Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression

Lévy, M.; Boulle, Fabien; Steinbusch, Harry W.M.; Hove, Daniël L.A. van den; Kenis, Günter; Lanfumey, Laurence

doi:10.1007/s00213-018-4950-4

Cited by 210 publications

(123 citation statements)

References 367 publications

(428 reference statements)

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“…BDNF and GDNF, two important members of the neurotrophin family (Levy et al, 2018), are involved in the survival, differentiation, and growth of neurons (Halappa et al, 2018) and are considered two pivotal biomarkers of mood disorders. BDNF and GDNF participate in the neurobiology of depression and are involved in the therapeutic effects of antidepressants (Park and Lee, 2018).…”

Section: Discussionmentioning

confidence: 99%

N-Palmitoylethanolamide Exerts Antidepressant-Like Effects in Rats: Involvement of PPARα Pathway in the Hippocampus

Wang

et al. 2019

J Pharmacol Exp Ther

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N-Palmitoylethanolamide (PEA), an endocannabinoid-like molecule, participates in controlling behaviors associated with mental disorders as an endogenous neuroprotective factor. On the basis of accumulating evidence and our previous data, we tested the hypothesis that the antidepressantlike effects of PEA observed during chronic unpredictable mild stress (CUMS) are mediated by possible targets in the peroxisome proliferator-activated receptor alpha (PPARa) pathway. In this study, rats were subjected to 35 days of CUMS and treated with drugs such as PEA (2.5, 5.0, or 10 mg/kg, by mouth), fluoxetine (10 mg/kg, by mouth), or the combination of PEA and MK886 (1-[(4-chlorophenyl) methyl]-3-[(1,1-dimethylethyl) thio]-a,a-dimethyl-5-(1-methylethyl)-1H-indole-2-propanoic acid). After behavioral tests, the animals were sacrificed and their hippocampi were dissected for subsequent studies. PEA normalized weight gain, sucrose preferences, locomotor activity in an open-field test, and levels of the PPARa mRNA and protein in the hippocampus, and it reduced serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) levels in rats subjected to CUMS. PEA reversed the abnormal levels of several oxidative stress biomarkers and increased the concentrations of two neurotrophic factors in the hippocampus of CUMS-induced rats. In addition, PEA alleviated the decrease in hippocampal weight. However, the aforementioned effects of PEA were completely or partially abolished by MK886, a selective PPARa antagonist. On the basis of these findings, the PPARa pathway in the hippocampus is a possible target of the antidepressant effects of PEA, and the maintenance of a stable hypothalamicpituitary-adrenal axis, the antioxidant defenses, and normalization of neurotrophic factor levels in the hippocampus are involved in this process.

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Section: Discussionmentioning

confidence: 99%

N-Palmitoylethanolamide Exerts Antidepressant-Like Effects in Rats: Involvement of PPARα Pathway in the Hippocampus

Wang

et al. 2019

J Pharmacol Exp Ther

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“…Conversely, antidepressant intervention has been suggested to exert an important part of the antidepressant effects through regulation of neuroplasticity (Duman and Aghajanian 2012;Duman et al 2016). It is believed that various neurotrophins, a family of small peptide growth factors, regulate neuroplasticity, which include proliferation, differentiation, survival and death of neuronal cells and supporting tissue (Levy et al 2018). Brain-derived neurotrophic factor (BDNF), the predominant neurotrophin in the brain, binds to the tropomyosin receptor kinase B (TrkB) receptor and subsequently activates intracellular signalling pathways governing transcription and dendritic translation of proteins necessary for cellular survival, differentiation and learning/ memory formation in the hippocampus (Leal et al 2017).…”

Section: No Signalling and Neuroplasticity In Depressionmentioning

confidence: 99%

Nitric oxide signalling and antidepressant action revisited

et al. 2019

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Studies about the pathogenesis of mood disorders have consistently shown that multiple factors, including genetic and environmental, play a crucial role on their development and neurobiology. Multiple pathological theories have been proposed, of which several ultimately affects or is a consequence of dysfunction in brain neuroplasticity and homeostatic mechanisms. However, current clinical available pharmacological intervention, which is predominantly monoamine-based, suffers from a partial and lacking response even after weeks of continuous treatment. These issues raise the need for better understanding of aetiologies and brain abnormalities in depression, as well as developing novel treatment strategies. Nitric oxide (NO) is a gaseous unconventional neurotransmitter, which regulates and governs several important physiological functions in the central nervous system, including processes, which can be associated with the development of mood disorders. This review will present general aspects of the NO system in depression, highlighting potential targets that may be utilized and further explored as novel therapeutic targets in the future pharmacotherapy of depression. In particular, the review will link the importance of neuroplasticity mechanisms governed by NO to a possible molecular basis for the antidepressant effects.

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“…The delayed efficacy of antidepressants can be explained by the neurotrophic hypothesis, a new molecular theory in the pathogenesis of MDD that does not rule out, but rather strengthens, the previous monoaminergic theory. The neurotrophic hypothesis arises from evidence that revealed an action of antidepressant drugs on neurotrophins, a class of small proteins supporting neural survival in embryonic development and promoting differentiation, enabling axonal growth, driving nerve-growth direction, preserving the survival of mature neurons, and accelerating neurogenesis (Levy et al, 2018). In particular, antidepressant drugs are known to enhance neuronal trophism by counteracting the reduction of axon growth and the abnormalities in dendritic arborization and spine density observed in animal models of depression.…”

Section: Introductionmentioning

confidence: 99%

The Emerging Role of SGK1 (Serum- and Glucocorticoid-Regulated Kinase 1) in Major Depressive Disorder: Hypothesis and Mechanisms

et al. 2020

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Major depressive disorder (MDD) is a heterogeneous psychiatric disease characterized by persistent low mood, diminished interests, and impaired cognitive and social functions. The multifactorial etiology of MDD is still largely unknown because of the complex genetic and environmental interactions involved. Therefore, no established mechanism can explain all the aspects of the disease. In this light, an extensive research about the pathophysiology of MDD has been carried out. Several pathogenic hypotheses, such as monoamines deficiency and neurobiological alterations in the stress-responsive system, including the hypothalamic-pituitary-adrenal (HPA) axis and the immune system, have been proposed for MDD. Over time, remarkable studies, mainly on preclinical rodent models, linked the serum-and glucocorticoid-regulated kinase 1 (SGK1) to the main features of MDD. SGK1 is a serine/threonine kinase belonging to the AGK Kinase family. SGK1 is ubiquitously expressed, which plays a pivotal role in the hormonal regulation of several ion channels, carriers, pumps, and transcription factors or regulators. SGK1 expression is modulated by cell stress and hormones, including gluco-and mineralocorticoids. Compelling evidence suggests that increased SGK1 expression or function is related to the pathogenic stress hypothesis of major depression. Therefore, the first part of the present review highlights the putative role of SGK1 as a critical mediator in the dysregulation of the HPA axis, observed under chronic stress conditions, and its controversial role in the neuroinflammation as well. The second part depicts the negative regulation exerted by SGK1 in the expression of both the brain-derived neurotrophic factor (BDNF) and the vascular endothelial growth factor (VEGF), resulting in an anti-neurogenic activity. Finally, the review focuses on the antidepressant-like effects of anti-oxidative nutraceuticals in several preclinical model of depression, resulting from the restoration of the physiological expression and/or activity of SGK1, which leads to an increase in neurogenesis. In summary, the purpose of this review is a systematic analysis of literature depicting SGK1 as molecular junction of the complex mechanisms underlying the MDD in an effort to suggest the kinase as a potential biomarker and strategic target in modern molecular antidepressant therapy.

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Neurotrophic factors and neuroplasticity pathways in the pathophysiology and treatment of depression

Cited by 210 publications

References 367 publications

N-Palmitoylethanolamide Exerts Antidepressant-Like Effects in Rats: Involvement of PPARα Pathway in the Hippocampus

N-Palmitoylethanolamide Exerts Antidepressant-Like Effects in Rats: Involvement of PPARα Pathway in the Hippocampus

Nitric oxide signalling and antidepressant action revisited

The Emerging Role of SGK1 (Serum- and Glucocorticoid-Regulated Kinase 1) in Major Depressive Disorder: Hypothesis and Mechanisms

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