IκB kinase inhibition remodeled connexins, pannexin‐1, and excitatory amino‐acid transporters expressions to promote neuroprotection of galantamine and morphine

Abstract

Inflammatory pathway and disruption in glutamate homeostasis join at the level of the glia, resulting in various neurological disorders. In vitro studies have provided evidence that membrane proteins connexions (Cxs) are involved in glutamate release, meanwhile, excitatory amino-acid transporters (EAATs) are crucial for glutamate reuptake (clearance). Moreover, pannexin-1 (Panx-1) activation is more detrimental to neurons. Their expression patterns during inflammation and the impacts of IκB kinase (IKK) inhibition, morphine, and galantamine on the inflammatory-associated glutamate imbalance remain elusive.To investigate this, rats were injected with saline or lipopolysaccharide.Thereafter, vehicles, morphine, galantamine, and BAY-117082 were administered in different groups of animals. Subsequently, electroencephalography, enzyme-linked immunosorbent assay, western blot, and histopathological examinations were carried out and various indicators of inflammation and glutamate level were determined. Parallel analysis of Cxs, Panx-1, and EAAts in the brain was performed. Our findings strengthen the concept that unregulated expressions of Cxs, Panx-1, and EAATs contribute to glutamate accumulation and neuronal cell loss. Nuclear factor-kB (NF-κB) pathway can significantly contribute to glutamate homeostasis via modulating Cxs, Panx-1, and EAATs expressions. BAY-117082, via inhibition of IkK, promoted the antiinflammatory effects of morphine as well as galantamine. We concluded that NF-κB is an important component of reshaping the expressions of Cxs, panx-1, and EAATs and the development of glutamate-induced neuronal degeneration.

Therapeutic Effects of Baicalin on Diseases Related to Gut–Brain Axis Dysfunctions

“…These results suggest that baicalin exerts therapeutic effects on UC by inhibiting the IKK/IKB/NF-κB signaling pathway and apoptosis-related proteins [ 51 ]. However, Magdy et al indicated that the NF-κB pathway alleviated glutamate accumulation and neuronal cell damage by regulating the expression of membrane proteins (connexins (Cxs), Panx1, and excitatory amino-acid transporters) in the brain tissue [ 107 ]. Baicalin (25, 50, and 100 mg/kg bodyweight) protected against trinitrobenzenesulfonic acid (TNBS)-induced UC in rats by inhibiting the upregulation of ROS and MDA in the colon tissue of rats, downregulation of the GSH and SOD levels, and modulation of Th17/T regulatory (Treg) cell balance, gut microbiota, and SCFAs [ 52 ].…”

Research Progress on Neuroprotective Effects of Isoquinoline Alkaloids

“…However, we are cognizant that in recent years, many studies have shown that morphine can also exert neuroprotective effects through various mechanisms [ 28 ]. The main mechanisms include reducing intracellular Ca 2+ overload, reducing cell oxidative damage, activating autophagy, and inhibiting intracellular toxic protein production to promote neuronal regeneration and differentiation [ 29 , 30 , 31 , 32 ]. At the same time, researchers have applied very low doses of morphine to very preterm infants, which has effectively improved the neurodevelopmental status of the infants [ 33 ].…”

Iron dyshomeostasis and time-course changes in iron-uptake systems and ferritin level in relation to pro-inflammatory microglia polarization in sepsis-induced encephalopathy

“…Immunohistochemical assessment of the macrophage phenotype markers CD8, CD68, and CD 163 and the microglial marker Iba-1 was performed using the avidin-biotin peroxidase method as described previously (Magdy et al, 2021). Briefly, paraffin-embedded brain sections were dewaxed in xylene, rehydrated in a decreasing alcohol gradient, and microwave-treated (0.01 M trisodium citrate), for antigen retrieval.…”