The Combined Effect of Green Tea, Saffron, Resveratrol, and Citicoline against Neurodegeneration Induced by Oxidative Stress in an In Vitro Model of Cognitive Decline.

During ageing, the brain is vulnerable to a growing imbalance of the antioxidant defence system, resulting in increased oxidative stress. This condition may be mainly responsible for cognitive decline, resulting in synaptic transmission disruptions and the onset of neuronal dysfunction. In this context, developing efficient preventive and therapeutic strategies against increased oxidative stress and decreased antioxidant defence mechanisms should be considered a public health priority to promote healthy ageing. Therefore, the current study explored the benefits of a novel combination of green tea, saffron, trans-Reveratrol, and citicoline, called MIX, on improving intracellular processes to ameliorate the mechanisms linked to cognitive decline under oxidative stress conditions. First, the ability of MIX to cross the blood-brain barrier (BBB) was evaluated in an in vitro model, analysing TEER value and the specific tight junctions; second, the CCF-STTG1 cell line was pretreated with 200 µM H2O2 for 30 min to explore the effects of the single active compounds and their combination under oxidative stress conditions. Our results demonstrated for the first time the synergistic effects of the new combination to improve the absorption rate of individual agents through the BBB and maintain its integrity. Subsequently, further research was done to assess the positive role of the combination to counteract oxidative damage; as expected, MIX restored the neurodegenerative state activated by 200 µM H2O2, reducing mitochondrial damage, and improving survival pathways. Additionally, MIX acted as a regulator of both cellular energy metabolism and apoptosis, reducing the inflammatory state activated by oxidative stress. Finally, MIX can balance neurotrophin production to prevent mitochondrial disruption. In conclusion, MIX counteracted the adverse effects of brain oxidative stress, suggesting that this new proposed formulation prevents the molecular mechanisms underlying the onset of cognitive decline, even in support of conventional therapy.

Palmitoylethanolamide as a Supplement: The Importance of Dose-Dependent Effects for Improving Nervous Tissue Health in an In Vitro Model.

Palmitoylethanolamide (PEA) is a highly lipophilic molecule with low solubility, making absorption difficult. Recent techniques like micronisation, ultra-micronisation and combining PEA with solvents have improved their bioavailability and stability. Our study analysed particle size differences and absorption kinetics using specific solvents (PEAΩ and PEA DynoΩ) over time (0.5 h-6 h) in a dose-dependent manner (200 mg-1800 mg). The results showed that PEAΩ and PEA DynoΩ achieved 82-63% absorption at 3 h, compared to 30-60% for micronised, ultra-micronised PEA and a commercial product, highlighting the optimal dose range of 300 mg-600 mg. In addition, a 3D model of the peripheral nerve was utilised to explain the efficacy after gut passage and support the most effective dose (300 mg or 600 mg) achieved at the gut level. PEAΩ and PEA DynoΩ, which are associated with better intestinal bioavailability compared to PEA-micronised, PEA ultra-micronised and a commercial product, have allowed not only a reduction in the inflammatory context but also an improvement of peripheral nerve well-being by increasing specific markers like MPZ (26-36% vs. 8-15%), p75 (25-32% vs. 13-16%) and NRG1 (22-29.5% vs. 11-14%). These results highlight the potential of advanced PEA formulations to overcome solubility challenges and maintain in vitro efficacy, modulating peripheral nerve well-being.

The influence of the gut-brain axis on anxiety and depression: A review of the literature on the use of probiotics.

This review aims to argue how using probiotics can improve anxiety and depressive behaviour without adverse effects, also exploring the impact of postbiotics on it. Specifically, probiotics have drawn more attention as effective alternative treatments, considering the rising cost of antidepressant and anti-anxiety drugs and the high risk of side effects. Depression and anxiety disorders are among the most common mental illnesses in the world's population, characterised by low mood, poor general interest, and cognitive or motor dysfunction. Thus, this study analysed published literature on anxiety, depression, and probiotic supplementation from PubMed and Scopus, focusing on the last twenty years. This study focused on the effect of probiotics on mental health as they have drawn more attention because of their extensive clinical applications and positive impact on various diseases. Numerous studies have demonstrated how the gut microbiota might be critical for mood regulation and how probiotics can affect host health by regulating the gut-brain axis. By comparing the different works analysed, it was possible to identify a strategy by which they are selected and employed and, at the same time, to assess how the effect of probiotics can be optimised using postbiotics, an innovation to improve mental well-being in humans.

An Innovative Probiotic-Based Supplement to Mitigate Molecular Factors Connected to Depression and Anxiety: An In Vitro Study.

The gut-brain axis is a bidirectional relationship between the microbiota and the brain; genes related to the brain and gut synaptic formation are similar. Research on the causal effects of gut microbiota on human behavior, brain development, and function, as well as the underlying molecular processes, has emerged in recent decades. Probiotics have been shown in several trials to help reduce anxiety and depressive symptoms. Because of this, probiotic combinations have been tested in in vitro models to see whether they might modulate the gut and alleviate depression and anxiety. Therefore, we sought to determine whether a novel formulation might affect the pathways controlling anxiety and depression states and alter gut barrier activities in a 3D model without having harmful side effects. Our findings indicate that B. bifidum novaBBF7 10 mg/mL, B. longum novaBLG2 5 mg/mL, and L. paracasei TJB8 10 mg/mL may influence the intestinal barrier and enhance the synthesis of short-chain fatty acids. Additionally, the probiotics studied did not cause neuronal damage and, in combination, exert a protective effect against the condition of anxiety and depression triggered by L-Glutamate. All these findings show that probiotics can affect gut function to alter the pathways underlying anxiety and depression.

Design of Mixed Medicinal Plants, Rich in Polyphenols, Vitamins B, and Palmitoylethanolamide-Based Supplement to Help Reduce Nerve Pain: A Preclinical Study.

Neuropathy affects 7-10% of the general population and is caused by a lesion or disease of the somatosensory system. The limitations of current therapies highlight the necessity of a new innovative approach to treating neuropathic pain (NP) based on the close correlation between oxidative stress, inflammatory process, and antioxidant action. The advantageous outcomes of a novel combination composed of Hop extract, Propolis, Ginkgo Biloba, Vitamin B, and palmitoylethanolamide (PEA) used as a treatment was evaluated in this study. To assess the absorption and biodistribution of the combination, its bioavailability was first examined in a 3D intestinal barrier model that replicated intestinal absorption. Further, a 3D nerve tissue model was developed to study the biological impacts of the combination during the essential pathways involved in NP. Our findings show that the combination could cross the intestinal barrier and reach the peripheral nervous system, where it modulates the oxidative stress, inflammation levels, and myelination mechanism (increased NRG, MPZ, ERB, and p75 levels) under Schwann cells damaging. This study proves the effectiveness of Ginkgo Biloba, Propolis, Hop extract, Vitamin B, and PEA in avoiding nerve damage and suggests a potential alternative nutraceutical treatment for NP and neuropathies.

The Combined Antioxidant Effects of N-Acetylcysteine, Vitamin D3, and Glutathione from the Intestinal-Neuronal In Vitro Model.

Chronic oxidative stress has been consistently linked to age-related diseases, conditions, and degenerative syndromes. Specifically, the brain is the organ that significantly contributes to declining quality of life in ageing. Since the body cannot completely counteract the detrimental effects of oxidative stress, nutraceuticals' antioxidant properties have received significant attention in recent years. This study assesses the potential health benefits of a novel combination of glutathione, vitamin D3, and N-acetylcysteine. To examine the combination's absorption and biodistribution and confirm that it has no harmful effects, the bioavailability of the mixture was first evaluated in a 3D model that mimicked the intestinal barrier. Further analyses on the blood-brain barrier was conducted to determine the antioxidant effects of the combination in the nervous system. The results show that the combination reaches the target and successfully crosses the blood-brain and intestinal barriers, demonstrating enhanced advantages on the neurological system, such as a reduction (about 10.5%) in inflammation and enhancement in cell myelination (about 20.4%) and brain tropism (about 18.1%) compared to the control. The results support the cooperative effect of N-acetylcysteine, vitamin D3, and glutathione to achieve multiple health benefits, outlining the possibility of an alternative nutraceutical approach.

Effects of Nutraceutical Compositions Containing Rhizoma Gastrodiae or Lipoic Acid in an In Vitro Induced Neuropathic Pain Model.

BACKGROUND: Peripheral neuropathy is caused by a malfunction in the axons and myelin sheaths of peripheral nerves and motor and sensory neurons. In this context, nonpharmacological treatments with antioxidant potential have attracted much attention due to the issues that some conventional pharmaceutical therapy can generate. Most of these treatments contain lipoic acid, but issues have emerged regarding its use. Considering this, the present study evaluated the beneficial effects of nutraceuticals based on Gastrodiae elata dry extract 10:1 or lipoic acid in combination with other substances (such as citicholine, B vitamins, and acetyl L-carnitine). METHOD: To assess the combination's absorption and biodistribution and exclude cytotoxicity, its bioavailability was first examined in a 3D intestinal barrier model that replicated oral ingestion. Subsequently, a 3D model of nerve tissue was constructed to investigate the impacts of the new combination on the significant pathways dysregulated in peripheral neuropathy. RESULTS: Our findings show that the novel combination outperformed in initial pain relief response and in recovering the mechanism of nerve healing following Schwann cell injury by successfully crossing the gut barrier and reaching the target site. CONCLUSION: This article describes a potential alternative nutraceutical approach supporting the effectiveness of combinations with Gastrodiae elata extract in decreasing neuropathy and regulating pain pathways.

Enhancing Vitamin D3 Efficacy: Insights from Complexation with Cyclodextrin Nanosponges and Its Impact on Gut-Brain Axes in Physiology and IBS Syndrome.

Vitamin D3 (VitD3) plays a crucial role in various cellular functions through its receptor interaction. The biological activity of Vitamin D3 can vary based on its solubility and stability. Thus, the challenge lies in maximizing its biological effects through its complexation within cyclodextrin (ßNS-CDI 1:4) nanosponges (NS) (defined as VitD3NS). Therefore, its activity has been evaluated on two different gut-brain axes (healthy gut/degenerative brain and inflammatory bowel syndrome gut/degenerative brain axis). At the gut level, VitD3-NS mitigated liposaccharide-induced damage (100 ng/mL; for 48 h), restoring viability, integrity, and activity of tight junctions and reducing ROS production, lipid peroxidation, and cytokines levels. Following intestinal transit, VitD3-NS improved the neurodegenerative condition in the healthy axis and the IBS model, suggesting the ability of VitD3-NS to preserve efficacy and beneficial effects even in IBS conditions. In conclusion, this study demonstrates the ability of this novel form of VitD3, named VitD3-NS, to act on the gut-brain axis in healthy and damaged conditions, emphasizing enhanced biological activity through VitD3 complexation, as such complexation increases the beneficial effect of vitamin D3 in both the gut and brain by about 50%.

The Role of Bifidobacterium bifidum novaBBF7, Bifidobacterium longum novaBLG2 and Lactobacillus paracasei TJB8 to Improve Mechanisms Linked to Neuronal Cells Protection against Oxidative Condition in a Gut-Brain Axis Model.

Despite the identification of several innovative targets for avoiding cognitive decline, there has yet to be a widely accepted approach that deals with minimising the deterioration of cognitive function. In this light, recent studies suggest that regulating the gut-brain axis with probiotics is a potential therapeutic strategy to support brain health. For this reason, in vitro models were used to examine the efficacy of different probiotic combinations to enhance intestinal homeostasis and positively affect the brain. Therefore, the new formulation has been evaluated for its capacity to modify intestinal barrier functions in a 3D in vitro model without any adverse effects and directly impact the mechanisms underlying cognitive function in a gut-brain axis model. According to our findings, B. bifidum novaBBF7 10 mg/mL, B. longum novaBLG2 5 mg/mL and L. paracasei TJB8 10 mg/mL may successfully modify the intestinal barrier and improve SCFA production. Successively, the probiotics studied caused no harm at the neuronal level, as demonstrated by iNOS, mitochondrial potential, and cell viability tests, confirming their safety features and enhancing antioxidant mechanisms and antineuroinflammation activity. Additionally, the damage caused by oxidative stress was also healed, and critical pathways that result in cognitive impairment were changed by synergetic action, supporting the hypothesis that brain ageing and neurodegeneration are slowed down. All these findings demonstrate the ability of probiotics to affect cognitive processes and their ability to sustain the mechanisms underlying cognitive function by acting on intestinal function.

Neutralizing activity of Usnic acid and ß-cyclodextrins complex against SARS-CoV-2 spike pseudovirus.

The rapid spread of SARS-CoV-2 and its infection severity require an urgent development of antiviral agents. In this respect, Usnic acid (UA), a natural dibenzofuran derivative, exerts antiviral activity against several viruses, though presenting very low solubility and high cytotoxicity. Here, UA was complexed with ß-cyclodextrins (ß-CDs), a pharmaceutical excipient used to improve drug solubility. The cytotoxic activity, tested on Vero E6 cells, revealed no effect for ß-CDs alone whereas significant cytotoxicity for the UA/ß-CDs complex was recorded at concentrations ≥ 0.05%. The neutralizing activity towards the fusion of SARS-CoV-2 Spike Pseudovirus showed no effects for ß-CDs alone whereas the UA/ß-CDs complex, when pre-incubated with the viral particles, efficiently inhibited the Pseudoviral fusion of about 90 and 82% at non-cytotoxic concentrations of 0.03 and 0.01%, respectively. In conclusion, although further evidences are needed to clarify the exact inhibition mechanism, UA/ß-CDs complex could be useful in SARS-CoV-2 infection.

Novel Approach to the Treatment of Neuropathic Pain Using a Combination with Palmitoylethanolamide and Equisetum arvense L. in an In Vitro Study.

Neuropathic pain is a typical patient disorder resulting from damage and dysfunction of the peripheral neuraxis. Injury to peripheral nerves in the upper extremities can result in a lifelong reduction in quality of life and a devastating loss of sensory and motor function. Since some standard pharmaceutical therapies can cause dependence or intolerance, nonpharmacological treatments have gained great interest in recent years. In this context, the beneficial effects of a new combination of palmitoylethanolamide and Equisetum arvense L. are evaluated in the present study. The bioavailability of the combination was initially analyzed in a 3D intestinal barrier simulating oral intake to analyze its absorption/biodistribution and exclude cytotoxicity. In a further step, a 3D nerve tissue model was performed to study the biological effects of the combination during the key mechanisms leading to peripheral neuropathy. Our results demonstrate that the combination successfully crossed the intestinal barrier and reached the target site, modulating the nerve recovery mechanism after Schwann cell injury and offering the initial response of relieving pain. This work supported the efficacy of palmitoylethanolamide and Equisetum arvense L. in reducing neuropathy and modifying the major pain mechanisms, outlining a possible alternative nutraceutical approach.

Effects of Usnic Acid to Prevent Infections by Creating a Protective Barrier in an In Vitro Study.

Nasal sprays are medical devices useful for preventing infection and the subsequent spread of airborne pathogens. The effectiveness of these devices depends on the activity of chosen compounds which can create a physical barrier against viral uptake as well as incorporate different substances with antiviral activity. Among antiviral compounds, UA, a dibenzofuran derived from lichens, has the mechanical ability to modify its structure by creating a branch capable of forming a protective barrier. The mechanical ability of UA to protect cells from virus infection was investigated by analyzing the branching capacity of UA, and then the protection mechanism in an in vitro model was also studied. As expected, UA at 37 °C was able to create a barrier confirming its ramification property. At the same time, UA was able to block the infection of Vero E6 and HNEpC cells by interfering with a biological interaction between cells and viruses as revealed also by the UA quantification. Therefore, UA can block virus activity through a mechanical barrier effect without altering the physiological nasal homeostasis. The findings of this research could be of great relevance in view of the growing alarm regarding the spread of airborne viral diseases.

A Combination of α-Lipoic Acid (ALA) and Palmitoylethanolamide (PEA) Blocks Endotoxin-Induced Oxidative Stress and Cytokine Storm: A Possible Intervention for COVID-19.

The global scientific community is striving to understand the pathophysiological mechanisms and develop effective therapeutic strategies for COVID-19. Despite overwhelming data, there is limited knowledge about the molecular mechanisms involved in the prominent cytokine storm syndrome and multiple organ failure and fatality in COVID-19 cases. The aim of this work is to investigate the possible role of of α-lipoic acid (ALA) and palmitoylethanolamide (PEA), in countering the mechanisms in overproduction of reactive oxygen species (ROS), and inflammatory cytokines. An in vitro model of lipopolysaccharide (LPS)-stimulated human epithelial lung cells that mimics the pathogen-associated molecular pattern and reproduces the cell signaling pathways in cytokine storm syndrome has been used. In this model of acute lung injury, the combination effects of ALAPEA, administered before and after LPS injury, were investigated. Our data demonstrated that a combination of 50 µM ALA + 5 µM PEA can reduce ROS and nitric oxide (NO) levels modulating the major cytokines involved on COVID-19 infection when administered either before or after LPS-induced damage. The best outcome was observed when administered after LPS, thus reinforcing the hypothesis that ALA combined with PEA to modulate the key point of cytokine storm syndrome. This work supports for the first time that the combination of ALA with PEA may represent a novel intervention strategy to counteract inflammatory damage related to COVID-19 by restoring the cascade activation of the immune response and acting as a powerful antioxidant.

New Hyaluronic Acid from Plant Origin to Improve Joint Protection-An In Vitro Study.

BACKGROUND: In recent decades, hyaluronic acid (HA) has attracted great attention as a new treatment option for osteoarthritis. Classical therapies are not able to stop the cartilage degeneration process nor do they favor tissue repair. Nowadays, it is accepted that high molecular weight HA can reduce inflammation by promoting tissue regeneration; therefore, the aim of this study was to verify the efficacy of a new high molecular weight HA of plant origin (called GreenIuronic®) in maintaining joint homeostasis and preventing the harmful processes of osteoarthritis. METHODS: The bioavailability of GreenIuronic® was investigated in a 3D intestinal barrier model that mimics human oral intake while excluding damage to the intestinal barrier. Furthermore, the chemical significance and biological properties of GreenIuronic® were investigated in conditions that simulate osteoarthritis. RESULTS: Our data demonstrated that GreenIuronic® crosses the intestinal barrier without side effects as it has a chemical-biological profile, which could be responsible for many specific chondrocyte functions. Furthermore, in the osteoarthritis model, GreenIuronic® can modulate the molecular mechanism responsible for preventing and restoring the degradation of cartilage. CONCLUSION: According to our results, this new form of HA appears to be well absorbed and distributed to chondrocytes, preserving their biological activities. Therefore, the oral administration of GreenIuronic® in humans can be considered a valid strategy to obtain beneficial therapeutic effects during osteoarthritis.

The Activity of Ten Natural Extracts Combined in a Unique Blend to Maintain Cholesterol Homeostasis-In Vitro Model.

BACKGROUND: Hypercholesterolemia is a major cause of cardiovascular disease and statins, the HMGCoA inhibitors, are the most prescribed drugs. Statins reduce the production of hepatic cholesterol, leading to greater expression of the LDL receptor and greater absorption of circulating LDL, reducing peripheral LDL levels. Unfortunately, statins are believed to induce myopathy and other severe diseases. To overcome this problem, safe nutraceuticals with the same activity as statins could hold great promise in the prevention and treatment of hypercholesterolemia. In this study, the anti-cholesterol efficacy of a new nutraceutical, called Esterol10®, was evaluated. METHODS: HepG2 cells were used to study the biological mechanisms exerted by Esterol10® analyzing different processes involved in cholesterol metabolism, also comparing data with Atorvastatin. RESULTS: Our results indicate that Esterol10® leads to a reduction in total hepatocyte cholesterol and an improvement in the biosynthesis of free cholesterol and bile acids. Furthermore, the anti-cholesterol activity of Esterol10® was also confirmed by the modulation of the LDL receptor and by the accumulation of lipids, as well as by the main intracellular pathways involved in the metabolism of cholesterol. CONCLUSIONS: Esterol10® is safe and effective with anti-cholesterol activity, potentially providing an alternative therapy to those based on statins for hypercholesterolemia disease.

Ovotransferrin Supplementation Improves the Iron Absorption: An In Vitro Gastro-Intestinal Model.

Transferrins constitute the most important iron regulation system in vertebrates and some invertebrates. Soluble transferrins, such as bovine lactoferrin and hen egg white ovotransferrin, are glycoproteins with a very similar structure with lobes that complex with iron. In this in vitro study, a comparison of bovine lactoferrin and ovotransferrin was undertaken to confirm the comparability of biological effects. An in vitro gastric barrier model using gastric epithelial cells GTL-16 and an in vitro intestinal barrier model using CaCo-2 cells was employed to evaluate iron absorption and barrier integrity. An analysis of the molecular pathways involving DMT-1 (divalent metal transporter 1), ferritin and ferroportin was also carried out. These in vitro data demonstrate the activity of both 15% saturated and 100% saturated ovotransferrin on the iron regulation system. Compared with the commercial bovine lactoferrin, both 15% saturated and 100% saturated ovotransferrin were found to act in a more physiological manner. Based on these data, it is possible to hypothesise that ovotransferrin may be an excellent candidate for iron supplementation in humans; in particular, 15% saturated ovotransferrin is the overall best performing product. In vivo studies should be performed to confirm this in vitro data.

Preventing c2c12 muscular cells damage combining magnesium and potassium with vitamin D3 and curcumin.

BACKGROUND AND AIM: Physical activity is defined as any bodily movement produced by skeletal muscles which causes energy consumption; moderate and constant physical activity is known to be beneficial and to slow the muscle loss process associated with aging. The aim of the present study was to test, in an in vitro exercise model, the biological effects of a new formulation composed of magnesium and potassium combined with vitamin D and curcumin created to support muscle activity and to prevent hypercontraction damage. EXPERIMENTAL PROCEDURE: C2C12 cells were treated with vitamin D, buffered magnesium bisglycinate, curcumin, and potassium citrate. Cell viability, morpho-functional changes, calcium and magnesium movements, and the main kinases involved in glucose uptake were analyzed. The glycogen level and lactate were also evaluated. RESULTS AND CONCLUSION: Important results about a positive effect on mitochondrial activity, ATP production, oxygen consumption and in the physiological differentiation of C2C12 cells were obtained. Further experiments were performed under conditions that mimic the biological aspects of strenuous exercise. The combination of magnesium, vitamin D3, curcumin, and potassium citrate revealed beneficial effects on skeletal muscle cells under physiological conditions as well as while mimicking intense activity. In particular, in an in vitro model, they were able to control the hypercontraction, restoring ion fluxes, reducing inflammation signaling and supporting the main mechanism involved on aerobic activity. Our results have indicated for the first time that this new combination could be considered as a new nutraceutical formulation to improve physical performance and muscle recovery.

Effects of a New Combination of Natural Extracts on Glaucoma-Related Retinal Degeneration.

BACKGROUND: Glaucoma is currently the leading cause of irreversible blindness; it is a neuropathy characterized by structural alterations of the optic nerve, leading to visual impairments. The aim of this work is to develop a new oral formulation able to counteract the early changes connected to glaucomatous degeneration. The composition is based on gastrodin and vitamin D3 combined with vitamin C, blackcurrant, and lycopene. METHODS: Cells and tissues of the retina were used to study biological mechanisms involved in glaucoma, to slow down the progression of the disease. Experiments mimicking the conditions of glaucoma were carried out to examine the etiology of retinal degeneration. RESULTS: Our results show a significant ability to restore glaucoma-induced damage, by counteracting ROS production and promoting cell survival by inhibiting apoptosis. These effects were confirmed by the intracellular mechanism that was activated following administration of the compound, either before or after the glaucoma induction. In particular, the main results were obtained as a preventive action of glaucoma, showing a beneficial action on all selected markers, both on cells and on eyecup preparations. It is therefore possible to hypothesize both the preventive and therapeutic use of this formulation, in the presence of risk factors, and due to its ability to inhibit the apoptotic cycle and to stimulate cell survival mechanisms, respectively. CONCLUSION: This formulation has exhibited an active role in the prevention or restoration of glaucoma damage for the first time.

A New Palmitoylethanolamide Form Combined with Antioxidant Molecules to Improve Its Effectivess on Neuronal Aging.

Palmitoylethanolamide is a nutraceutical compound naturally produced in many plants and animal source foods, but the natural form is poorly water-soluble. It has demonstrated an anti-inflammatory role as a neuroprotective mediator, acting on several molecular targets of the central nervous system involved on brain aging process. In healthy adults, palmitoylethanolamide is an endogenous PPAR-α (peroxisome proliferator-activated receptor α) agonist through which it performs anti-inflammatory activity and provides its effects by activating the cannabinoid receptor. The different formulations of palmitoylethanolamide (micronized palmitoylethanolamide, FM-LipoMatrix® palmitoylethanolamide and FM-LipoMatrix® palmitoylethanolamide plus lipoic acid and vitamin D3) were analyzed starting from intestinal barrier, to verify their bioavailability, to in primary astrocytes in which cell viability, reactive oxygen species (ROS) and nitric oxide (NO) production, NFKB activity, MAPK, p53 and PPARα activities were investigated. Additionally, cannabinoid and estrogen receptors were analyzed using the western blot technique. The combination of palmitoylethanolamide in FM-LipoMatrix®, lipoic acid and vitamin D3 shows better absorption predicting an improvement on plasma concentration; this formulation also shows a reduction in ROS and NO production and the data show the interaction of palmitoylethanolamide with cannabinoids and estrogen receptors inhibiting neuroinflammatory markers. All these data support the hypothesis of a new potential strategy to restore brain function and slow down brain aging in humans.