This review discusses the mechanisms by which RIPK1 participates in the pathological process of depression, including its role in neuroinflammation and synaptic plasticity, and outlines the effects of RIPK1 inhibitors in animal models.
Abstract
Depression, a prevalent mental health disorder, has attracted increasing attention owing to its association with neuroinflammation. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a crucial role in maintaining cellular and tissue homeostasis by regulating inflammatory responses and cell death signalling pathways, both of which are closely linked to various physiological and pathological processes. Accordingly, RIPK1 functions as an upstream kinase that modulates inflammation and cell death. Tumour necrosis factor-α (TNF-α), a key pro-inflammatory cytokine implicated in the pathogenesis of various human diseases, acts as a principal upstream activator of RIPK1. Accumulating evidence further indicates that RIPK1 may contribute to a detrimental neuroinflammatory environment in mental disorders such as depression. However, its specific regulatory role and underlying mechanisms in depression remain incompletely understood. This review first summarises current advances in understanding the molecular structure and biological functions of RIPK1, with particular emphasis on multiple cellular pathways associated with depression. Subsequently, it discusses the mechanisms by which RIPK1 participates in the pathological process of depression, including its role in neuroinflammation and synaptic plasticity. Finally, we outline the effects of RIPK1 inhibitors in animal models, which have been shown to prevent neuronal cell death and reduce neuroinflammation. Collectively, these findings suggest that targeting RIPK1 may represent a promising therapeutic strategy with potential for clinical translation, highlighting its value as a potential therapeutic target in depression. However, further work is still needed to bridge the gap between preclinical mechanisms related to the RIPK1 inflammatory pathway and their actual clinical efficacy.
Neuroinflammation is increasingly recognized as a pivotal mechanism linking immune dysregulation with the onset, progression, and treatment resistance of major psychiatric disorders. Once considered distinct from classical neurodegenerative diseases, psychiatric conditions such as Major Depressive Disorder (MDD), schizophrenia, bipolar disorder, and anxiety disorders are now known to involve chronic, low-grade inflammation within the Central Nervous System (CNS). Persistent activation of microglia and astrocytes, together with disruption of Blood-Brain Barrier (BBB) integrity, initiates neurotoxic cascades that alter the balance between pro-inflammatory and anti-inflammatory cytokines. These alterations impair neurotransmission, reduce neuroplasticity, increase oxidative stress, and ultimately contribute to neuronal dysfunction. Several molecular pathways, including Nuclear Factor Kappa B (NF-κB), the NLRP3 inflammasome, and the kynurenine pathway (KP), play central roles in mediating these inflammatory responses. Activation of the KP diverts tryptophan metabolism away from serotonin synthesis toward the production of neuroactive metabolites such as quinolinic acid, thereby promoting excitotoxicity and neurodegeneration. Elevated circulating inflammatory biomarkers, including C-Reactive Protein (CRP), interleukin-6 (IL-6), and Tumor Necrosis Factor- alpha (TNF-α), have been consistently associated with increased disease severity and poor response to conventional monoaminergic therapies. Consequently, pharmacological modulation of neuroinflammation has emerged as a promising therapeutic strategy. Current and emerging approaches include cyclooxygenase-2 (COX-2) inhibitors, cytokine-targeted therapies, modulators of microglial activation, antioxidant agents such as N-acetylcysteine and omega-3 fatty acids, as well as novel therapeutics targeting the NLRP3 inflammasome, P2X7 receptors, and microglial polarization. Furthermore, integrating inflammatory biomarker profiling with advanced neuroimaging techniques, including Translocator Protein Positron Emission Tomography (TSPO-PET), may facilitate patient stratification and enable precision psychiatry. A comprehensive understanding of neuroinflammatory mechanisms may therefore provide new opportunities for developing targeted therapeutic interventions and improving clinical outcomes in psychiatric disorders.
P. Karwa, Vaibhav Parekar, Sarthak Buttepatil et al.· Current pharmaceutical desig...· 0 citations
Neurodegenerative diseases are progressive disorders characterised by the deterioration of neuronal structure and function, ultimately leading to cognitive deficits and functional impairment. Due to neuroinflammation, oxidative stress, and mitochondrial dysfunction, neurones, which cannot regenerate themselves, are highly susceptible to degeneration. There are many possible side effects associated with traditional pharmacotherapies, although they often offer symptomatic relief, highlighting the need for safer and more effective therapeutics. Natural products such as terpenoids, a structurally diverse class of isoprenoid compounds, have shown promising neuroprotective effects. Classes of terpenoids exhibit anti-inflammatory, antioxidant, anti-apoptotic, and mitochondrialprotective effects by regulating crucial signalling cascades, including Nuclear Factor kappa B (NF- κB), Mitogen-activated protein kinase (MAPK), c-Jun N-terminal Kinase (JNK), Phosphoinositide 3-kinase/Protein kinase B (PI3K/Akt), and Nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme oxygenase-1 (HO-1). Across preclinical models, representative compounds like catalpol, geniposide, artesunate, ginkgolides, alisol A 24-acetate, echinocystic acid, lycopene, and astaxanthin have demonstrated efficacy against Parkinson's disease, Alzheimer's disease, stroke, ischaemia, and haemorrhage by preserving neuronal integrity and function. Despite these promising findings, challenges such as poor bioavailability, limited blood-brain barrier penetration, metabolic instability, and a lack of standardised human safety data limit translational progress. Structural optimisation and advanced delivery systems, such as nanoparticles, cyclodextrin inclusion, combined therapeutic strategies, precision-targeted interventions, and rigorous clinical trials, may be considered future directions. In short, terpenoids have the potential to be developed as novel multitarget neurotherapeutic agents with further research to bridge preclinical promise and clinical validation.
Nidhi Gairola, Sushmita Uniyal, Jaya Martolia et al.· Mini-Reviews in Medical Chem...· 0 citations
MicroRNAs are non-coding small RNA molecules that play a significant role in regulating gene expression. Increasing lines of evidence have highlighted the microRNA dysregulation and neuroinflammation-associated apoptosis in common brain diseases, including Parkinson’s disease, Alzheimer’s disease, epilepsy, traumatic brain injury, depression, and migraine. In fact, microRNAs regulate multiple physiological and pathological processes, thus implicating them in both health and disease. Though studies have suggested that the alterations or modifications in microRNA-associated regulatory pathways might contribute to the disease pathogenesis, the underlying molecular mechanisms and the targeted genes remain exclusively unknown. We hope that the idea of using microRNAs as therapeutic targets for brain disorders is not far from reality, but important issues must be addressed before moving into clinical practice. The aim of this review is to enlighten the molecular mechanisms and targeted genes of microRNA implicated in the multifaceted brain disorders. Moreover, several microRNAs have been reported to be up-regulated following disease, but their targeted pathways have not been elucidated yet. This review also highlighted microRNAs that are expected to warrant further exploration of their mechanism of action. This comprehensive overview of the prediction of microRNAs’ functions might be helpful in providing more efficient insight for the development of microRNA-based therapeutic interventions for neuropsychiatric and neurodegenerative diseases.
Nimra Aziz, G. Hussain, Q. Abbas· Iranian Journal of Basic Med...· 0 citations
Depression is a multidimensional mental disorder that extends beyond changes in mood and adversely affects cognitive functioning, social adjustment, quality of life, and physical health. Although its biological basis was long interpreted primarily through the monoamine hypothesis, current evidence indicates that depression is too complex to be explained by alterations in a single neurotransmitter system. In recent years, impaired neuronal plasticity, disruption of neurotrophic support mechanisms, neuroinflammation, oxidative stress, mitochondrial dysfunction, and glial-cell responses have emerged as central processes in the pathophysiology of depression. In particular, the role of brain-derived neurotrophic factor (BDNF) in neuronal survival, synaptic plasticity, dendritic development, and hippocampal neurogenesis provides an important framework for understanding the cellular and molecular basis of the disorder. At the same time, microglial and astrocytic activation, increased production of pro-inflammatory cytokines, oxidative damage, and disturbances in mitochondrial energy metabolism may compromise neuronal network integrity and thereby contribute to both the onset and persistence of depression. This review provides an integrated account of the roles of BDNF and related neurotrophic factors, neuroinflammation, oxidative stress, mitochondrial dysfunction, experimental models of depression, and contemporary therapeutic approaches. It also discusses the value of histological, immunohistochemical, molecular, and biomarker-based strategies for identifying biological subtypes of depression and developing more targeted treatments.
