Neuroinflammatory Basis of Depression: Learning From Experimental Models

Abstract

The neuroinflammatory basis of depression encompasses the detrimental role of otherwise supportive non-neuronal cells and neuroinflammation in hampering neuronal function, leading to depressive behavior. Animals subjected to different stress paradigms show glial cell activation and a surge in proinflammatory cytokines in various brain regions. The concept of sterile inflammation observed in animal models of depression has intrigued many researchers to determine the possible triggers of central immune cell activation. Notably, microglial activation and subsequent phenotypic polarization in depression have been strongly advocated by the wealth of recent preclinical studies; however, findings from human studies have shown contradictory results. Despite intensive investigation, many research gaps still exist to elucidate the molecular mechanisms of neuroinflammatory cascades underlying the pathophysiology of depression. In this mini-review, recent progress in understanding neuroinflammatory mechanisms in light of experimental models of depression will be thoroughly discussed. The challenges of mirroring depression in animal and in vitro models will also be highlighted. Furthermore, prospects of targeting neuroinflammation to treat depressive disorder will be covered.

Influence of Smallanthus sonchifolius (Yacon) on the Activity of Antidepressant Drugs in Mice

“…Though our experiments did not assess the molecular mechanism of the antidepressantlike activity of Yacon tuber extract, we guess that it can be at least partially caused by the antioxidant [10,41], anti-inflammatory, and probiotic properties of its main components, particularly fructooligosaccharides, inulin, polyphenols, and tryptophan. It would be in line with new theories of depression, which associate the development of this disease with oxidative stress [50], (neuro)inflammation [51], and disturbances in the gut-microbiotabrain axis [52]. In diabetic rats, Yacon supplementation resulted in a considerable reduction in the hepatic and renal levels of malondialdehyde and activities of superoxide dismutase and catalase.…”

Therapeutic potential of selective serotonin reuptake inhibitor and anti-inflammatory COX-2 inhibitors drugs for epilepsy

“…Such a mechanism is important for neuroprotection and neuroplasticity, however the high excitability and greater influx of calcium is involved in the formation of reactive oxygen species and cell death, with strong excitotoxicity, as occurs in the stimulation by QUIN. In addition, inflammatory states lead to death of astrocytes, which end up not capturing glutamate in the cleft, thus increasing the availability of this neurotransmitter, with subsequent greater neural excitability and harmful toxicity (Wang & Reddy, 2018;Mattson, 2019;Afridi & Suk, 2021).…”

“…Although the causes of such diseases are not yet fully understood, the drugs that exist to treat such conditions are based on the diverse circuits that have influences on such diseases. Neurodegeneration involves, for example, activation of the sympathetic system and glucocorticoid release in the face of psychological stress, which increases the secretion of proinflammatory cytokines, causes astrocytic degeneration and upregulation of the IDO enzyme (indoleamine 2,3 dioxygenase) in the microglia, responsible for neurotoxicity and changes in the production of monoaminergic neurotransmitters such as serotonin (Afridi & Suk, 2021).…”

Ion Channel Dysfunction and Neuroinflammation in Migraine and Depression

“…Despite this well-established epidemiological data, the biological basis of this comorbidity is unclear. Emerging data from animal models and human imaging studies suggest that neuroinflammation could be a common pathway in the pathophysiology of both disorders ( Mueller and Schwarz, 2007 ; Richards et al, 2018 ; Albrecht et al, 2019 ; Hadjikhani et al, 2020 ; Afridi and Suk, 2021 ). However, how neuroinflammatory signaling is initiated without an injury to the brain tissue is unknown.…”

“…However, how neuroinflammatory signaling is initiated without an injury to the brain tissue is unknown. A non-homeostatic synaptic transmission has been suggested as an initiator of neuroinflammatory signaling ( Dalkara and Kilic, 2013 ; Kilic et al, 2018 ; Afridi and Suk, 2021 ; Petit et al, 2021 ). In this regard, some ion channels and activation of cellular stress sensors such as pannexin1 (Panx1) and P2X7 channels and the downstream inflammatory cascade may play a role.…”