Caffeine May Abrogate LPS-Induced Oxidative Stress and Neuroinflammation by Regulating Nrf2/TLR4 in Adult Mouse Brains

Abstract

Herein, we assayed the antioxidant and anti-inflammatory potential of caffeine in a lipopolysaccharide (LPS)-injected mouse model of neurodegeneration and synaptic impairment. For this purpose, LPS was injected for two weeks on an alternate-day basis (250 µg/kg/i.p. for a total of seven doses), while caffeine was injected daily for four weeks (30 mg/kg/i.p/four weeks). According to our findings, there was a significant increase in the level of reactive oxygen species (ROS), as evaluated from the levels of lipid peroxidation (LPO) and ROS assays. Also, we evaluated the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) and the enzyme hemeoxygenase 1 (HO-1) in the mouse groups and found reduced expression of Nrf2 and HO-1 in the LPS-treated mice brains, but they were markedly upregulated in the LPS + caffeine co-treated group. We also noted enhanced expression of toll-Like Receptor 4 (TLR4), phospho-nuclear factor kappa B (p-NF-kB), and phospho-c-Jun n-terminal kinase (p-JNK) in the LPS-treated mice brains, which was significantly reduced in the LPS + caffeine co-treated group. Moreover, we found enhanced expression of Bcl2-associated X, apoptosis regulator (Bax), and cleaved caspase-3, and reduced expression of B-cell lymphoma 2 (Bcl-2) in the LPS-treated group, which were markedly reversed in the LPS + caffeine co-treated group. Furthermore, we analyzed the expression of synaptic proteins in the treated groups and found a marked reduction in the expression of synaptic markers in the LPS-treated group; these were significantly upregulated in the LPS + caffeine co-treated group. In summary, we conclude that caffeine may inhibit LPS-induced oxidative stress, neuroinflammation, and synaptic dysfunction.

Lactobacillus rhamnosus GG and Oat Beta‐Glucan Regulated Fatty Acid Profiles along the Gut‐Liver‐Brain Axis of Mice Fed with High Fat Diet and Demonstrated Antioxidant and Anti‐Inflammatory Potentials

“…For instance, neuroinflammation and oxidative stress induced in the mouse brain by LPS was attributed to the downregulation of Nrf2, while for it to be restored, reduced activated NFκB and TNFα via TLR4 pathway was required. [ 49 ] A similar mechanistic scenario was also depicted by Yang's group in the mice liver, where LPS suppressed the Nrf2 expression, resulting in an upregulated NFκB pathway and an augmented release of IL‐1β and IL‐6. [ 50 ]…”

Oral Administration of Alpha Linoleic Acid Rescues Aβ-Induced Glia-Mediated Neuroinflammation and Cognitive Dysfunction in C57BL/6N Mice

“…Previous research studies extensively highlighted inflammation as a crucial player in cardiovascular disease [43] and neurodegenerative conditions [6,44], specifically AD [17] and PD [45]. Here, we found that the chronic oral administration of ALA may inhibit Aβ-induced neuroinflammation by regulating the levels of activated TLR4 and its downstream targets, such as GFAP and Iba-1.…”

“…After behavioral analyses, the mice were anesthetized via a combination of ketamine and xylazine and euthanized, as previously described [6,38]. The brain parts were separated and homogenized in PRO-PREP TM extraction solution (iNtRON Biotechnology, Inc., Sungnam, South Korea) and centrifuged (13,000 RPM for 25 min at 4 • C).…”

“…The exact mechanism of AD is unknown, but genetic [3] and environmental factors, such as aging, family history, comorbidities such as diabetes and cardiovascular disease [4,5], a substandard lifestyle, and nutrition are thought to play roles in its spread. Besides the accumulation of amyloid-beta (Aβ 1-42 ) plaques and hyperphosphorylation of neurofibrillary tangles (NFTs), which are considered to be the two main hallmarks of AD, other contributors to disease onset include oxidative stress [6], neuroinflammation, and apoptotic cell death [7].…”

Methylxanthines Inhibit Primary Amine Oxidase and Monoamine Oxidase Activities of Human Adipose Tissue

“…While this is clearly significant, it remains speculative until detailed studies with pure enzyme are carried out. Nonetheless, it is known that these compounds have a wide variety of health benefits when present in the diet, especially on neurodegenerative disease [4,5,60,61] and must, therefore, reach levels sufficient to exert pharmacological action. The true levels of methylxanthine interacting with the enzyme under the conditions of this study were impossible to estimate due to the possibility of interaction with lipids and tissue components.…”