NF-ΚB-ASSOCIATED INFLAMMATION AND COGNITIVE IMPAIRMENT IN SCHIZOPHRENIA: A REVIEW

Cognitive impairment is recognized as a core and enduring characteristic of schizophrenia, with considerable impacts on daily functioning One of the key molecular pathways implicated is nuclear factor kappa B (NF-κB), a major transcription factor that regulates inflammatory activity in the brain and peripheral immune cells. Prior studies have highlighted the significant role of inflammatory processes in these impairments. Therefore, this literature review seeks to examine and integrate existing evidence on the role of NF-κB-mediated inflammation in the onset and persistence of cognitive impairment in schizophrenia. Relevant studies were identified through searches of the PubMed, Scopus, and ScienceDirect databases. Articles examining and discussing NF-κB signaling, neuroinflammatory mechanisms, peripheral inflammation, and cognitive dysfunction in schizophrenia were included. Meta-analyses, systematic reviews, clinical, postmortem, and preclinical studies were analyzed and integrated. The reviewed studies consistently demonstrate disruption of NF-κB signaling in schizophrenia, reflected by elevated expression and activation of NF-κB in central and peripheral tissues and its downstream pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β), CRP, and chemokines. NF-κB-mediated inflammation is associated with increased proinflammatory cytokines, blood-brain barrier (BBB) ​​disruption, microglia activation, astrocyte reactivity, oxidative stress leading to synaptic dysfunction, impaired neuroplasticity, disturbances in neurotransmitter balance and brain volume atrophy in brain regions that regulate cognition, particularly the prefrontal cortex and hippocampus. These neurobiological alterations are closely linked to deficits in working memory, attention, and executive function. Modulation of NF-κB signaling may improve cognitive performance. NF-κB-mediated neuroinflammation represents a key molecular pathway underlying cognitive impairment in schizophrenia. Targeting NF-κB signaling may offer a promising therapeutic strategy to address cognitive deficits, an unmet need in current schizophrenia treatment. Future research should prioritize longitudinal human studies, standardized biomarkers of NF-κB activity, and nested clinical trials to determine which patient subgroups benefit most from NF-κB modulatory interventions.