Our pharmacokinetic studies show that rapamycin RAD001 brain levels are about 1 that of systemic levels at 48 hours after the last dose, in both acute and chronic treatment paradigms. These findings are consistent with the obvious treatment benefit observed. When treatment is discontinued the build up of every drug that’s seen with time in the brain might serve as a reservoir Celecoxib ic50 for slow release. This phenomenon can help to explain the extended symptom free interval and survival seen after drug withdrawal at P30 in the treated mice. Although rapamycin/RAD001 levels achieved in these mice were significantly greater than are generally sought in patients, it’s significant a lower dose of drug has been used to achieve both reduced therapeutic range brain levels and concurrent large therapeutic range plasma levels. This is in line with more limited studies Urogenital pelvic malignancy we’ve done, by which both rapamycin and RAD001 at 1 or 3 mg/kg given 3 times to IP weekly resulted in clear therapeutic advantage in this model. Loss of TSC1/TSC2 is now well known to result in constitutive level of Rheb GTP levels and resultant constitutive activation of mTORC1, which in turn causes transcriptional outcomes to influence cell size increase and growth by phosphorylation and activation of S6Kinase, and phosphorylation and inactivation of 4E BP1. In addition to these direct or downstream effects, TSC1/TSC2 damage also results in indirect effects that limit the phosphorylation and activation of AKT. This is actually the first work to show these complicated effects of loss of Tsc1/Tsc2 within the head, with strong AKT down regulation viewed concurrent with activation of mTORC1. Rapamcyin/RAD001 had notable activity in preventing both direct and indirect ramifications of mTORC1 service, restoring Akt phosphorylation. Though it’s difficult due to the existence of three different AKT isoforms with varying expression levels in several tissues, paid off AKT expression continues to be engineered in mice. Rats with significant lowering of brain AKT expression have a significant phenotype with microcephaly and size and reduced numbers of neurons, though neurologic and behavioral problems have not been investigated in detail. Paid down AKT term contributes to an important decrease in pAKT levels in these brains, while pTsc2 and pGSK3B levels were near normal. Once we see the opposite clinical phenotype in the Tsc1null neuron mice, with brain and neuronal development, it’s obvious why these potential effects of AKT down regulation are overcome by the effects of mTORC1 activation within the Tsc1null neuron mice.