The Neuroinflammation Perspective of Depression: Reuniting the Outstanding Mechanisms of the Pathophysiology

Abstract

The neuroinflammation perspective of depression: reuniting the outstanding mechanisms of the pathophysiology Major Depressive Disorder (MDD) is a serious mental health problem that leads to patients' disability and has huge impact on social and economic burden to society. The current available medications for the treatment of depression are mainly targeted on enhancing monoamine neurotransmission. However, antidepressant treatments are still lacking high efficacy in many cases which is associated with low treatment response and remission rates. However, the latest knowledge regarding the pathophysiology of depression indicates that depression is developed by highly complex and integrated mechanisms in which monoaminergic deficiency could only be part of. The paradigm is now shifting from monoaminergic hypothesis to significance of other novel mechanisms that could possibly play substantial role for the development of depression in a highly interrelated manner. In fact, neuroinflammation, amongst other mechanisms does seem to be a key pathological component by having impact on certain pathway pathologies including glutamatergic neurotransmission, oxidative processes, neurotropic factors, neurotransmitter metabolism, and glucocorticoid functions in the central nervous system (CNS) and in the periphery, thereby triggers the pathological alterations that is thought to contribute to the development of depression. The neuroinflammation comprehends the processes exampled from excessive pro-inflammatory cytokine release to activation of microglia and indolamine 2,3-dioxygenase (IDO) pathway, excessive glutamatergic neurotransmission, hyperactive hypothalamus-pituitary-adrenal (HPA) axis, decreased neurogenesis and synaptic plasticity. In fact, the antidepressant effect of ketamine as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist might be at least partially linked to inflammatory modulations. The significance of inflammation in depression is not only mentioned by the literature of basic researches from a mechanistic aspect but also by the possible clinical implications suggested by the clinical reports. Although the exact role of inflammation in depression and its clinical translation have not been determined yet, the inflammationmediated point of view might provide novel insights for improving the diagnosis at clinic (e.g., inflammatory biomarkers), predicting antidepressant treatment response and thereby re-evaluating the treatment strategy. Moreover, with all that, the inflammation aspect raises the question for the possible significance of utilizing anti-inflammatory approaches in the treatment of depression.

Fluoxetine regulates eEF2 activity (phosphorylation) via HDAC1 inhibitory mechanism in an LPS-induced mouse model of depression

“…Activating mTOR rescues eEF2 from eEF2 kinase over-activating, which in turn upregulates BDNF [ 74 , 75 ]. Next, we extend our investigation line to examine mTOR, BDNF, SNAP25, PSD95, and GSK3β changes after NH125 treatment.…”

Dietary Inflammatory Potential and the Risk of Incident Depression in Adults: A Systematic Review

“…Hoogland et al (57) showed that systemic stimulation with live Escherichia coli causes microglial activation and an inflammatory response in the brain. Neuroinflammation predisposes to the development of depression by increasing glutamatergic neurotransmission, reducing neurotropic factors, and altering the metabolism of neurotransmitters in the brain (59,60). In depressed patients, changes to several neurotransmitters or neurotrophins in the central nervous system, including serotonin, norepinephrine, corticotropinreleasing factor, and brain-derived neurotrophic factor, have all been reported (61)(62)(63)(64).…”

Antidepressant-like Effects Induced by Chronic Blockade of the Purinergic 2X7 Receptor through Inhibition of Non-like Receptor Protein 1 Inflammasome in Chronic Unpredictable Mild Stress Model of Depression in Rats

“…Major depressive disorder (MDD) represents a serious and highly prevalent public health concern with a huge impact on the life quality of affected individuals 1–3). One out of three MDD patients do not act in adequate response to existing pharmacological treatments, which mainly enhance monoaminergic neurotransmission 4,5). This clearly indicates that the monoamine hypothesis alone is not sufficient to explain the pathogenesis of depression.…”