Using Northern blot hybridization we show that the increased seizure susceptibility at 25 days coincides with an increased expression of the plasticity-associated proteins, growth-associated protein-43 (GAP-43), microtubule-associated protein 1B (MAP1B), and tissue plasminogen activator (tPA) mRNAs in the hippocampus. By in situ hybridization and immunocytochemistry on tissue sections, we also show an increased expression for GAP-43 in the polymorphic layer of the dentate gyrus, mossy fibers, and pyramidal cells in the CA3 region of the hippocampus. The demonstration of a long, defined developmental interval for inducing the kindling criterion should enable a dissection of the cellular and genetic events underlying this phenomenon in the rat.
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PMID:Kindling status in sprague-dawley rats induced by pentylenetetrazole: involvement of a critical development period. 1259 35


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