Antidepressive-like effects of rapamycin in animal models: Implications for mTOR inhibition as a new target for treatment of affective disorders

Cleary, C.; Lin-de, Jing; Hiscock, K.M.; Hadas, Itay; Belmaker, Robert H.; Agam, Galila; Flaisher-Grinberg, Shlomit; Einat, Haim

doi:10.1016/j.brainresbull.2008.03.005

Cited by 116 publications

(83 citation statements)

References 38 publications

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“…Interestingly, a deficit in the autophagy pathway was recently claimed to underlie the onset of mood disorders, while rapamycin as an autophagy inducer possesses antidepressant effects. 148 …”

Section: Lithium and Neuronal Progenitor Cellsmentioning

confidence: 97%

Autophagy, lithium, and amyotrophic lateral sclerosis

et al. 2009

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In this article we provide an overview of the intersection between amyotrophic lateral sclerosis (ALS) and the autophagy pathway and discuss the potential protective effects of lithium through mechanisms that recruit autophagy and other effects. The autophagy pathway is recruited during motor neuron (MN) death both in vitro and in vivo. Despite a few controversial issues concerning the significance (detrimental/protective) of autophagy in ALS, recent findings indicate a protective role. Lithium in low doses is a well-known autophagy inducer that clears misfolded proteins and altered mitochondria from MNs. Moreover, lithium preserves mitochondria and sustains their genesis. This effect is replicated by rapamycin, which is an autophagy inducer but with a different mechanism from lithium. Lithium also increases the number of Renshaw cells that are affected early during the progression of experimental ALS. Again, lithium has been reported to decrease glial proliferation in the ALS spinal cord and induces sprouting in corticospinal fibers. Muscle Nerve 40: 173-194, 2009.

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Section: Lithium and Neuronal Progenitor Cellsmentioning

confidence: 97%

Autophagy, lithium, and amyotrophic lateral sclerosis

et al. 2009

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“…Many antidepressants like sertraline activate mTOR. However, antidepressant activity of rapamycin (an mTOR inhibitor) has also been reported in an animal model [63] . Moreover, autophagic markers, such as beclin1, are increased following antidepressant treatment in mouse brain [64] .…”

Section: Antidepressants and Autophagymentioning

confidence: 99%

Molecular network of neuronal autophagy in the pathophysiology and treatment of depression

Jia

Le²

2015

Neurosci. Bull.

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Major depressive disorder (MDD) is a complicated multifactorial induced disease, characterized by depressed mood, anhedonia, fatigue, and altered cognitive function. Recently, many studies have shown that antidepressants regulate autophagy. In fact, autophagy, a conserved lysosomal degradation pathway, is essential for the central nervous system. Dysregulation of autophagic pathways, such as the mammalian target of rapamycin (mTOR) signaling pathway and the beclin pathway, has been studied in neurodegenerative diseases. However, autophagy in MDD has not been fully studied. Here, we discuss whether the dysregulation of autophagy contributes to the pathophysiology and treatment of MDD and summarize the current evidence that shows the involvement of autophagy in MDD.

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“…As both AMI and CIT showed moderate increases in the expression of autophagic markers paralleled by enhanced protein turnover, we suggest that these compounds could represent potential candidates controlling the turnover of aggregate-prone proteins in neurodegenerative disorders. Of note, rapamycin exerts antidepressive-like effects in animal models, suggesting that autophagy might not solely be a promising target for the treatment of neurodegenerative, but also psychiatric, conditions (Cleary et al, 2008b;Cleary et al, 2008a). Apart from an imbalance of the neurotransmitter homeostasis, aberrant metabolic as well as immune-related functions are thought to contribute to the pathogenesis of affective disorders.…”

Section: Discussionmentioning

confidence: 99%

Antidepressant Drugs Diversely Affect Autophagy Pathways in Astrocytes and Neurons—Dissociation from Cholesterol Homeostasis

Zschocke

Zimmermann

Berning

et al. 2011

Neuropsychopharmacol

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In the search for antidepressants' (ADs') mechanisms of action beyond their influence on monoaminergic neurotransmission, we analyzed the effects of three structurally and pharmacologically different ADs on autophagic processes in rat primary astrocytes and neurons. Autophagy has a significant role in controlling protein turnover and energy supply. Both, the tricyclic AD amitriptyline (AMI) and the selective serotonin re-uptake inhibitor citalopram (CIT) induced autophagy as mirrored by pronounced upregulation and cellular redistribution of the marker LC3B-II. Redistribution was characterized by formation of LC3B-II-positive structures indicative of autophagosomes, which associated with AVs in a time-dependent manner. Deletion of Atg5, representing a central mediator of autophagy in MEFs, led to abrogation of AMI-induced LC3B-I/II conversion. By contrast, VEN, a selective serotonin and noradrenaline reuptake inhibitor, did not promote autophagic processes in either cell type. The stimulatory impact of AMI on autophagy partly involved class-III PI3 kinase-dependent pathways as 3-methyladenine slightly diminished the effects of AMI. Autophagic flux as defined by autophagosome turnover was vastly undisturbed, and degradation of long-lived proteins was augmented upon AMI treatment. Enhanced autophagy was dissociated from drug-induced alterations in cholesterol homeostasis. Subsequent to AMI-and CIT-mediated autophagy induction, neuronal and glial viability decreased, with neurons showing signs of apoptosis. In conclusion, we report that distinct ADs promote autophagy in neural cells, with important implications on energy homeostasis.

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Antidepressive-like effects of rapamycin in animal models: Implications for mTOR inhibition as a new target for treatment of affective disorders

Cited by 116 publications

References 38 publications

Autophagy, lithium, and amyotrophic lateral sclerosis

Autophagy, lithium, and amyotrophic lateral sclerosis

Molecular network of neuronal autophagy in the pathophysiology and treatment of depression

Antidepressant Drugs Diversely Affect Autophagy Pathways in Astrocytes and Neurons—Dissociation from Cholesterol Homeostasis

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