Chronic neuroinflammation is responsible for multiple neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Lipopolysaccharide (LPS) is an essential component of the gram-negative bacterial cell wall and acts as a potent stimulator of neuroinflammation that mediates neurodegeneration. Quercetin is a natural flavonoid that is abundantly found in fruits and vegetables and has been shown to possess multiple forms of desirable biological activity including anti-inflammatory and antioxidant properties. This study aimed to evaluate the neuroprotective effect of quercetin against the detrimental effects of LPS, such as neuroinflammation-mediated neurodegeneration and synaptic/memory dysfunction, in adult mice. LPS [0.25 mg/kg/day, intraperitoneally (I.P.) injections for 1 week]-induced glial activation causes the secretion of cytokines/chemokines and other inflammatory mediators, which further activate the mitochondrial apoptotic pathway and neuronal degeneration. Compared to LPS alone, quercetin (30 mg/kg/day, I.P.) for 2 weeks (1 week prior to the LPS and 1 week cotreated with LPS) significantly reduced activated gliosis and various inflammatory markers and prevented neuroinflammation in the cortex and hippocampus of adult mice. Furthermore, quercetin rescued the mitochondrial apoptotic pathway and neuronal degeneration by regulating Bax/Bcl2, and decreasing activated cytochrome c, caspase-3 activity and cleaving PARP-1 in the cortical and hippocampal regions of the mouse brain. The quercetin treatment significantly reversed the LPS-induced synaptic loss in the cortex and hippocampus of the adult mouse brain and improved the memory performance of the LPS-treated mice. In summary, our results demonstrate that natural flavonoids such as quercetin can be beneficial against LPS-induced neurotoxicity in adult mice.

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Neurodegenerative disorders have emerged as a serious health issue in the current era. The most common neurodegenerative disorders are Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS). These diseases involve progressive impairment of neurodegeneration and memory impairment. A wide range of compounds have been identified as potential neuroprotective agents against different models of neurodegeneration both in vivo and in vitro. Hesperetin, a flavanone class of citrus flavonoid, is a derivative of hesperidin found in citrus fruits such as oranges, grapes, and lemons. It has been extensively reported that hesperetin exerts neuroprotective effects in experimental models of neurodegenerative diseases. In this systematic review, we have compiled all the studies conducted on hesperetin in both in vivo and in vitro models of neurodegeneration. Here, we have used an approach to lessen the bias in each study, providing a least biased, broad understanding of findings and impartial conclusions of the strength of evidence and the reliability of findings. In this review, we collected different papers from a wide range of journals describing the beneficial effects of hesperetin on animal models of neurodegeneration. Our results demonstrated consistent neuroprotective effects of hesperetin against different models of neurodegeneration. In addition, we have summarized its underlying mechanisms. This study provides the foundations for future studies and recommendations of further mechanistic approaches to conduct preclinical studies on hesperetin in different models.

Cadmium (Cd), a nonbiodegradable heavy metal and one of the most neurotoxic environmental and industrial pollutants, promotes disturbances in major organs and tissues following both acute and chronic exposure. In this study, we assessed the neuroprotective potential of caffeine (30 mg/kg) against Cd (5 mg/kg)-induced oxidative stress-mediated neuroinflammation, neuronal apoptosis, and cognitive deficits in male C57BL/6N mice in vivo and in HT-22 and BV-2 cell lines in vitro. Interestingly, our findings indicate that caffeine markedly reduced reactive oxygen species (ROS) and lipid peroxidation (LPO) levels and enhanced the expression of nuclear factor-2 erythroid-2 (Nrf-2) and hemeoxygenase-1 (HO-1), which act as endogenous antioxidant regulators. Also, 8-dihydro-8-oxoguanine (8-OXO-G) expression was considerably reduced in the caffeine-treated group as compared to the Cd-treated group. Similarly, caffeine ameliorated Cd-mediated glial activation by reducing the expression of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), and other inflammatory mediators in the cortical and hippocampal regions of the mouse brain. Moreover, caffeine markedly attenuated Cd-induced neuronal loss, synaptic dysfunction, and learning and cognitive deficits. Of note, nuclear factor-2 erythroid-2 (Nrf-2) gene silencing and nuclear factor-κB (NF-κB) inhibition studies revealed that caffeine exerted neuroprotection via regulation of Nrf-2- and NF-κB-dependent mechanisms in the HT-22 and BV-2 cell lines, respectively. On the whole, these findings reveal that caffeine rescues Cd-induced oxidative stress-mediated neuroinflammation, neurodegeneration, and memory impairment. The present study suggests that caffeine might be a potential antioxidant and neuroprotective agent against Cd-induced neurodegeneration.