The ability of endocannabinoid (eCB) to change functional microglial phenotype can be explored as a possible target for therapeutic intervention. Since the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of anandamide (AEA), may provide beneficial effects in mice model of Alzheimer’s disease (AD)-like pathology, we aimed at determining whether the FAAH inhibitor URB597 might target microglia polarization and alter the cytoskeleton reorganization induced by the amyloid-β peptide (Aβ). The morphological evaluation showed that Aβ treatment increased the surface area of BV-2 cells, which acquired a flat and polygonal morphology. URB597 treatment partially rescued the control phenotype of BV-2 cells when co-incubated with Aβ. Moreover, URB597 reduced both the increase of Rho protein activation in Aβ-treated BV-2 cells and the Aβ-induced migration of BV-2 cells, while an increase of Cdc42 protein activation was observed in all samples. URB597 also increased the number of BV-2 cells involved in phagocytosis. URB597 treatment induced the polarization of microglial cells towards an anti-inflammatory phenotype, as demonstrated by the decreased expression of iNOS and pro-inflammatory cytokines along with the parallel increase of Arg-1 and anti-inflammatory cytokines. Taken together, these data suggest that FAAH inhibition promotes cytoskeleton reorganization, regulates phagocytosis and cell migration processes, thus driving microglial polarization towards an anti-inflammatory phenotype.

Neurodegenerative disorders are a widespread cause of morbidity and mortality worldwide, characterized by neuroinflammation, oxidative stress and neuronal depletion. The broad-spectrum neuroprotective activity of the Mediterranean diet is widely documented, but it is not yet known whether its nutritional and caloric balance can induce a modulation of the endocannabinoid system. In recent decades, many studies have shown how endocannabinoid tone enhancement may be a promising new therapeutic strategy to counteract the main hallmarks of neurodegeneration. From a phylogenetic point of view, the human co-evolution between the endocannabinoid system and dietary habits could play a key role in the pro-homeostatic activity of the Mediterranean lifestyle: this adaptive balance among our ancestors has been compromised by the modern Western diet, resulting in a “clinical endocannabinoid deficiency syndrome”. This review aims to evaluate the evidence accumulated in the literature on the neuroprotective, immunomodulatory and antioxidant properties of the Mediterranean diet related to the modulation of the endocannabinoid system, suggesting new prospects for research and clinical interventions against neurodegenerative diseases in light of a nutraceutical paradigm.

The onset of neurodegenerative diseases involves a complex interplay of pathological mechanisms, including protein aggregation, oxidative stress, and impaired autophagy. This review focuses on the intricate connection between oxidative stress and autophagy in neurodegenerative disorders, highlighting autophagy as pivotal in disease pathogenesis. Reactive oxygen species (ROS) play dual roles in cellular homeostasis and autophagy regulation, with disruptions of redox signaling contributing to neurodegeneration. The activation of the Nrf2 pathway represents a critical antioxidant mechanism, while autophagy maintains cellular homeostasis by degrading altered cell components. The interaction among p62/SQSTM1, Nrf2, and Keap1 forms a regulatory pathway essential for cellular stress response, whose dysregulation leads to impaired autophagy and aggregate accumulation. Targeting the Nrf2-p62/SQSTM1 pathway holds promise for therapeutic intervention, mitigating oxidative stress and preserving cellular functions. Additionally, this review explores the potential synergy between the endocannabinoid system and Nrf2 signaling for neuroprotection. Further research is needed to elucidate the involved molecular mechanisms and develop effective therapeutic strategies against neurodegeneration.

Microglia, the innate immune cells of the CNS, respond to brain injury by activating and modifying their morphology. Our study arises from the great interest that has been focused on blueberry (BB) for the antioxidant and pharmacological properties displayed by its components. We analyzed the influence of hydroalcoholic BB extract in resting or lipopolysaccharide (LPS)-stimulated microglia BV-2 cells. BB exerted a protective effect against LPS-induced cytotoxicity, as indicated by cell viability. BB was also able to influence the actin cytoskeleton organization, to recover the control phenotype after LPS insult, and also to reduce LPS-driven migration. We evaluated the activity of Rho and Rac1 GTPases, which regulate both actin cytoskeletal organization and migratory capacity. LPS caused an increase in Rac1 activity, which was counteracted by BB extract. Furthermore, we demonstrated that, in the presence of BB, mRNA expression of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α decreased, as did the immunofluorescence signal of iNOS, whereas that of Arg-1 was increased. Taken together, our results show that, during the inflammatory response, BB extract shifts the M1 polarization towards the M2 phenotype through an actin cytoskeletal rearrangement. Based on that, we might consider BB as a nutraceutical with anti-inflammatory activities.

Curcumin, a polyphenolic compound derived from Curcuma longa, has gained significant attention for its potential therapeutic benefits, particularly counteracting inflammation, oxidative stress, and metabolic disorders. Its chemical structure, featuring conjugated double bonds between two aromatic rings, allows it to act as an electron donor, thereby mitigating free radical formation. Despite its poor solubility in water, curcumin is stable in acidic environments and undergoes significant metabolism in both the liver and the gut. Intestinal microbiota, particularly at the colon level, further metabolizes curcumin into several derivatives, including dihydrocurcumin and tetrahydrocurcumin, which exhibit antioxidant and anti-inflammatory properties. Studies suggest that curcumin can reduce body mass index (BMI) and improve other body composition parameters, especially when used in combination with lifestyle changes, though its bioavailability is low due to its rapid metabolism and the resulting low blood concentration. In obesity, dysfunctional adipose tissue remodeling and chronic inflammation play critical roles in the development of metabolic complications. Curcumin’s anti-inflammatory properties are related to the inhibition of the NF-κB pathway, leading to the reduction in inflammatory markers in adipocytes and macrophages. Additionally, curcumin modulates oxidative stress by activating the NRF2 pathway, enhancing cellular antioxidant defenses. Emerging evidence also supports curcumin’s potential in improving gut health by modulating microbiota composition, enhancing intestinal barrier function, and reducing systemic inflammation. This interaction with the gut–brain axis highlights the broader implications of curcumin in neuroprotection, as it positively affects cognitive function and mitigates neuroinflammation in neurodegenerative diseases like Alzheimer’s. disease. Thus, curcumin holds promise as a multifaceted agent in the management of obesity and associated diseases.

The endocannabinoid N‐arachidonoylethanolamine (AEA) is a pro‐homeostatic bioactive lipid known for its anti‐inflammatory, anti‐oxidative, immunomodulatory, and neuroprotective properties, which may contrast/mitigate Alzheimer's disease (AD) pathology. This study explores the therapeutic potential of targeting fatty acid amide hydrolase (FAAH), the major enzyme degrading AEA, in mouse models of amyloidosis (APP/PS1 and Tg2576). Enhancing AEA signaling by genetic deletion of FAAH delayed cognitive deficits in APP/PS1 mice and improved cognitive symptoms in 12‐month‐old AD‐like mice. Chronic pharmacological FAAH inhibition fully reverted neurocognitive decline, attenuated neuroinflammation, and promoted neuroprotective mechanisms in Tg2576 mice. Additionally, pharmacological FAAH inhibition robustly suppressed β‐amyloid production and accumulation, associated with decreased expression of β‐site amyloid precursor protein cleaving enzyme 1 (BACE1), possibly through a cannabinoid receptor 1‐dependent epigenetic mechanism. These findings improve our understanding of AEA signaling in AD pathogenesis and provide proof of concept that selective targeting of FAAH activity could be a promising therapeutic strategy against AD.