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Metabolism master switch

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Metabolism master switch

  1. 1. What is mTOR and why is it a “hot topic” in psychiatry today?The micro-universe that we are all made of, the cell, can be in two metabolic states, anabolism orcatabolism. In times of famine(caloric restriction), catabolism prevails-also called autophagy. Intimes of plenty, anabolism prevails, manifested by protein synthesis, glucose uptake,angiogenesis and cell proliferation.The scientists were able to locate in the cells, including neurons, the master molecular switchbetween anabolism and catabolism.Mammalian target of rapamycin (mTOR), a kinase, is the cells’ master switch foranabolism/catabolism, protein synthesis, caloric intake and response to stress. For thisreason it is of interest to oncologists, psychiatrists and aging researchers alike.mTOR IS THE CELLULAR ANABOLISM/CATABOLISM SWITCHRapamycin is able to turn the metabolic switch OFF (catabolism), while ketamine turns theswitch ON (anabolism). Longevity specialists acknowledge only two life-extending interventions in mammals: calorierestriction and genetic manipulation. Inhibition of mTOR by rapamycin mimics calorierestriction by shutting down the same molecular pathway as restricted caloric intake does.Experiments showed increased longevity (10% -28%) in mice fed a special diet containingrapamycin.
  2. 2. Currently rapamycin is in clinical trials for Alzheimer’s disease and other neurodegenerativediseases. By increasing brain autophagy (catabolism) , rapamycin seems to clear out amyloidplaques. Rapamycin (Sirolimus) is an immunosuppressant drug used for preventing rejection in organtransplantation. In addition to its immunosuppressant action rapamycin has antiproliferativeproperties and is used in cancer therapy.IMPLICATIONS FOR PSYCHIATRYSeveral clinical studies showed that a single sub-anesthetic dose of ketamine( activator ofmTOR) caused a rapid antidepressant effect within hours of administration in treatment-refractory patients with major depression.Ketamine is known to produce psychosis as well as cognitive impairment (by blocking NMDAreceptors), yet it can improve depression in at least a subset of patients.Ketamine is an antagonist at NMDA receptors. It works at the same site (insidethe channel) where PCP also binds.
  3. 3. Hints about NMDA receptor antagonists causing improvement in depression existed since 1959(reported by Crane).In 2000 Berman et al. reported antidepressant effects from NMDA receptor antagonists.More recently Carlos Zarate, at NIMH, reported in 2010 that “ robust and rapid antidepressanteffects resulted from a single intravenous dose of ketamine”.On August 30, 2010 Ron Duman from Yale identified cellular signaling pathway in rat prefrontalcortex activated by ketamine with a rapid and direct influence on behavior. This group reportedthat a single dose of ketamine activates the mammalian target of the rapamycin (mTOR)signaling pathway, resulting in increased synaptic protein expression within 2 hours andincreased dendritic spine density and synaptic activity within 24 hours.On the other hand inhibition of mTOR through infusion of rapamycin completely blockedketamine’s influence on synaptic protein synthesis, synaptogenesis, and dendritic spineformation.Depression seems to occur when dendritic spine formation is inhibited, while increaseddendritic spine formation has been associated with euthymic states. Ketamine leads toincreased dendritic spine density within minutes from infusion, by turning ON the mTOR switchto catabolism.Dendritic spines grow within minutes from ketamine infusion causing improvement in depressivesymptoms.
  4. 4. Available antidepressants cause growth of dendritic spines.Aberant TOR activity was found not only in depression, but also in diabetes, obesity, heart disease,muscle degeneration and cancer.Reason enough for excitement among many specialties.A.Sfera

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