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Rapamycin acts in the brain to decrease body weight gain. A and B: RAP i.c.v. injection (Day 0, broken line) induces a transient decrease in body weight gain (A), which results in prolonged shift in body weight (B). C: Food intake is inhibited by RAP i.c.v. D: Food efficiency is inhibited by RAP i.c.v. *p,0.05, **p,0.01, ***p,0.001 (two-way Mixed-ANOVA). doi:10.1371/journal.pone.0093691.g007
Source publication
Manipulation of body weight set point may be an effective weight loss and maintenance strategy as the homeostatic mechanism governing energy balance remains intact even in obese conditions and counters the effort to lose weight. However, how the set point is determined is not well understood. We show that a single injection of rapamycin (RAP), an m...
Contexts in source publication
Context 1
... i.c.v. (n = 9) reduced the daily weight gain, FI and FE transiently (Fig.7A,C,D) and cumulative weight gain for up to 15 days compared to those that received equal volume (1 mL) of VEH i.c.v. ...
Context 2
... = 9) reduced the daily weight gain, FI and FE transiently (Fig.7A,C,D) and cumulative weight gain for up to 15 days compared to those that received equal volume (1 mL) of VEH i.c.v. (n = 11) (Fig.7B). There was some delay in the effect; suppression of FI and cumulative weight gain became significant on Day 2 and Day 4 post-injection, respectively. ...
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Citations
... A high peak concentration may affect neurons, protected by the blood brain barrier, and stem cells in their niches. A high single dose of rapamycin was shown to maintain lower body weight by shifting the set point long-term in rats [45]. ...
Both individuals taking rapamycin, an anti-aging drug, and those not taking it will ultimately succumb to age-related diseases. However, the former, if administered disease-oriented dosages for a long time, may experience a delayed onset of such diseases and live longer. The goal is to delay a particular disease that is expected to be life-limiting in a particular person. Age-related diseases, quasi-programmed during development, progress at varying rates in different individuals. Rapamycin is a prophylactic anti-aging drug that decelerates early development of age-related diseases. I further discuss hyperfunction theory of quasi-programmed diseases, which challenges the need for the traditional concept of aging itself.
... Supporting the notion of rapamycin-induced reprogramming, previous studies found that (a) even transient treatment with rapamycin can extend lifespan [27,36,39] (b) a single rapamycin injection can lower body weight set point in the long run [42] and (c) rapamycin can affect the mTOR pathway activity long term by preventing obesity [43,44]. ...
... Independently, rapamycin itself has equivocal antidepressant effects [34] . However, systemic alterations in metabolic and inflammatory activity have been observed in humans and animals, lasting months after a single dose [35,36] . Mechanistically, mTORC1 acts as a rheostat, creating a "set-point" for baseline inflammatory and growth activity based on the availability of nutrients and environmental conditions [28] . ...
While psychedelic-assisted therapies are currently being studied for several indications in clinical trials, there is legal and ethical ambiguity for mental health professionals concerning these compounds. Seventy-six mental health professionals completed an online survey asking them to rank their interest in topics related to psychedelic therapy, research, legal obstacles, barriers to incorporating psychedelics in practice, and terminology related to the field. Results showed that providers want more clearly defined terminology and operating procedures concerning business matters such as malpractice and clinic guidelines, legal and ethical clarity on administering psychedelics in private practice and integration work, and further opportunities for psychedelic therapy training. The survey responses were reflected upon through the legal and ethical lens of the current psychedelic landscape.
... Even a single dose has long lasting effects. For example, a single administration decreases weight gain for at least 10 weeks, by shifting the set point long-term [161]. Rapamycin treatment for 2 weeks in young mice results in long-term preservation of primordial follicles and prolongation of ovarian lifespan in old mice [162]. ...
Senolytics are basically anti-cancer drugs, repurposed to kill senescent cells selectively. It is even more difficult to selectively kill senescent cells than to kill cancer cells. Based on lessons of cancer therapy, here I suggest how to exploit oncogene-addiction and to combine drugs to achieve selectivity. However, even if selective senolytic combinations will be developed, there is little evidence that a few senescent cells are responsible for organismal aging. I also discuss gerostatics, such as rapamycin and other rapalogs, pan-mTOR inhibitors, dual PI3K/mTOR inhibitors, which inhibit growth- and aging-promoting pathways. Unlike senolytics, gerostatics do not kill cells but slow down cellular geroconversion to senescence. Numerous studies demonstrated that inhibition of the mTOR pathways by any means (genetic, pharmacological and dietary) extends lifespan. Currently, only two studies demonstrated that senolytics (fisetin and a combination Dasatinib plus Quercetin) extend lifespan in mice. These senolytics slightly inhibit the mTOR pathway. Thus, life extension by these senolytics can be explained by their slight rapamycin-like (gerostatic) effects.
... The LD50 of rapamycin, a measure of drug lethality, could not be measured in rats as it was higher than 2500 mg/kg. A single dose of rapamycin is safe, but sufficient to prolong life and reduce obesity in various rodent models (36,49). Moreover, temporary treatment with rapamycin can be long lasting, prolong life and prevent obesity long after drug withdrawal (50)(51)(52)(53)(54). Another restriction in dose selection is the negative effects of rapamycin and its analogs on spermatogenesis. ...
Objective:Testicle torsion/detorsion cause ischemia. Rapamycin has immune suppressive and antioxidant defense mechanisms. Nucleolar-organizing regions(NORs) are loops of ribosomal DNA. Methods: To evaluate mean AgNOR number and total AgNOR area/total nuclear area(TAA/TNA) ratio and the relation between these proteins and rapamycin in the Torsion/Detorsion process of testes. The six groups as control, sham, early and late torsion-detorsion (ETD<D) groups, and early and late rapamycin treatment groups (ETD+R<D+R) were included. The TAA/TNA and mean AgNOR number of testes cells and biochemical analysis of GPx, SOD, and TBARS activities were detected. Results: Significant differences were detected among the groups for mean AgNOR number and TAA/TNA(p<0.05). For both mean AgNOR number and TAA/TNA, significant differences were found between control and ETD, between control and ETD+R, between control and LTD, between control and LTD+R. Also, a statistically significant relationship between both mean AgNOR numbers and TAA/TNA of testes cells and all the antioxidant enzymes (SOD, TBARS, and GPX) were detected(p<0.05). Conclusion: We may obtain information about the levels and duration of testes injury considering the levels of these proteins. Thus it can be said that these proteins may be used in the development of new and more effective therapeutic approaches to prevent the negative effects of T/D injury.
... In addition to these effects on freezing behavior, we found that the protein synthesis inhibitors (i.e., rapamycin, anisomycin, and cycloheximide) had long-lasting effects on body weight. After a single injection, animals in the drug conditions gained significantly less weight than vehicle controls over a period of several days, in line with prior studies [47,48]. Last but not least, we investigated whether we were able to interfere with consolidation, rather than reconsolidation (experiment 8). ...
Background
Long-term memory formation is generally assumed to involve the permanent storage of recently acquired memories, making them relatively insensitive to disruption, a process referred to as memory consolidation. However, when retrieved under specific circumstances, consolidated fear memories are thought to return to a labile state, thereby opening a window for modification (e.g., attenuation) of the memory. Several interventions during a critical time frame after this destabilization seem to be able to alter the retrieved memory, for example by pharmacologically interfering with the restabilization process, either by direct protein synthesis inhibition or indirectly, using drugs that can be safely administered in patients (e.g., propranolol). Here, we find that, contrary to expectations, systemic pharmacological manipulations in auditory fear-conditioned rats do not lead to drug-induced post-retrieval amnesia.
Results
In a series of well-powered auditory fear conditioning experiments (four with propranolol, 10 mg/kg, two with rapamycin, 20–40 mg/kg, one with anisomycin, 150 mg/kg and cycloheximide, 1.5 mg/kg), we found no evidence for reduced cued fear memory expression during a drug-free test in adult male Sprague-Dawley rats that had previously received a systemic drug injection upon retrieval of the tone fear memory. All experiments used standard fear conditioning and reactivation procedures with freezing as the behavioral read-out (conceptual or exact replications of published reports) and common pharmacological agents. Additional tests confirmed that the applied drug doses and administration routes were effective in inducing their conventional effects on expression of fear (propranolol, acutely), body weight (rapamycin, anisomycin, cycloheximide), and consolidation of extinction memories (cycloheximide).
Conclusions
In contrast with previously published studies, we did not find evidence for drug-induced post-retrieval amnesia, underlining that this effect, as well as its clinical applicability, may be considerably more constrained and less readily reproduced than what the current literature would suggest.
... As already mentioned, no group differences regarding locomotor activity quantified by the total distance covered on the EPM, were seen. Chronic (Deblon et al., 2012) and acute (Hebert et al., 2014) systemic administration of rapamycin indeed reduced both, food intake and body weight gain in free-feeding animals. But, these effects which were most probably mediated via inhibited mTORC1 signaling in the hypothalamus (Cota et al., 2006;Toklu et al., 2016) and have been observed without apparent signs of malaise (Hebert et al., 2014). ...
... Chronic (Deblon et al., 2012) and acute (Hebert et al., 2014) systemic administration of rapamycin indeed reduced both, food intake and body weight gain in free-feeding animals. But, these effects which were most probably mediated via inhibited mTORC1 signaling in the hypothalamus (Cota et al., 2006;Toklu et al., 2016) and have been observed without apparent signs of malaise (Hebert et al., 2014). Likewise, no distaste behavior towards rapamycin was found in conditioned taste avoidance procedures (Herbert and Cohen, 1993;Lückemann et al., 2019). ...
Psychiatric symptoms as seen in affective and anxiety disorders frequently appear during glioblastoma (GBM) treatment and disease progression, additionally deteriorate patient's daily life routine. These central comorbidi-ties are difficult to recognize and the causes for these effects are unknown. Since overactivation of mechanistic target of rapamycin (mTOR)-signaling is one key driver in GBM growth, the present study aimed at examining in rats with experimentally induced GBM, neurobehavioral consequences during disease progression and therapy. Male Fisher 344 rats were implanted with syngeneic RG2 tumor cells in the right striatum and treated with the mTOR inhibitor rapamycin (3 mg/kg; once daily, for eight days) before behavioral performance, brain protein expression, and blood samples were analyzed. We could show that treatment with rapamycin diminished GBM tumor growth, confirming mTOR-signaling as one key driver for tumor growth. Importantly, in GBM ani-mals' anxiety-like behavior was observed but only after treatment with rapamycin. These behavioral alterations were moreover accompanied by aberrant glucocorticoid receptor, phosphorylated p70 ribosomal S6 kinase alpha (p-p70s6k), and brain derived neurotrophic factor protein expression in the hippocampus and amygdala in the non-tumor-infiltrated hemisphere of the brain. Despite the beneficial effects on GBM tumor growth, our findings indicate that therapy with rapamycin impaired neurobehavioral functioning. This experimental approach has a high translational value. For one, it emphasizes aberrant mTOR functioning as a central feature mechanistically linking complex brain diseases and behavioral disturbances. For another, it highlights the importance of elaborating the cause of unwanted central effects of immunosuppressive and antiproliferative drugs used in transplan-tation medicine, immunotherapy, and oncology.
... In addition to its lifespan-extending properties, additional studies have shown that rapamycin can ameliorate age-related disease phenotypes in cell-based models of cancer [184][185][186], CVD [187,188], premature aging diseases (e.g., HGPS [189][190][191]), and ND [192]. These findings can be recapitulated at the organismal level, including in ND (e.g., amyotrophic lateral sclerosis [193], tauopathies [194], Alzheimer's disease [195][196][197], Parkinson's disease [198]), cancer [199,200], obesity [201], disrupted circadian clock [202,203], and laminopathies [204,205]. Furthermore, rapamycin pretreatment improves the success of pancreatic islet cell engraftment through the inhibition of inflammatory chemokines in mice models and human patients with type I diabetes [206]. ...
Caloric restriction (CR), the reduction of caloric intake without inducing malnutrition, is the most reproducible method of extending health and lifespan across numerous organisms, including humans. However, with nearly one-third of the world's population overweight, it is obvious that caloric restriction approaches are difficult for individuals to achieve. Therefore, identifying compounds that mimic CR is desirable to promote longer, healthier lifespans without the rigors of restricting diet. Many compounds, such as rapamycin (and its derivatives), metformin, or other naturally occurring products in our diets (nutraceuticals), induce CR-like states in laboratory models. An alternative to CR is the removal of specific elements (such as individual amino acids) from the diet. Despite our increasing knowledge of the multitude of CR approaches and CR mimetics, the extent to which these strategies overlap mechanistically remains unclear. Here we provide an update of CR and CR mimetic research, summarizing mechanisms by which these strategies influence genome function required to treat age-related pathologies and identify the molecular fountain of youth.
... The day after auditory fear conditioning, at the start of the active (dark) cycle between 1800 and 1900 and prior to extinction training, rats in the Sedentary and Run groups were randomly chosen to receive a microinjection of rapamycin (RAP; N = 20; 50.0 μg in 2.0 μl dimethyl sulfoxide (DMSO) solution) or vehicle (Veh; N = 20; DMSO) through the guide cannula into the lateral ventricle. The dose and concentration of RAP was chosen based on other studies that have successfully blocked mTOR signaling using an ICV injection of RAP (Cota, Proulx, Smith, Kozma, & Thomas, 2006, Hebert, Licursi, Jensen, Baker, & Milway, 2014. During microinjections, rats were lightly held in a towel, the dummy cannulae were removed, and an injector tip was inserted through the guide cannula to deliver the injection. ...
Impaired fear extinction, combined with the likelihood of fear relapse after exposure therapy, contributes to the persistence of many trauma-related disorders such as anxiety and post-traumatic stress disorder. Identifying mechanisms to aid fear extinction and reduce relapse could provide novel strategies for augmentation of exposure therapy. Exercise can enhance learning and memory and augment fear extinction of traumatic memories in humans and rodents. One factor that could contribute to enhanced fear extinction following exercise is the mammalian target of rapamycin (mTOR). mTOR is a translation regulator involved in synaptic plasticity and is sensitive to many exercise signals such as monoamines, growth factors, and cellular metabolism. Further, mTOR signaling is increased after chronic exercise in brain regions involved in learning and emotional behavior. Therefore, mTOR is a compelling potential facilitator of the memory-enhancing and overall beneficial effects of exercise on mental health. The goal of the current study is to test the hypothesis that mTOR signaling is necessary for the enhancement of fear extinction produced by acute, voluntary exercise. We observed that in-tracerebral-ventricular administration of the mTOR inhibitor rapamycin reduced immunoreactivity of phos-phorylated S6, a downstream target of mTOR, in brain regions involved in fear extinction and eliminated the enhancement of fear extinction memory produced by acute exercise, without reducing voluntary exercise behavior or altering fear extinction in sedentary rats. These results suggest that mTOR signaling contributes to exercise-augmentation of fear extinction.
... https://doi.org/10.1101/2020.07.08.193383 doi: bioRxiv preprint inhibitors (i.e., rapamycin, anisomycin and cycloheximide) had long-lasting effects on body weight. After a single injection, animals in the drug conditions gained significantly less weight than vehicle controls over a period of several days, in line with prior studies (Adamec, Strasser, Blundell, Burton, & McKay, 2006;Hebert et al., 2014). Last but not least, we investigated whether we were able to interfere with consolidation, rather than reconsolidation (Experiment 8). ...
When retrieved under specific circumstances, consolidated fear memories are thought to return to a labile state, thereby opening a window for modification (e.g., attenuation) of the memory. Several interventions during a critical time frame after this destabilization seem to be able to alter the retrieved memory, for example through pharmacological interference with the restabilization process, either by direct protein synthesis inhibition or indirectly, using drugs that can be safely administered in patients (e.g., propranolol).
In a series of well-powered auditory fear conditioning experiments (four with propranolol, 10 mg/kg, two with rapamycin, 20-40 mg/kg, one with anisomycin, 150 mg/kg and cycloheximide, 1.5 mg/kg), we found no evidence for reduced cued fear memory expression during a drug-free test in adult male Sprague-Dawley rats that had previously received a systemic drug injection upon retrieval of the tone fear memory. All experiments used standard fear conditioning and reactivation procedures with freezing as the behavioral read-out (conceptual or exact replications of published reports) and common pharmacological agents. Additional tests confirmed that the applied drug doses and administration routes were effective in inducing their conventional effects on expression of fear (propranolol, acutely), body weight (rapamycin, anisomycin, cycloheximide) and consolidation of extinction memories (cycloheximide).
Thus, in contrast with most published studies, we did not find evidence for drug-induced post-retrieval amnesia, underlining that this effect, as well as its clinical applicability, may be considerably more constrained and less readily reproduced than what the current literature would suggest.
Highlights
We aimed to replicate post-retrieval amnesia for auditory fear memories in rats
We performed a series of well-powered pharmacological interference experiments
Propranolol, rapamycin, anisomycin or cycloheximide was injected upon retrieval
Bayesian stats found substantial evidence for the absence of post-retrieval amnesia
The effect is less reproducible and generalizable than what the literature suggests
