Problematic ChatGPT use: Manifestations, etiologies, and evaluation.

Neuroinflammation is an inflammatory response in the presence of pathogens or harmful substances within the central nervous system (CNS). This response is mediated by glial cells like microglia and astrocytes []. In short terms, neuroinflammation serves as a defense mechanism of the CNS, in which pathogenic substances are eliminated by several mechanisms including microglial phagocytosis, oxidative stress, and degrading enzymes. However, chronic and persistent inflammation can lead to the excessive release of proinflammatory mediators and free radicals, resulting in neuronal damage [–]. Factors contributing to chronic inflammation include endogenous factors, such as protein aggregates and genetic mutations, and exogenous factors, such as systemic infection, trauma, gut microbiota dysbiosis, and aging [, ]. Notably, the existence of protein aggregates that trigger chronic neuroinflammation is a shared characteristic in many neurodegenerative diseases [, ]. Neurodegenerative diseases are a group of disorders characterized by the loss of neurons in terms of both quantity and function. The examples of these diseases are Alzheimer’s diseases (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), prion diseases, and Huntington’s disease []. It was suggested that neuronal loss occurring in these diseases stems from similar mechanisms: persistent neuroinflammation induced by the deposition of pathogenic protein within the brain. Chronically activated glial cells not only have reduced phagocytic capability, but also they might be responsible for neuronal damage and the exacerbation of pathogenic protein aggregation. Moreover, cell debris from damaged neurons can activate glial cells into releasing even more proinflammatory, neurotoxic mediators, forming a vicious cycle [, , , ]. Therefore, neuroinflammation is considered one of the key factors influencing the development and progression of these diseases. Microglia are one of the glial cells responsible for supporting neurons. In particular, microglia serve as the resident immune cells of the brain and have important roles in maintaining homeostasis [, ]. In a healthy brain, microglia exist in the resting state, mainly performing immunosurveillance and housekeeping roles, such as synaptic pruning [, ]. However, in response to threats including pathogens, injuries, or harmful substances, they could undergo a process called microglial activation into either M1 (classical) or M2 (alternative) phenotypes [, ]. The M1 phenotype is generally considered the proinflammatory phenotype, as it produces inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin (IL)−1β, IL-6, CC chemokine ligand (CCL) 2, nitric oxide (NO), and reactive oxygen species (ROS), all of which contribute to neuronal damage through various mechanisms including apoptosis induction and oxidative stress. In contrast, the M2 phenotype is associated with neuroprotection. This is due to its role in resolving inflammation and promoting tissue repair through the release of anti-inflammatory mediators such as IL-10, transforming growth factor (TGF)-β), found in inflammatory zone 1 (FIZZ1), and arginase 1 (Arg1) [, ]. Despite this, the activation of microglia into either phenotype is not set in stone, as the M1 phenotype can polarize into M2, depending on several modulators [].