Hydroxychloroquine attenuates neuroinflammation following traumatic brain injury by regulating the TLR4/NF-κB signaling pathway

Abstract

Background After traumatic brain injury (TBI), an acute, robust inflammatory cascade occurs that is characterized by the activation of resident cells such as microglia, the migration and recruitment of peripheral immune cells and the release of inflammatory mediators that induce secondary cell death and impede neurological recovery. In addition, neuroinflammation can alter blood–brain barrier (BBB) permeability. Controlling inflammatory responses is considered a promising therapeutic approach for TBI. Hydroxychloroquine (HCQ) has already been used clinically for decades, and it is still widely used to treat various autoimmune diseases. However, the effects of HCQ on inflammation and the potential mechanism after TBI remain to be defined. The aim of the current study was to elucidate whether HCQ could improve the neurological recovery of mice post-TBI by inhibiting the inflammatory response via the TLR4/NF-κB signaling pathway. Methods C57BL/6 mice were subjected to controlled cortical impact (CCI) and randomly divided into groups that received intraperitoneal HCQ or vehicle daily after TBI. TAK-242 (3.0 mg/kg), an exogenous TLR4 antagonist, was injected intraperitoneally 1 h before TBI. Behavioral assessments were performed on days 1 and 3 post-TBI, and the gene expression levels of inflammatory cytokines were analyzed by qRT-PCR. The presence of infiltrated immune cells was examined by flow cytometry and immunostaining. In addition, BBB permeability, tight junction expression and brain edema were investigated. Results HCQ administration significantly ameliorated TBI-induced neurological deficits. HCQ alleviated neuroinflammation, the activation and accumulation of microglia and immune cell infiltration in the brain, attenuated BBB disruption and brain edema, and upregulated tight junction expression. Combined administration of HCQ and TAK-242 did not enhance the neuroprotective effects of HCQ. Conclusions HCQ reduced proinflammatory cytokine expression, and the underlying mechanism may involve suppressing the TLR4/NF-κB signaling pathway, suggesting that HCQ is a potential therapeutic agent for TBI treatment.

Isoflurane alleviates systemic inflammation-induced neuroinflammation by decreasing the blood-brain barrier's damage and regulating the microglia's polarization

“…This is one of the hallmarks of neuroin ammation --recruitment of immune cells [10]. Following, the above stimulation caused microglia activation, and the synthesis of NO and other factors further destroyed the integrity of the BBB [19]. In addition, the BBB increases permeability due to pro-in ammatory factors, resulting in cerebral edema [37].…”

“…M1 microglia produce interleukin (IL)-1β, tumor necrosis factor (TNF)-α, nitric oxide (NO), and other proin ammatory factors to accelerate the development of neuroin ammation, resulting in irreversible loss of neurons and aggravating damage to the CNS [16][17][18]. Furthermore, M1-type microglia secrete cytokines and NO, which destroy the BBB, causing endothelial cell necrosis, exacerbating the invasion of other peripheral immune cells, and exacerbating neuroin ammation [17,19]. M2-type microglia produce IL-10, transforming growth factor (TGF)-β, and other anti-in ammatory and neurotrophic factors involved in neuroprotection and maintain the integrity of the BBB [13,20,21].…”

Biology of cyclooxygenase-2: An application in depression therapeutics

“…Inflammatory cytokines in the blood can activate the hypothalamic-pituitary-adrenal (HPA) axis, and HPA dysfunction leads to corticotropin releasing hormone (CRH), adrenocorticotropic hormone (ACTH), increased secretion of corticosterone (CORT) and its negative feedback dysfunction, upregulate the release of glucocorticoids(GC) and cortisol in the adrenal cortex as well as cause dysregulation of monoamine transmitters, while inflammatory factors decrease the release of glucocorticoids and cortisol through activation of indoleamine-2,3-dioxygenase (IDO) enzyme, IDO activation reduces tryptophan and increases toxic metabolites of the kynurenine pathway, which leads to damage to astrocytes, microglia, and neurons, triggering neuroinflammation, which is positively associated with Major Depressive Disorder (MDD) (18)(19)(20). In addition, inflammatory factors can also induce damage to the blood-brain barrier (BBB) and enter the brain (21,22). Damage to the hippocampal BBB, an important portal for maintaining a homeostatic environment for neurons and glial cells, would allow increased permeability and trigger neuroinflammation (23), which may be an important pathological factor in triggering depression (24).…”

Traumatic Brain Injury and Secondary Neurodegenerative Disease

“…Doxycycline decreases matrix metalloprotease-9 (MMP-9) activity, thus preventing blood-brain-barrier disruption and microvascular hyperpermeability [ 111 ]. Hydroxychloroquine and chloroquine have been shown to reduce neuroinflammation by decreasing microglia activation and blood-brain-barrier disruption following cortical impact TBI in animal models [ 112 , 113 ].…”