Evaluation of the effect of thymoquinone in d‐galactose‐induced memory impairments in rats: Role of MAPK, oxidative stress, and neuroinflammation pathways and telomere length

Abstract

D‐galactose (d‐gal) induces aging and memory impairment via oxidative stress and neuroinflammation pathways. This study evaluated the neuroprotective activity of thymoquinone (TQ) against d‐gal. d‐gal (400 mg/kg, SC), d‐gal plus TQ (2.5, 5, 10 mg/kg, i.p.), and TQ alone (2.5 and 10 mg/kg) for 8 weeks were administered to rats. The effect of TQ on learning and memory were studied using the Morris water maze test. Malondialdehyde (MDA) and glutathione (GSH) levels were determined in the hippocampus. The levels of MAPKs (p‐ERK/ERK, p‐P38/P38), cAMP response elements binding (p‐CREB/CREB), advanced glycation end products (AGEs), inflammatory markers (TNFα, IL‐1β), glial fibrillary acidic protein (GFAP), and brain‐derived neurotrophic factor (BDNF) were analyzed by western blotting. Telomere length was evaluated using real‐time PCR. Memory and learning impairment, MDA enhancement, GSH reduction, and neuroinflammation via increasing the TNFα, IL‐1β, and GFAP contents were observed in d‐gal group. TQ with d‐gal, improved memory impairment, reduced oxidative stress, and alleviated neuroinflammation. The elevated level of AGEs decreased by TQ compared to d‐gal. No changes were observed in the levels of p‐ERK/ERK, p‐CREB/CREB, p‐P38/P38, BDNF, and telomere length following administration of d‐gal or TQ plus d‐gal. TQ improved memory deficits of d‐gal through anti‐oxidative and anti‐inflammatory mechanisms.

Qiangji Decoction Alleviates Neurodegenerative Changes and Hippocampal Neuron Apoptosis Induced by D-Galactose via Regulating AMPK/SIRT1/NF-κB Signaling Pathway

“…The microglia and astrocytes activation is the critical factor for the release of pro-inflammatory cytokines. Growing researches have confirmed that chronic D-gal administration can induce the microglia and astrocytes activation, thereby accelerating the release of pro-inflammatory cytokines ( Lu et al, 2010 ; Jeong et al, 2021 ; Oskouei et al, 2021 ). So, we used the immunofluorescence staining to detect the levels of IBA1 and GFAP.…”

“…Neuroinflammation is significantly involved in aggravating cognitive impairment and neurodegenerative changes of brain aging (Singhal et al, 2014). Accumulated researches have confirmed that long-term D-gal subcutaneous injection can induce neuroinflammation by stimulating the activation of microglia and astrocytes (Lu et al, 2010;Jeong et al, 2021;Oskouei et al, 2021). Meanwhile, the activation of microglia and astrocytes will further trigger neuroinflammation, and finally releasing the proinflammatory factors, such as TNF-α, IL-1β, and IL-6, in D-gal-induced mice.…”

“…Cognitive and memory deficits are one of the major clinical symptoms in brain aging. Numerous studies have confirmed that long-term D-gal subcutaneous injection (100 mg/kg) can induce memory impairment of rodents, so we employed the D-gal to establish the model of brain aging, and the mice were treated with D-gal by subcutaneous injection for 8 weeks in the present research ( Chen et al, 2019 ; Jeong et al, 2021 ; Oskouei et al, 2021 ). Metformin is the activator of AMP-activated protein kinase (AMPK) ( Steinberg and Carling., 2019 ).…”

“…But at higher concentrations, D-gal can be converted to aldose and hydrogen peroxide, causing the disposition of superoxide anion and oxygenderived free radicals in the brain, and finally lead to brain damage (Sun et al, 2018). Mounting studies have confirmed that chronic D-gal administration leads to the cognitive impairment of rodents by the accumulated oxidative stress, mitochondrial deficits, and neuroinflammation (Chen et al, 2019;Jeong et al, 2021;Oskouei et al, 2021). For these reasons, chronic administration of D-gal is well-established in the experimental rodent models of aging-related cognitive impairment and investigating the anti-aging pharmacological studies.…”

Development and in vivo Evaluation of Hydroxy-α-Sanshool Intranasal Liposomes as a Potential Remedial Treatment for Alzheimer’s Disease

“…32 D-galactose, a reducing sugar widely present in food and humans, is excreted from the body autonomously at low doses. 33 However, when D-galactose is present in the body at high doses, it is converted to aldose and hydrogen peroxide through a reaction catalysed by galactose oxidase, which in turn leads to the excess production and accumulation of reactive oxygen species in the body, inducing a series of responses such as oxidative stress and cognitive dysfunction. [34][35][36] Therefore, the mouse D-galactoseinduced damage model is often used to screen drugs for the treatment of cognitive dysfunction in AD.…”