Biology of cyclooxygenase-2: An application in depression therapeutics

He, Ying; Han, Yuanshan; Liao, Xiaolin; Zou, Manshu; Wang, Yuhong

doi:10.3389/fpsyt.2022.1037588

Cited by 10 publications

(8 citation statements)

References 132 publications

(153 reference statements)

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“…These findings have led to an increasing amount of research on the potential role of COX-2 inhibitors in the treatment of depression (161). Administering celecoxib, a COX-2 inhibitor, reverses the effects of chronic unpredictable stress and reduces COX-2 expression in a dose-dependent manner (162).…”

Section: Nsaidsmentioning

confidence: 99%

Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories

Hassamal

2023

Front. Psychiatry

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In a subset of patients, chronic exposure to stress is an etiological risk factor for neuroinflammation and depression. Neuroinflammation affects up to 27% of patients with MDD and is associated with a more severe, chronic, and treatment-resistant trajectory. Inflammation is not unique to depression and has transdiagnostic effects suggesting a shared etiological risk factor underlying psychopathologies and metabolic disorders. Research supports an association but not necessarily a causation with depression. Putative mechanisms link chronic stress to dysregulation of the HPA axis and immune cell glucocorticoid resistance resulting in hyperactivation of the peripheral immune system. The chronic extracellular release of DAMPs and immune cell DAMP-PRR signaling creates a feed forward loop that accelerates peripheral and central inflammation. Higher plasma levels of inflammatory cytokines, most consistently interleukin IL-1β, IL-6, and TNF-α, are correlated with greater depressive symptomatology. Cytokines sensitize the HPA axis, disrupt the negative feedback loop, and further propagate inflammatory reactions. Peripheral inflammation exacerbates central inflammation (neuroinflammation) through several mechanisms including disruption of the blood–brain barrier, immune cellular trafficking, and activation of glial cells. Activated glial cells release cytokines, chemokines, and reactive oxygen and nitrogen species into the extra-synaptic space dysregulating neurotransmitter systems, imbalancing the excitatory to inhibitory ratio, and disrupting neural circuitry plasticity and adaptation. In particular, microglial activation and toxicity plays a central role in the pathophysiology of neuroinflammation. Magnetic resonance imaging (MRI) studies most consistently show reduced hippocampal volumes. Neural circuitry dysfunction such as hypoactivation between the ventral striatum and the ventromedial prefrontal cortex underlies the melancholic phenotype of depression. Chronic administration of monoamine-based antidepressants counters the inflammatory response, but with a delayed therapeutic onset. Therapeutics targeting cell mediated immunity, generalized and specific inflammatory signaling pathways, and nitro-oxidative stress have enormous potential to advance the treatment landscape. Future clinical trials will need to include immune system perturbations as biomarker outcome measures to facilitate novel antidepressant development. In this overview, we explore the inflammatory correlates of depression and elucidate pathomechanisms to facilitate the development of novel biomarkers and therapeutics.

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Section: Nsaidsmentioning

confidence: 99%

Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories

Hassamal

2023

Front. Psychiatry

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“…The reduced number of astrocytes could contribute to both a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission 24 . Further search for antidepressant agents should take into account anti‐inflammatory drugs; for example, cyclooxygenase‐2 (COX2) inhibitors might exert antidepressant effects by acting on 5HT deficiency, glutamatergic hyperfunction, and the antagonizing neurotoxic effects of quinolinic acid 25 …”

Section: Introductionmentioning

confidence: 99%

“… 24 Further search for antidepressant agents should take into account anti‐inflammatory drugs; for example, cyclooxygenase‐2 (COX2) inhibitors might exert antidepressant effects by acting on 5HT deficiency, glutamatergic hyperfunction, and the antagonizing neurotoxic effects of quinolinic acid. 25 …”

Section: Introductionmentioning

confidence: 99%

Role of brain renin–angiotensin system in depression: A new perspective

Ali,

Al‐Kuraishy,

Al‐Gareeb

et al. 2023

CNS Neurosci Ther

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Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression is related to the deficiency of serotonin (5HT), which is derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of depression. Notably, the renin–angiotensin system (RAS) is involved in the pathogenesis of depression, and different findings revealed that angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in depression. However, the underlying mechanism for the role of dysregulated brain RAS‐induced depression remains speculative. Therefore, this review aimed to revise the conceivable role of ACEIs and ARBs and how these agents ameliorate the pathophysiology of depression. Dysregulation of brain RAS triggers the development and progression of depression through the reduction of brain 5HT and expression of brain‐derived neurotrophic factor (BDNF) and the induction of mitochondrial dysfunction, oxidative stress, and neuroinflammation. Therefore, inhibition of central classical RAS by ARBS and ACEIs and activation of non‐classical RAS prevent the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation.

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“…This process includes the release of IL-1 β, TNF-α, and prostaglandin E2 (PGE2). Excessive COX2 enzyme activity can promote the production of PGE2, a pro-inflammatory factor [ 60 ]. In the LPS-induced depression mouse model, the transcription function of the CREB/ATF-2 family is upregulated, leading to an overexpression of COX2.…”

Section: Discussionmentioning

confidence: 99%

Interpreting the Mechanism of Active Ingredients in Polygonati Rhizoma in Treating Depression by Combining Systemic Pharmacology and In Vitro Experiments

Wei,

Wang,

Liu

et al. 2024

Nutrients

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Polygonati Rhizoma (PR) has certain neuroprotective effects as a homology of medicine and food. In this study, systematic pharmacology, molecular docking, and in vitro experiments were integrated to verify the antidepressant active ingredients in PR and their mechanisms. A total of seven compounds in PR were found to be associated with 45 targets of depression. Preliminarily, DFV docking with cyclooxygenase 2 (COX2) showed good affinity. In vitro, DFV inhibited lipopolysaccharide (LPS)-induced inflammation of BV-2 cells, reversed amoeba-like morphological changes, and increased mitochondrial membrane potential. DFV reversed the malondialdehyde (MDA) overexpression and superoxide dismutase (SOD) expression inhibition in LPS-induced BV-2 cells and decreased interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and IL-6 mRNA expression levels in a dose-dependent manner. DFV inhibited both mRNA and protein expression levels of COX2 induced by LPS, and the activation of NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) and caspase1 was suppressed, thus exerting an antidepressant effect. This study proves that DFV may be an important component basis for PR to play an antidepressant role.

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Biology of cyclooxygenase-2: An application in depression therapeutics

Cited by 10 publications

References 132 publications

Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories

Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories

Role of brain renin–angiotensin system in depression: A new perspective

Interpreting the Mechanism of Active Ingredients in Polygonati Rhizoma in Treating Depression by Combining Systemic Pharmacology and In Vitro Experiments

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