sirolimus and Spasm

The mechanistic target of the rapamycin (mTOR) pathway is involved in cortical development. However, the efficacy of mTOR inhibitors in malformations of cortical dysplasia (MCD) outside of the tuberous sclerosis complex is unknown. We selected the MCD rat model with prenatal MAM exposure to test the efficacy of mTOR inhibitors in MCDs. We explored the early cortical changes of mTOR pathway protein expression in rats aged P15. We also monitored the early treatment effect of the mTOR inhibitor, rapamycin, on N-methyl-D-aspartate (NMDA)-induced spasms at P15 and their behavior in the juvenile stage. In vivo MR spectroscopy was performed after rapamycin treatment and compared with vehicle controls. There was no difference in mTORC1 pathway protein expression between MAM-exposed MCD rats and controls at P15, and prolonged treatment of rapamycin had no impact on NMDA-induced spasms despite poor weight gain. Prenatal MAM-exposed juvenile rats treated with rapamycin showed increased social approaching and freezing behavior during habituation. MR spectroscopy showed altered neurometabolites, including Gln, Glu+Gln, Tau, and Cr. Despite behavioral changes and in vivo neurometabolic alteration with early prolonged rapamycin treatment, rapamycin had no effect on spasms susceptibility in prenatal MAM-exposed infantile rats with MCD without mTORC1 activation. For MAM-exposed MCD rats without mTORC1 activation, treatment options outside of mTOR pathway inhibitors should be explored.

Topics: Animals; Female; Malformations of Cortical Development; Mechanistic Target of Rapamycin Complex 1; N-Methylaspartate; Pregnancy; Rats; Seizures; Sirolimus; Spasm; TOR Serine-Threonine Kinases

Renal transplantation is the treatment of choice for patients with end-stage renal disease. While transplantation improves the quality of life and reduces the mortality risk for most patients when compared with maintenance dialysis, it introduces significant morbidity associated with induction and maintenance immune suppression. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, is frequently used as a second-line maintenance immunosuppressive agent in solid organ transplant recipients. Sirolimus may, however, have adverse vascular effects and has previously been shown to induce endothelial cell dysfunction and impaired nitric oxide production in vitro. Sirolimus-eluting coronary artery stents have been associated with rare reports of severe coronary artery vasospasm; however, systemic sirolimus therapy has not previously been associated with vasospastic complications.

Topics: Coronary Vasospasm; Coronary Vessels; Drug-Eluting Stents; Humans; Immunosuppressive Agents; Percutaneous Coronary Intervention; Quality of Life; Renal Dialysis; Sirolimus; Spasm; ST Elevation Myocardial Infarction; Treatment Outcome

Infantile spasms may evolve into persistent epilepsies including Lennox-Gastaut syndrome. We compared adult epilepsy outcomes in models of infantile spasms due to structural etiology (multiple-hit model) or focal cortical inflammation and determined the anti-epileptogenic effects of pulse-rapamycin, previously shown to stop spasms in multiple-hit rats.. Spasms were induced in 3-day-old male rats via right intracerebral doxorubicin/lipopolysaccharide (multiple-hit model) infusions. Controls and sham rats were used. Separate multiple-hit rats received pulse-rapamycin or vehicle intraperitoneally between postnatal days 4 and 6. In adult mice, video-EEG (electroencephalography) scoring for seizures and sleep and histology were done blinded to treatment.. Motor-type seizures developed in 66.7% of multiple-hit rats, usually from sleep, but were reduced in the pulse-rapamycin-treated group (20%, p = .043 vs multiple-hit) and rare in other groups (0-9.1%, p < .05 vs multiple-hit). Spike-and-wave bursts had a slower frequency in multiple-hit rats (5.4-5.8Hz) than in the other groups (7.6-8.3Hz) (p < .05); pulse rapamycin had no effect on the hourly spike-and-wave burst rates in adulthood. Rapamycin, however, reduced the time spent in slow-wave-sleep (17.2%), which was increased in multiple-hit rats (71.6%, p = .003). Sham rats spent more time in wakefulness (43.7%) compared to controls (30.6%, p = .043). Multiple-hit rats, with or without rapamycin treatment, had right more than left corticohippocampal, basal ganglia lesions. There was no macroscopic pathology in the other groups.. Structural corticohippocampal/basal ganglia lesions increase the risk for post-infantile spasms epilepsy, Lennox-Gastaut syndrome features, and sleep dysregulation. Pulse rapamycin treatment for infantile spasms has anti-epileptogenic effects, despite the structural lesions, and decreases the time spent in slow wave sleep.

Topics: Animals; Disease Models, Animal; Electroencephalography; Epilepsy; Lennox Gastaut Syndrome; Male; Mice; Rats; Seizures; Sirolimus; Spasm

Topics: Animals; Cell Death; Disease Models, Animal; Female; Hippocampus; N-Methylaspartate; Phosphatidylinositol 3-Kinase; Phosphorylation; Protein Kinase Inhibitors; Rats, Sprague-Dawley; Signal Transduction; Sirolimus; Spasm; TOR Serine-Threonine Kinases; Wortmannin