The ketogenic diet, originally developed for the treatment of epilepsy in non-responder children, is spreading to be used in the treatment of many diseases, including Alzheimer’s disease. The main activity of the ketogenic diet has been related to improved mitochondrial function and decreased oxidative stress. B-Hydroxybutyrate, the most studied ketone body, has been shown to reduce the production of reactive oxygen species (ROS), improving mitochondrial respiration: it stimulates the cellular endogenous antioxidant system with the activation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2), it modulates the ratio between the oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD+/NADH) and it increases the efficiency of electron transport chain through the expression of uncoupling proteins. Furthermore, the ketogenic diet performs anti-inflammatory activity by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) activation and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome as well as inhibiting histone deacetylases (HDACs), improving memory encoding. The underlying mechanisms and the perspectives for the treatment of Alzheimer’s disease are discussed.

The contribution of neuroimmune functioning and brain-derived neurotrophic factor (BDNF) to functional dysregulation in autism spectrum disorder was assessed in 29 patients under treatment in two specialized centers of Basilicata (Chiaromonte and Matera), Southern Italy, through analysis of serum levels of cytokines and BDNF. Elevated levels of the pro-inflammatory cytokine, including interleukin-1, interleukin-6, interleukin-12, interleukin-23, tumor necrosis factor-α and BDNF were observed, regardless of age and gender. Comparisons were made with age- and gender-related healthy controls. The present findings reinforce current notions regarding immunoexcitotoxic mechanisms contributing to the pathophysiology of autistic disorder.

At the concentrations normally found in the brain extracellular space the glial-derived protein, S100B, protects neurons against neurotoxic agents by interacting with the receptor for advanced glycation end products (RAGE). It is known that at relatively high concentrations S100B is neurotoxic causing neuronal death via excessive stimulation of RAGE. S100B is detected within senile plaques in Alzheimer's disease, where its role is unknown. The present study was undertaken to evaluate a putative neuroprotective role of S100B against Abeta amyloid-induced neurotoxicity. We treated LAN-5 neuroblastoma cultures with toxic amounts of Abeta25-35 amyloid peptide. Our results show that at nanomolar concentrations S100B protects cells against Abeta-mediated cytotoxicity, as assessed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and terminal deoxynucleotidyl transferase-mediated dUTP-fluorescein isothiocyanate nick end-labeling (TUNEL) experiments, by countering the Abeta-mediated decrease in the expression of the anti-apoptotic factor Bcl-2. This effect depends on S100B binding to RAGE because S100B is unable to contrast Abeta-mediated neurotoxicity in neurons overexpressing a signaling-deficient RAGE mutant lacking the cytosolic and transducing domain. Our data suggest that at nanomolar doses S100B counteracts Abeta peptide neurotoxicity in a RAGE-mediated manner. However, at micromolar doses S100B is toxic to LAN-5 cells and its toxicity adds to that of the Abeta peptide, suggesting that additional molecular mechanisms may be involved in the neurotoxic process.

Macrophages consist of two main subsets: the proinflammatory M1 subset and the anti-inflammatory M2 one. 7-oxo-cholesterol, the most abundant cholesterol autoxidation product within atherosclerotic plaque, is able to skew the M1/M2 balance towards a proinflammatory profile. In the present study, we explored the ability of the polyphenolic compound resveratrol to counteract the 7-oxo-cholesterol-triggered proinflammatory signaling in macrophages. Resveratrol-pretreated human monocyte-derived M1 and M2 macrophages were challenged with 7-oxo-cholesterol and analyzed for phenotype and endocytic ability by flow cytometry, for metalloproteinase- (MMP-) 2 and MMP-9 by gelatin zymography, and for cytokine, chemokine, and growth factor secretome by a multiplex immunoassay. We also investigated the NF-κB signaling pathway. In the M1 subset, resveratrol prevented the downregulation of CD16 and the upregulation of MMP-2 in response to 7-oxo-cholesterol, whereas in M2 macrophages it prevented the upregulation of CD14, MMP-2, and MMP-9 and the downregulation of endocytosis. Resveratrol prevented the upregulation of several proinflammatory and proangiogenic molecules in both subsets. We identified modulation of NF-κB as a potential mechanism implicated in 7-oxo-cholesterol and resveratrol effects. Our results strengthen previous findings on the immunomodulatory ability of resveratrol and highlight its role as potential therapeutic or preventive compound, to counteract the proatherogenic oxysterol signaling within atherosclerotic plaque.

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