Alzheimer’s disease (AD) is a neurodegenerative disorder associated with marked oxidative stress at the level of the brain. Recent studies indicate that increasing the antioxidant capacity could represent a very promising therapeutic strategy for AD treatment. Astaxanthin (AST), a powerful natural antioxidant, could be a good candidate for AD treatment, although its use in clinical practice is compromised by its high instability. In order to overcome this limit, our attention focused on the development of innovative AST-loaded stealth lipid nanoparticles (AST-SSLNs) able to improve AST bioavailability in the brain. AST-SSLNs prepared by solvent-diffusion technique showed technological parameters suitable for parenteral administration (<200 nm). Formulated nanosystems were characterized by calorimetric studies, while their toxicological profile was evaluated by the MTT assay on the stem cell line OECs (Olfactory Ensheathing Cells). Furthemore, the protective effect of the nanocarriers was assessed by a long-term stability study and a UV stability assay confirming that the lipid shell of the nanocarriers was able to preserve AST concentration in the formulation. SSLNs were also capable of preserving AST’s antioxidant capacity as demonstrated in the oxygen radical absorbance capacity (ORAC) assay. In conclusion, these preliminary studies outline that SSLNs could be regarded as promising carriers for systemic administration of compounds such as AST aimed at AD treatment.

Curcumin (CUR) has a wide range of pharmacological properties, including anti-inflammatory and antioxidant activities, and it can be considered a good candidate for the potential treatment of central nervous system (CNS) pathologies, although its use in clinical practice is compromised due to its high lipophilicity. Solid lipid nanoparticles (SLNs) are well-known nanocarriers representing a consolidated approach for the delivery of lipophilic compounds, but their systemic use is limited due their short half-life. The formulation of stealth SLNs (pSLNs) could be a valid strategy to overcome this limit. Curcumin-loaded-pSLNs were prepared by the solvent evaporation method. Formulation was characterized for their mean size, zeta potential, size distribution, and morphology. Drug antioxidant activity was evaluated by Oxygen Radical Absorbance Capacity (ORAC) assay. Finally, the obtained formulations were analyzed in terms of long-term stability. Curcumin-loaded-pSLNs showed good technological parameters with a mean particle size below 200 nm, as confirmed by TEM images, and a zeta potential value around −30 mV, predicting good long-term stability. Differential Scanning Calorimetry (DSC) analysis confirmed that PEG micelles interacted with the SLN surface; this suggests the location of the PEG on the pSLN surface. Therefore, these preliminary studies suggest that the produced formulation could be regarded as a promising carrier for the systemic administration.

Alzheimer’s disease (AD) is a neurodegenerative disease representing the most prevalent cause of dementia. It is also related to the aberrant amyloid-beta (Aβ) protein deposition in the brain. Since oxidative stress is involved in AD, there is a possible role of antioxidants present in the effected person’s diet. Thus, we assessed the effect of the systemic administration of solid lipid nanoparticles (SLNs) to facilitate curcumin (CUR) delivery on TG2 isoform expression levels in Wild Type (WT) and in TgCRND8 (Tg) mice. An experimental model of AD, which expresses two mutated human amyloid precursor protein (APP) genes, was used. Behavioral studies were also performed to evaluate the improvement of cognitive performance and memory function induced by all treatments. The expression levels of Bcl-2, Cyclin-D₁, and caspase-3 cleavage were evaluated as well. In this research, for the first time, we demonstrated that the systemic administration of SLNs-CUR, both in WT and in Tg mice, allows one to differently modulate TG2 isoforms, which act either on apoptotic pathway activation or on the ability of the protein to repair cellular damage in the brains of Tg mice. In this study, we also suggest that SLNs-CUR could be an innovative tool for the treatment of AD.

Tomato by-products represent a good source of phytochemical compounds with health properties, such as the steroidal glycoalkaloid α-tomatine (α-TM) and its aglycone tomatidine (TD). Both molecules have numerous beneficial properties, such as potential anticancer activity. Unfortunately, their therapeutic application is limited due to stability and bioavailability issues. Therefore, a valid strategy seems to be their encapsulation into Solid Lipid Nanoparticles (SLN). The nanoformulations containing α-TM (α-TM-SLN) and TD (TD-SLN) were prepared by solvent-diffusion technique and subsequently characterized in terms of technological parameters (particle size, polydispersity index, zeta potential, microscopy, and calorimetric studies). To assess the effect of α-TM and TD on the percentage of cellular viability in Olfactory Ensheathing Cells (OECs), a peculiar glial cell type of the olfactory system used as normal cells, and in SH-SY5Y, a neuroblastoma cancer cell line, an MTT test was performed. In addition, the effects of empty, α-TM-SLN, and TD-SLN were tested. Our results show that the treatment of OECs with blank-SLN, free α-TM (0.25 µg/mL), and TD (0.50 µg/mL) did not induce any significant change in the percentage of cell viability when compared with the control. In contrast, in SH-SY5Y-treated cells, a significant decrease in the percentage of cell viability when compared with the control was found. In particular, the effect appeared more evident when SH-SY5Y cells were exposed to α-TM-SLN and TD-SLN. No significant effect in blank-SLN-treated SH-SY5T cells was observed. Therefore, SLN is a promising approach for the delivery of α-TM and TD.

Herein, we assessed the effect of full native peptide of amyloid-beta (Aβ) (1-42) and its fragments (25-35 and 35-25) on tissue transglutaminase (TG2) and its isoforms (TG2-Long and TG2-Short) expression levels on olfactory ensheathing cells (OECs). Vimentin and glial fibrillary acid protein (GFAP) were also studied. The effect of the pre-treatment with indicaxanthin from Opuntia ficus-indica fruit on TG2 expression levels and its isoforms, cell viability, total reactive oxygen species (ROS), superoxide anion (O₂⁻), and apoptotic pathway activation was assessed. The levels of Nestin and cyclin D1 were also evaluated. Our findings highlight that OECs exposure to Aβ(1-42) and its fragments induced an increase in TG2 expression levels and a different expression pattern of its isoforms. Indicaxanthin pre-treatment reduced TG2 overexpression, modulating the expression of TG2 isoforms. It reduced total ROS and O₂⁻ production, GFAP and Vimentin levels, inhibiting apoptotic pathway activation. It also induced an increase in the Nestin and cyclin D1 expression levels. Our data demonstrated that indicaxanthin pre-treatment stimulated OECs self-renewal through the reparative activity played by TG2. They also suggest that Aβ might modify TG2 conformation in OECs and that indicaxanthin pre-treatment might modulate TG2 conformation, stimulating neural regeneration in Alzheimer’s disease.

Astaxanthin, a natural compound of Haematococcus pluvialis, possesses antioxidant, anti-inflammatory, anti-tumor and immunomodulatory activities. It also represents a potential therapeutic in Alzheimer’s disease (AD), that is related to oxidative stress and agglomeration of proteins such as amyloid-beta (Aβ). Aβ is a neurotoxic protein and a substrate of tissue transglutaminase (TG2), an ubiquitary protein involved in AD. Herein, the effect of astaxanthin pretreatment on olfactory ensheathing cells (OECs) exposed to Aβ(1–42) or by Aβ(25–35) or Aβ(35–25), and on TG2 expression were assessed. Vimentin, GFAP, nestin, cyclin D₁ and caspase-3 were evaluated. ROS levels and the percentage of cell viability were also detected. In parallel, delayed luminescence (DL) was used to monitor mitochondrial status. ASTA reduced TG2, GFAP and vimentin overexpression, inhibiting cyclin D₁ levels and apoptotic pathway activation which induced an increase in the nestin levels. In addition, significant changes in DL intensities were particularly observed in OECs exposed to Aβ toxic fragment (25–35), that completely disappear when OECs were pre-incubated in astaxantin. Therefore, we suggest that ASTA pre-treatment might represent an innovative mechanism to contrast TG2 overexpression in AD.