Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42345 (mTOR)
 26,049 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the possible roles of the Akt/PKB-mTOR-p70S6K-S6 and cap-dependent translation (eIF4G) pathways in the pathogenesis of tuberous sclerosis complex (TSC)-associated cortical tubers and focal cortical dysplasia (FCD), we performed qualitative and semiquantitative immunohistochemical evaluation on surgically resected corticectomy specimens to detect phosphorylated molecules as activated downstream targets of the signaling pathways. A tissue microarray paraffin block was constructed from 63 archival specimens of surgically resected TSC tubers, FCDs with balloon cells, cortical dysplasia without balloon cells, and histologically normal-appearing neocortex obtained from cases with Rasmussen encephalitis, cystic-gliotic encephalopathy, and temporal lobe epilepsy. Abnormal neuroglial cells were positive for phospho-S6 and phospho-eIF4G with various staining intensities in FCDs and TSC tubers. Both proteins were much less abundantly expressed in normal-appearing neocortex. Phospho-mTOR expression was observed in neurons in all groups. The expression of phospho-S6 and phospho-eIF4G was associated with dysplastic lesions (p < 0.05), and the cytoplasmic phospho-p70S6K expression was most specific for and abundant in TSC tubers and much less prominent in other groups (p < 0.01). These results suggest that constitutive activation of cytoplasmic p70S6K plays a pivotal role in the pathogenesis of TSC tubers and that FCDs possess a distinct mechanism for activation of S6 and eIF4G.
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PMID:Insulin signaling pathways in cortical dysplasia and TSC-tubers: tissue microarray analysis. 1545 98

Understanding molecular mechanisms mediating epileptogenesis is critical for developing more effective therapies for epilepsy. We recently found that the mammalian target of rapamycin (mTOR) signaling pathway is involved in epileptogenesis, and mTOR inhibitors prevent epilepsy in a mouse model of tuberous sclerosis complex. Here, we investigated the potential role of mTOR in a rat model of temporal lobe epilepsy initiated by status epilepticus. Acute kainate-induced seizures resulted in biphasic activation of the mTOR pathway, as evident by an increase in phospho-S6 (P-S6) expression. An initial rise in P-S6 expression started approximately 1 h after seizure onset, peaked at 3-6 h, and returned to baseline by 24 h in both hippocampus and neocortex, reflecting widespread stimulation of mTOR signaling by acute seizure activity. After resolution of status epilepticus, a second increase in P-S6 was observed in hippocampus only, which started at 3 d, peaked 5-10 d, and persisted for several weeks after kainate injection, correlating with the development of chronic epileptogenesis within hippocampus. The mTOR inhibitor rapamycin, administered before kainate, blocked both the acute and chronic phases of seizure-induced mTOR activation and decreased kainate-induced neuronal cell death, neurogenesis, mossy fiber sprouting, and the development of spontaneous epilepsy. Late rapamycin treatment, after termination of status epilepticus, blocked the chronic phase of mTOR activation and reduced mossy fiber sprouting and epilepsy but not neurogenesis or neuronal death. These findings indicate that mTOR signaling mediates mechanisms of epileptogenesis in the kainate rat model and that mTOR inhibitors have potential antiepileptogenic effects in this model.
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PMID:The mammalian target of rapamycin signaling pathway mediates epileptogenesis in a model of temporal lobe epilepsy. 1981 12

Dentate granule cell axon (mossy fiber) sprouting is a common abnormality in patients with temporal lobe epilepsy. Mossy fiber sprouting creates an aberrant positive-feedback network among granule cells that does not normally exist. Its role in epileptogenesis is unclear and controversial. If it were possible to block mossy fiber sprouting from developing after epileptogenic treatments, its potential role in the pathogenesis of epilepsy could be tested. Previous attempts to block mossy fiber sprouting have been unsuccessful. The present study targeted the mammalian target of rapamycin (mTOR) signaling pathway, which regulates cell growth and is blocked by rapamycin. Rapamycin was focally, continuously, and unilaterally infused into the dorsal hippocampus for prolonged periods beginning within hours after rats sustained pilocarpine-induced status epilepticus. Infusion for 1 month reduced aberrant Timm staining (a marker of mossy fibers) in the granule cell layer and molecular layer. Infusion for 2 months inhibited mossy fiber sprouting more. However, after rapamycin infusion ceased, aberrant Timm staining developed and approached untreated levels. When onset of infusion began after mossy fiber sprouting had developed for 2 months, rapamycin did not reverse aberrant Timm staining. These findings suggest that inhibition of the mTOR signaling pathway suppressed development of mossy fiber sprouting. However, suppression required continual treatment, and rapamycin treatment did not reverse already established axon reorganization.
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PMID:Inhibition of the mammalian target of rapamycin signaling pathway suppresses dentate granule cell axon sprouting in a rodent model of temporal lobe epilepsy. 1955 65

Temporal lobe epilepsy is prevalent and can be difficult to treat effectively. Granule cell axon (mossy fiber) sprouting is a common neuropathological finding in patients with mesial temporal lobe epilepsy, but its role in epileptogenesis is unclear and controversial. Focally infused or systemic rapamycin inhibits the mammalian target of rapamycin (mTOR) signaling pathway and suppresses mossy fiber sprouting in rats. We tested whether long-term systemic treatment with rapamycin, beginning 1 d after pilocarpine-induced status epilepticus in mice, would suppress mossy fiber sprouting and affect the development of spontaneous seizures. Mice that had experienced status epilepticus and were treated for 2 months with rapamycin displayed significantly less mossy fiber sprouting (42% of vehicle-treated animals), and the effect was dose dependent. However, behavioral and video/EEG monitoring revealed that rapamycin- and vehicle-treated mice displayed spontaneous seizures at similar frequencies. These findings suggest mossy fiber sprouting is neither pro- nor anti-convulsant; however, there are caveats. Rapamycin treatment also reduced epilepsy-related hypertrophy of the dentate gyrus but did not significantly affect granule cell proliferation, hilar neuron loss, or generation of ectopic granule cells. These findings are consistent with the hypotheses that hilar neuron loss and ectopic granule cells might contribute to temporal lobe epileptogenesis.
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PMID:Rapamycin suppresses mossy fiber sprouting but not seizure frequency in a mouse model of temporal lobe epilepsy. 2130 69

Approximately 30% of all epilepsy cases are acquired. At present there is no effective strategy to stop epilepsy development after the precipitating insult. Recent data from experimental models pointed to the mTOR pathway, which can be potently inhibited by rapamycin. However, data on the antiepileptic and antiepileptogenic properties of rapamycin are conflicting. Therefore, we tested whether rapamycin post-treatment influences epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy in rats. Animals were treated with rapamycin (6mg/kg) or vehicle daily for 2 wks, beginning 24h after stimulation. Sham-operated animals were treated with rapamycin or vehicle but were not stimulated. Animals were video-EEG monitored to detect spontaneous seizures. Animals were sacrificed 4 wks later and brains were collected for Timm staining. There were no significant differences in the number of stimulated rats developing epilepsy; latency to first spontaneous seizure; number of seizures, or seizure frequency in epileptic animals. The area occupied by mossy fibers was significantly increased in stimulated vs. sham-operated animals but was not different in animals treated with rapamycin vs. vehicle. Collectively, our data suggest that the antiepileptic or antiepileptogenic action of rapamycin is not a universal phenomenon and might be limited to certain experimental models or experimental conditions.
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PMID:Post-treatment with rapamycin does not prevent epileptogenesis in the amygdala stimulation model of temporal lobe epilepsy. 2222 20

Recurrent excitatory circuits and abnormal recurrent excitatory inputs are essential in epileptogenesis. Studies in temporal lobe epilepsy have shown that mossy fiber sprouting, which represents synaptic reorganization, renders the formation of abnormal recurrent excitatory circuits and inputs. The mammalian target of rapamycin (mTOR) pathway has recently been proved important in mossy fiber sprouting. In the present study, rapamycin, a mTOR inhibiter, was injected into the mouse of temporal lobe epilepsy. Electrophysiological and histological properties of the hippocampus were investigated by whole cell patch clamp, extracellular recording and Timm staining. Following the development of epilepsy, frequency of spontaneous excitatory postsynaptic currents (EPSCs) and amplitude of antidromically evoked EPSCs in granule cells were remarkably increased, as well as the epileptiform activity and mossy fiber sprouting were detected, which indicated the formation of abnormal recurrent excitatory circuits. By the use of rapamycin, frequency of spontaneous EPSCs, amplitude of antidromically evoked EPSCs, the epileptiform activity and mossy fiber sprouting were all remarkably suppressed. Our findings suggested an anti-epileptogenic role of rapamycin by suppressing the recurrent excitatory circuits of dentate gyrus.
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PMID:Rapamycin suppresses the recurrent excitatory circuits of dentate gyrus in a mouse model of temporal lobe epilepsy. 2241 94

The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth, differentiation, proliferation, and metabolism. Loss-of-function mutations in upstream regulators of mTOR have been highly associated with dysplasias, epilepsy, and neurodevelopmental disorders. These include tuberous sclerosis, which is due to mutations in TSC1 or TSC2 genes; mutations in phosphatase and tensin homolog (PTEN) as in Cowden syndrome, polyhydramnios, megalencephaly, symptomatic epilepsy syndrome (PMSE) due to mutations in the STE20-related kinase adaptor alpha (STRADalpha); and neurofibromatosis type 1 attributed to neurofibromin 1 mutations. Inhibition of the mTOR pathway with rapamycin may prevent epilepsy and improve the underlying pathology in mouse models with disrupted mTOR signaling, due to PTEN or TSC mutations. However the timing and duration of its administration appear critical in defining the seizure and pathology-related outcomes. Rapamycin application in human cortical slices from patients with cortical dysplasias reduces the 4-aminopyridine-induced oscillations. In the multiple-hit model of infantile spasms, pulse high-dose rapamycin administration can reduce the cortical overactivation of the mTOR pathway, suppresses spasms, and has disease-modifying effects by partially improving cognitive deficits. In post-status epilepticus models of temporal lobe epilepsy, rapamycin may ameliorate the development of epilepsy-related pathology and reduce the expression of spontaneous seizures, but its effects depend on the timing and duration of administration, and possibly the model used. The observed recurrence of seizures and epilepsy-related pathology after rapamycin discontinuation suggests the need for continuous administration to maintain the benefit. However, the use of pulse administration protocols may be useful in certain age-specific epilepsy syndromes, like infantile spasms, whereas repetitive-pulse rapamycin protocols may suffice to sustain a long-term benefit in genetic disorders of the mTOR pathway. In summary, mTOR dysregulation has been implicated in several genetic and acquired forms of epileptogenesis. The use of mTOR inhibitors can reverse some of these epileptogenic processes, although their effects depend upon the timing and dose of administration as well as the model used.
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PMID:Finding a better drug for epilepsy: the mTOR pathway as an antiepileptogenic target. 2257 18

Mammalian target of rapamycin (mTOR) is a key protein kinase that regulates basic cellular processes, including development and growth. Mutations in mTOR cause tuberous sclerosis complex (TSC), a condition that is characterized by developmental brain malformations (cortical tubers) and epilepsy. Although considerable insight has been gained recently into the pathologic dysfunction of mTOR in tubers in TSC-related epilepsy, data on the mTOR cascade in mesial temporal lobe epilepsy (MTLE) are lacking. Immunohistochemical investigation with confocal microscopy was performed to evaluate mTOR cascade and to correlate its activity with cellular alterations observed in surgically resected samples of human neocortex and hippocampus in MTLE. We compared results in human tissue to findings in the rat pilocarpine model of sclerotic MTLE. In nonsclerotic and control hippocampus, many neurons in the CA1 subfield expressed high levels of phospho-S6 (p-S6), a reliable marker of mTOR activation. In nonsclerotic and control hippocampus, as well as in magnetic resonance imaging (MRI) normal human neocortex, protoplasmic astrocytes did not express p-S6. In contrast, in sclerotic hippocampus, prominent p-S6 immunostaining was observed mainly in astrocytes and microglia located in the areas of neuronal loss and astrogliosis, whereas neurons in preserved areas of CA1 expressed significantly lower levels of p-S6 immunopositivity than neurons in nonsclerotic or control CA1 subfields. In surgically resected neocortex with chronic astroglial scar tissue, only microglia revealed moderate p-S6 immunoreactivity. Different from human sclerotic epileptic hippocampus, astrogliosis in the chronic rat pilocarpine model of epilepsy was not characterized by glial cells with mTOR activation. The mTOR cascade is activated in astroglial cells in sclerotic MTLE, but not in astrocytes in chronic neocortical scarring or in the pilocarpine model of MTLE. These findings suggest that the astroglial "scar" in sclerotic MTLE has active, ongoing cellular changes. Targeting mTOR in MTLE may provide new pathways for the medical therapy of epilepsy.
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PMID:The mTOR pathway is activated in glial cells in mesial temporal sclerosis. 2261 12

Growing evidence from rodent models of temporal lobe epilepsy (TLE) indicates that dysregulation of the mammalian target of rapamycin (mTOR) pathway is involved in seizures and epileptogenesis. However, the role of the mTOR pathway in the epileptogenic process remains poorly understood. Here, we used an animal model of TLE and sclerotic hippocampus from patients with refractory TLE to determine whether cell-type specific activation of mTOR signaling occurs during each stage of epileptogenesis. In the TLE mouse model, we found that hyperactivation of the mTOR pathway is present in distinct hippocampal subfields at three different stages after kainate-induced seizures, and occurs in neurons of the granular and pyramidal cell layers, in reactive astrocytes, and in dispersed granule cells, respectively. In agreement with the findings in TLE mice, upregulated mTOR was observed in the sclerotic hippocampus of TLE patients. All sclerotic hippocampus (n = 13) exhibited widespread reactive astrocytes with overactivated mTOR, some of which invaded the dispersed granular layer. Moreover, two sclerotic hippocampus exhibited mTOR activation in some of the granule cells, which was accompanied by cell body hypertrophy. Taken together, our results indicate that mTOR activation is most prominent in reactive astrocytes in both an animal model of TLE and the sclerotic hippocampus from patients with drug resistant TLE.
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PMID:Mapping the spatio-temporal pattern of the mammalian target of rapamycin (mTOR) activation in temporal lobe epilepsy. 2276 30

Present medications for epilepsy have substantial limitations, such as medical intractability in many patients and lack of antiepileptogenic properties to prevent epilepsy. Drugs with novel mechanisms of action are needed to overcome these limitations. The mTOR signaling pathway has emerged as a possible therapeutic target for epilepsy. Preliminary clinical trials suggest that mTOR inhibitors reduce seizures in tuberous sclerosis complex (TSC) patients with intractable epilepsy. Furthermore, mTOR inhibitors have antiepileptogenic properties in preventing epilepsy in animal models of TSC. Besides TSC, accumulating preclinical data suggest that mTOR inhibitors may have antiseizure or antiepileptogenic actions in other types of epilepsy, including infantile spasms, neonatal hypoxic seizures, absence epilepsy and acquired temporal lobe epilepsy following brain injury, but these effects depend on a number of conditions. Future clinical and basic research is needed to establish whether mTOR inhibitors are an effective treatment for epilepsy.
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PMID:A critical review of mTOR inhibitors and epilepsy: from basic science to clinical trials. 2373 3


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