Palmitoylethanolamide dampens neuroinflammation and anxiety-like behavior in obese mice

Lama, Adriano; Pirozzi, Claudio; Severi, Ilenia; Morgese, Maria Grazia; Senzacqua, Martina; Annunziata, Chiara; Comella, Federica; Piano, Filomena Del; Schiavone, Stefania; Petrosino, Stefania; Mollica, Maria Pina; Diano, Sabrina; Trabace, Luigia; Calignano, Antonio; Giordano, Antonio; Raso, Giuseppina Mattace; Meli, Rosaria

doi:10.1016/j.bbi.2022.02.008

Cited by 54 publications

(44 citation statements)

References 57 publications

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“…These beneficial effects could be attributed to TMP195-attenuated inflammatory responses, as shown by reduced mRNA levels of Il-1α, Il-1β, Tnfα, Gfap, C3, and Lcn2. This is in accordance with previous studies that described the beneficial effects on anxiety-like behaviors by blocking inflammation [ 1 , 7 ]. In addition, inflammatory response is a common hallmark pathology of multiple neurodegenerative diseases, such as Alzheimer’s disease and Parkinson disease; our positive data on LPS-challenged models might bring new insights in these chronic inflammatory diseases.…”

Section: Discussionsupporting

confidence: 94%

“…Considering the ongoing COVID-19 pandemic that has resulted in quarantine and social isolation, the rise in individuals suffering from anxiety has been particularly noticeable. Accumulating evidence suggest a tight link between inflammation and the pathology in anxiety and other psychiatric disorders [ 1 , 2 ]. Astrocytes are the most abundant glial cells and their dysfunction and activation have attracted increasing attention in the study of anxiety [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

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HDAC7 Activates IKK/NF-κB Signaling to Regulate Astrocyte-Mediated Inflammation

Zhong

Deng

et al. 2022

Mol Neurobiol

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Class IIa histone deacetylases (HDAC) have been shown to drive innate immune cell-mediated inflammation in the peripheral system, but their roles in cerebral inflammatory responses remain largely unknown. Here, we elucidate that HDAC7 is selectively elevated in lipopolysaccharide (LPS)-challenged astrocytes both in vivo and in vitro. We identify that HDAC7 binds to the inhibitory kappa B kinase (IKK) to promote IKKα and IKKβ deacetylation and subsequent activation, leading to the activation of nuclear factor κB (NF-κB). Astrocyte-specific overexpression of HDAC7 results in NF-κB activation, pro-inflammatory gene upregulation and anxiety-like behaviors in mice, while downregulating HDAC7 reserves LPS-induced NF-κB activation and inflammatory responses. Furthermore, pharmacological inhibition of HDAC7 by a class IIa HDAC inhibitor attenuates LPS-induced NF-κB activation, inflammatory responses and anxiety-like behaviors both in vivo and in vitro. Together, our data reveal a novel mechanism of HDAC7 in astrocyte-mediated inflammation and suggest that targeting HDAC7 could be a potential therapeutic strategy for the treatment of anxiety and other inflammation-related diseases. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-022-02965-6.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

HDAC7 Activates IKK/NF-κB Signaling to Regulate Astrocyte-Mediated Inflammation

Zhong

Deng

et al. 2022

Mol Neurobiol

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“…Each sample contained 500 ng cDNA in 2X QuantiTect SYBR Green PCR Master Mix, and primers were performed with a Bio-Rad CFX96 Connect Realtime PCR System instrument and software (Bio-Rad Laboratories). The used primers were mouse Cox-2 (Ptgs2), IL-1β (Il1b), and IL-10 (Il10) (Qiagen, Hilden, Germany), and the PCR conditions were previously described [ 54 , 55 ]. The relative amount of each studied mRNA was normalized to GAPDH as a housekeeping gene, and the data were analyzed according to the 2 –ΔΔCT method.…”

Section: Methodsmentioning

confidence: 99%

Dual-Hit Model of Parkinson’s Disease: Impact of Dysbiosis on 6-Hydroxydopamine-Insulted Mice—Neuroprotective and Anti-Inflammatory Effects of Butyrate

Avagliano

Coretti

Lama

et al. 2022

IJMS

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Recent evidence highlights Parkinson’s disease (PD) initiation in the gut as the prodromal phase of neurodegeneration. Gut impairment due to microbial dysbiosis could affect PD pathogenesis and progression. Here, we propose a two-hit model of PD through ceftriaxone (CFX)-induced dysbiosis and gut inflammation before the 6-hydroxydopamine (6-OHDA) intrastriatal injection to mimic dysfunctional gut-associated mechanisms preceding PD onset. Therefore, we showed that dysbiosis and gut damage amplified PD progression, worsening motor deficits induced by 6-OHDA up to 14 days post intrastriatal injection. This effect was accompanied by a significant increase in neuronal dopaminergic loss (reduced tyrosine hydroxylase expression and increased Bcl-2/Bax ratio). Notably, CFX pretreatment also enhanced systemic and colon inflammation of dual-hit subjected mice. The exacerbated inflammatory response ran in tandem with a worsening of colonic architecture and gut microbiota perturbation. Finally, we demonstrated the beneficial effect of post-biotic sodium butyrate in limiting at once motor deficits, neuroinflammation, and colon damage and re-shaping microbiota composition in this novel dual-hit model of PD. Taken together, the bidirectional communication of the microbiota–gut–brain axis and the recapitulation of PD prodromal/pathogenic features make this new paradigm a useful tool for testing or repurposing new multi-target compounds in the treatment of PD.

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“…The BBB plays the prominent role in keeping homeostasis within the central nervous system through blocking foreign substances from the blood into the brain tissue (Chang et al, 2017). Cerebral I/R elicits BBB endothelial cell lesion and BBB destruction, which is linked with BBB leakage, incremental permeability and inflammatory cell infiltration (Lama et al, 2022;Lei et al, 2021), yet there are still unapproachable to efficacious clinic interventions of BBB breakdown following cerebral I/R injury. Our previous study revealed that TLB effectively protected against cerebral I/R injury inasmuch as it possesses excellent anti-inflammatory property (J.…”

Section: Discussionmentioning

confidence: 99%

Trilobatin attenuates cerebral ischemia/reperfusion-induced blood-brain-barrier dysfunction by targeting MMP9: The legend of a food additive

Feng

Lin

et al. 2023

Preprint

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Background and Purpose: Blood-brain barrier (BBB) breakdown is one of the most crucial pathological changes of cerebral ischemia-reperfusion (I/R) injury. Trilobatin (TLB), a naturally occurring food additive, exerts neuroprotective effect against cerebral I/R injury as demonstrated in our previous study. This study was designed to investigate the effect of TLB on disruption of BBB after cerebral I/R injury. Experimental Approach: Rats with focal cerebral ischemia caused by transient middle cerebral artery occlusion (MCAO) and brain microvascular endothelial cells along with human astrocytes to mimic blood brain barrier (BBB) injury caused by oxygen and glucose deprivation (OGD) followed by reoxygenation (OGD/R). Key results: The results showed that TLB effectively maintained the integrity of BBB and inhibited neuronal loss following cerebral I/R challenge. Furthermore, TLB dramatically increased tight junction proteins including ZO-1, occludin and claudin 5, as well as decreased the levels of apolipoprotein E (APOE) 4, cyclophilin A (CypA), and phosphorylated nuclear factor kappa B (NF-κB), thereby reduced proinflammatory cytokines. In addition, TLB also decreased Bax/Bcl-2 ratio and cleaved-caspase 3 level along with reduced the number of apoptotic neurons. Intriguingly, molecular docking and transcriptomics predicted MMP9 was a prominent gene evoked by TLB treatment. Furthermore, the protective effect of TLB on OGD/R-induced the loss of BBB integrity in human brain microvascular endothelial cell and astrocyte co-cultures in vitro was markedly reinforced by knockdown of MMP9. Conclusions and implications: Our findings reveal a novel property of TLB: saving BBB disruption following cerebral I/R via targeting MMP9 and inhibiting APOE4/CypA/NF-κB axis.

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Palmitoylethanolamide dampens neuroinflammation and anxiety-like behavior in obese mice

Cited by 54 publications

References 57 publications

HDAC7 Activates IKK/NF-κB Signaling to Regulate Astrocyte-Mediated Inflammation

HDAC7 Activates IKK/NF-κB Signaling to Regulate Astrocyte-Mediated Inflammation

Dual-Hit Model of Parkinson’s Disease: Impact of Dysbiosis on 6-Hydroxydopamine-Insulted Mice—Neuroprotective and Anti-Inflammatory Effects of Butyrate

Trilobatin attenuates cerebral ischemia/reperfusion-induced blood-brain-barrier dysfunction by targeting MMP9: The legend of a food additive

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