Alpha-Linolenic Acid Impedes Cadmium-Induced Oxidative Stress, Neuroinflammation, and Neurodegeneration in Mouse Brain

Alam, Sayed-Ibrar; Kim, Minwoo; Shah, Fawad Ali; Saeed, Kamran; Ullah, Rahat; Kim, Myeong-Ok

doi:10.3390/cells10092274

Cited by 33 publications

(24 citation statements)

References 48 publications

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“…Notably, the most abundant ion peak in MP fraction was identified as ALA, which was further proved to activate NRF2 signaling in HaCaT cells. These findings agree with previous studies that ALA or ALA-containing extracts activate NRF2 and increase the expression of its target genes [ 36 , 37 , 38 , 39 ].…”

Section: Discussionsupporting

confidence: 93%

Prinsepiae Nux Extract Activates NRF2 Activity and Protects UVB-Induced Damage in Keratinocyte

et al. 2022

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Ultraviolet B (UVB) is one of the most important environmental factors that cause extrinsic aging through increasing intracellular reactive oxygen species (ROS) production in the skin. Due to its protective roles against oxidative stress, nuclear factor erythroid-2-related factor (NRF2) has been traditionally considered as a target for skin aging prevention. Here, we identified the extract of Prinsepiae Nux, a top-grade drug listed in Shen Nong Ben Cao Jing, as a potent NRF2 activator by high-throughput screening. A bioassay-guided fractionation experiment revealed that NRF2-activating components were concentrated in the 90% methanol (MP) fraction. MP fraction significantly increased the expression of NRF2 and HO-1 protein and upregulated HO-1 and NQO1 mRNA expression in HaCaT cells. Moreover, MP fraction pre-treatment dramatically reversed UVB-induced depletion of NRF2 and HO-1, accumulation of intracellular ROS, NF-κB activation, and the upregulation of pro-inflammatory genes. Finally, the qualitative analysis using UPLC-tandem mass spectroscopy revealed the most abundant ion peak in MP fraction was identified as α-linolenic acid, which was further proved to activate NRF2 signaling. Altogether, the molecular evidence suggested that MP fraction has the potential to be an excellent source for the discovery of natural medicine to treat/prevent UVB-induced skin damage.

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Section: Discussionsupporting

confidence: 93%

Prinsepiae Nux Extract Activates NRF2 Activity and Protects UVB-Induced Damage in Keratinocyte

et al. 2022

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“…Cd has been shown to persistently activate protein markers related to neuronal apoptosis, such as caspase 3, in the rat brain (Khan et al, 2019). The results showed the greatest caspase‐3 immunoreactivity since the second month in Cd‐exposure groups, which confirmed previous results (Pulido et al, 2019; Alam et al, 2021). Reports indicate that Cd‐induced apoptosis occurs proportionally to the time of Cd exposure.…”

Section: Discussionsupporting

confidence: 90%

Effect of cadmium administration on the antioxidant system and neuronal death in the hippocampus of rats

Treviño

Pulido

Fuentes

et al. 2022

Synapse

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Cadmium (Cd) is a heavy metal classified as a carcinogen whose exposure could affect the function of the central nervous system. Studies suggest that Cd modifies neuronal morphology in the hippocampus and affects cognitive tasks. The oxidative stress pathway is proposed as a mechanism of toxicity. However, this mechanism is not precise yet. This study aimed to evaluate the effect of Cd administration on oxidative stress markers in the male rat's hippocampus. Male Wistar rats were divided into (1) control (drinking water) and (2) treatment with Cd (32.5 ppm of cadmium chloride (CdCl2) in water). The Cd was administered for 2, 3, and 4 months. The results show that the oral administration of CdCl2 increased the concentration of Cd in plasma and hippocampus, and this response is time‐dependent on its administration. Likewise, it caused an increase in lipid peroxidation and nitrosative stress markers. Moreover, it increased reactive astrogliosis and antioxidant enzyme activity. Consequently, the progression of the oxidative response exacerbated neurodegeneration in hippocampal cells. Our results suggest that Cd exposure induces a severe oxidative response that contributes critically to hippocampal neurodegeneration. It is suggested that exposure to Cd increases the risk of developing neurological diseases, which contributes to a decrease in the quality of life of the human and the environment in which it lives.

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“… 89 Previous studies have shown that ALA increases GSH biosynthesis by inducing nuclear factor (erythroid 2)-like 2 (Nrf2) or enhancing glutathione reductase (GR) that converts GSSG to GSH. 90 , 91 ALA also increases the availability of neuronal NADPH necessary for GSH synthesis and GSSG reduction. 92–94 However, the ALA-mediated inhibition of NOX activity is of particular clinical significance.…”

Section: Discussionmentioning

confidence: 99%

α-Lipoic Acid Reduces Ceramide Synthesis and Neuroinflammation in the Hypothalamus of Insulin-Resistant Rats, While in the Cerebral Cortex Diminishes the β-Amyloid Accumulation

Maciejczyk

Żebrowska

Nesterowicz

et al. 2022

JIR

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Background Oxidative stress underlies metabolic diseases and cognitive impairment; thus, the use of antioxidants may improve brain function in insulin-resistant conditions. We are the first to evaluate the effects of α-lipoic acid (ALA) on redox homeostasis, sphingolipid metabolism, neuroinflammation, apoptosis, and β-amyloid accumulation in the cerebral cortex and hypothalamus of insulin-resistant rats. Methods The experiment was conducted on male cmdb/outbred Wistar rats fed a high-fat diet (HFD) for 10 weeks with intragastric administration of ALA (30 mg/kg body weight) for 4 weeks. Pro-oxidant and pro-inflammatory enzymes, oxidative stress, sphingolipid metabolism, neuroinflammation, apoptosis, and β-amyloid level were assessed in the hypothalamus and cerebral cortex using colorimetric, fluorimetric, ELISA, and HPLC methods. Statistical analysis was performed using three-way ANOVA followed by the Tukey HSD test. Results ALA normalizes body weight, food intake, glycemia, insulinemia, and systemic insulin sensitivity in HFD-fed rats. ALA treatment reduces nicotinamide adenine dinucleotide phosphate (NADPH) and xanthine oxidase activity, increases ferric-reducing antioxidant power (FRAP) and thiol levels in the hypothalamus of insulin-resistant rats. In addition, it decreases myeloperoxidase, glucuronidase, and metalloproteinase-2 activity and pro-inflammatory cytokines (IL-1β, IL-6) levels, while in the cerebral cortex ALA reduces β-amyloid accumulation. In both brain structures, ALA diminishes ceramide synthesis and caspase-3 activity. ALA improves systemic oxidative status and reduces insulin-resistant rats’ serum cytokines, chemokines, and growth factors. Conclusion ALA normalizes lipid and carbohydrate metabolism in insulin-resistant rats. At the brain level, ALA primarily affects hypothalamic metabolism. ALA improves redox homeostasis by decreasing the activity of pro-oxidant enzymes, enhancing total antioxidant potential, and reducing protein and lipid oxidative damage in the hypothalamus of HFD-fed rats. ALA also reduces hypothalamic inflammation and metalloproteinases activity, and cortical β-amyloid accumulation. In both brain structures, ALA diminishes ceramide synthesis and neuronal apoptosis. Although further study is needed, ALA may be a potential treatment for patients with cerebral complications of insulin resistance.

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Alpha-Linolenic Acid Impedes Cadmium-Induced Oxidative Stress, Neuroinflammation, and Neurodegeneration in Mouse Brain

Cited by 33 publications

References 48 publications

Prinsepiae Nux Extract Activates NRF2 Activity and Protects UVB-Induced Damage in Keratinocyte

Prinsepiae Nux Extract Activates NRF2 Activity and Protects UVB-Induced Damage in Keratinocyte

Effect of cadmium administration on the antioxidant system and neuronal death in the hippocampus of rats

α-Lipoic Acid Reduces Ceramide Synthesis and Neuroinflammation in the Hypothalamus of Insulin-Resistant Rats, While in the Cerebral Cortex Diminishes the β-Amyloid Accumulation

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