Shared pathways for neuroprogression and somatoprogression in neuropsychiatric disorders

Morris, Gerwyn; Puri, Basant K.; Walker, Adam J.; Maes, Michaël; Carvalho, André F.; Bortolasci, Chiara C.; Walder, Ken; Berk, Michael

doi:10.1016/j.neubiorev.2019.09.025

Cited by 90 publications

(68 citation statements)

References 383 publications

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“…Neuroin ammation is closely associated with the pathophysiology of various neurological disorders, including primary and secondary depression, Parkinson's disease and Alzheimer's disease [22,23]. Newgeneration antidepressants, SSRIs and SNRIs, are wildly used in treatment of depressive symptoms, whereas the mechanisms remain to be further deciphered in regard with how they function and why they display differential e cacies.…”

Section: Discussionmentioning

confidence: 99%

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation

Liu

Peng

et al. 2020

Preprint

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Background: Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used new-generation drugs for depression. Depressive symptoms are thought to be closely related to neuroinflammation. In this study, we used up-to-date protocols of culture and stimulation and aimed to understand how astrocytes respond to the antidepressants. Methods: Primary astrocytes were isolated and cultured using neurobasal-based serum free medium. The cells were treated with a cytokine mixture comprising complement component 1q, tumor necrosis factor α and interleukin 1α with or without pretreatments of antidepressants. Cell viability, phenotypes, inflammatory responses and the underlying mechanisms were analyzed. Results: All the SSRIs, including paroxetine, fluoxetine, sertraline, citalopram, and fluvoxamine, show a visible cytotoxicity within the range of applied doses, and a paradoxical effect on astrocytic inflammatory responses as manifested by the promotion of inducible nitric oxide synthase (iNOS) and/or nitric oxide (NO) and the inhibition of interleukin 6 (IL-6) and/or interleukin 1β (IL-1β). The SNRI venlafaxine was the least toxic to astrocytes and inhibited the production of IL-6 and IL-1β but with no impact on iNOS and NO. All the drugs had no regulation on the polarization of astrocytic A1 and A2 types. Mechanisms associated with the antidepressants in astrocytic inflammation route via inhibition of JNK1 activation and STAT3 basal activity. Conclusions: The study demonstrated that the antidepressants possess differential cytotoxicity to astrocytes and function differently, also paradoxically for the SSRIs, to astrocytic inflammation. Our results provide novel pieces into understanding the differential efficacy and tolerability of the antidepressants in treating patients in the context of astrocytes.

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Section: Discussionmentioning

confidence: 99%

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation

Liu

Peng

et al. 2020

Preprint

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“…Increased leptin in the brain may result in improved function of K ATP channels, inhibition of AMPA receptors, and improved function of NMDA receptors via a mechanism dependent on increased PI3K signaling [340,341]. Reduced levels of insulin in the periphery in patients with metabolic syndrome or type 2 diabetes mellitus, frequently seen in patients with neuroprogressive disorders [342], can also exert neuroprotective effects by reducing the translocation of ceramide into the CNS which is often described as the liver-brain axis of neurodegeneration (reviewed by [343]). The range of neuroprotective effects potentially resulting from a metabolic state of increased leptin and reduced insulin in the periphery and the mechanisms involved are numerous and readers interested in pursuing this area are invited to consult an excellent review of the subject by [339].…”

Section: Caveats and Uncertaintymentioning

confidence: 99%

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

et al. 2020

Self Cite

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Nutritional ketosis, induced via either the classical ketogenic diet or the use of emulsified medium-chain triglycerides, is an established treatment for pharmaceutical resistant epilepsy in children and more recently in adults. In addition, the use of oral ketogenic compounds, fractionated coconut oil, very low carbohydrate intake, or ketone monoester supplementation has been reported to be potentially helpful in mild cognitive impairment, Parkinson’s disease, schizophrenia, bipolar disorder, and autistic spectrum disorder. In these and other neurodegenerative and neuroprogressive disorders, there are detrimental effects of oxidative stress, mitochondrial dysfunction, and neuroinflammation on neuronal function. However, they also adversely impact on neurone–glia interactions, disrupting the role of microglia and astrocytes in central nervous system (CNS) homeostasis. Astrocytes are the main site of CNS fatty acid oxidation; the resulting ketone bodies constitute an important source of oxidative fuel for neurones in an environment of glucose restriction. Importantly, the lactate shuttle between astrocytes and neurones is dependent on glycogenolysis and glycolysis, resulting from the fact that the astrocytic filopodia responsible for lactate release are too narrow to accommodate mitochondria. The entry into the CNS of ketone bodies and fatty acids, as a result of nutritional ketosis, has effects on the astrocytic glutamate–glutamine cycle, glutamate synthase activity, and on the function of vesicular glutamate transporters, EAAT, Na+, K+-ATPase, Kir4.1, aquaporin-4, Cx34 and KATP channels, as well as on astrogliosis. These mechanisms are detailed and it is suggested that they would tend to mitigate the changes seen in many neurodegenerative and neuroprogressive disorders. Hence, it is hypothesized that nutritional ketosis may have therapeutic applications in such disorders.

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“…A body of the literature suggests that activated immune/inflammatory and oxidative stress (IO and NS) pathways and consequent mitochondrial dysfunction may play a role in the pathophysiology of major psychiatric disorders including MDD by causing dysfunction in synaptic or neuronal plasticity and neuronal signaling, as well as in neuronal survival and death [105][106][107][108]. IO and NS pathways are also thought to contribute to the pathways underpinning the development of metabolic disorders, including insulin resistance [109].…”

Section: Immune/inflammatory Oxidative and Nitrosative Stressmentioning

confidence: 99%

“…Systemic oxidative stress upregulates stress-activated kinases (SAPK) including JNK and p38 MAPK, and SAPK phosphorylates the serine residues on PPAR to loss of activity. Hence, elevated levels of ROS and RNS could explain PPAR downregulation in obesity [107]. Moreover, NAD(+)-dependent histone deacetylase sirtuin-1 (SIRT1) expression is reduced in obesity, at least in part via iNOS-induced inactivation of SIRT1 [140,141].…”

Section: Immune/inflammatory Oxidative and Nitrosative Stressmentioning

confidence: 99%

Clinical Evidence of Antidepressant Effects of Insulin and Anti-Hyperglycemic Agents and Implications for the Pathophysiology of Depression—A Literature Review

Woo

Lim

Wang

et al. 2020

IJMS

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Close connections between depression and type 2 diabetes (T2DM) have been suggested by many epidemiological and experimental studies. Disturbances in insulin sensitivity due to the disruption of various molecular pathways cause insulin resistance, which underpins many metabolic disorders, including diabetes, as well as depression. Several anti-hyperglycemic agents have demonstrated antidepressant properties in clinical trials, probably due to their action on brain targets based on the shared pathophysiology of depression and T2DM. In this article, we review reports of clinical trials examining the antidepressant effect of these medications, including insulin, metformin, glucagon like peptide-1 receptor agonists (GLP-1RA), and peroxisome proliferator-activated receptor (PPAR)-γ agonists, and briefly consider possible molecular mechanisms underlying the associations between amelioration of insulin resistance and improvement of depressive symptoms. In doing so, we intend to suggest an integrative perspective for understanding the pathophysiology of depression.

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Shared pathways for neuroprogression and somatoprogression in neuropsychiatric disorders

Cited by 90 publications

References 383 publications

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation

Differential and paradoxical roles of new-generation antidepressants in primary astrocytic inflammation

Nutritional ketosis as an intervention to relieve astrogliosis: Possible therapeutic applications in the treatment of neurodegenerative and neuroprogressive disorders

Clinical Evidence of Antidepressant Effects of Insulin and Anti-Hyperglycemic Agents and Implications for the Pathophysiology of Depression—A Literature Review

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