Neuroprotection by Association of Palmitoylethanolamide with Luteolin in Experimental Alzheimer's Disease Models: the Control of Neuroinflammation
Abstract
Alzheimer's disease (AD) is the most common neurodegenerative disorder. Its neuropathological hallmarks include deposition of beta amyloid (Aβ) fibrils in senile plaques. Numerous biochemical events, leading to Aβ neurotoxicity in AD, have been proposed and it seems that neuroinflammation plays a prominent role among these. Thus, since inflammatory processes and oxidative stress are considered to play an important role in neuroinflammatory disorders and in AD pathology, in the present work we decided to test a new composite, which is a formulation constituted of an anti-inflammatory compound such as palmitoylethanolamide (PEA) and the well recognized antioxidant flavonoid luteolin (Lut), subjected to an ultra-micronization process, here designated co-ultraPEALut. We investigated the effect of co-ultraPEALut in both an in vitro and ex vivo organotypic model of AD. For the in vitro model, we used human neuronal cells, obtained by differentiating SH-SY5Y neuroblastoma cells into sustainable neuronal morphology. These well differentiated cells express features specific to mature neurons, such as synaptic structures and functional axonal vesicle transport, making this new concept for in vitro differentiation valuable for many neuroscientific research areas, including AD. Differentiated SH-SY5Y cells were pre-treated with co-ultraPEALut (reference concentrations: 27, 2.7 and 0.27 µM PEA) for 2 h. AD features were induced by Aβ₁₋₄₂ stimulation (1 µM). Twenty-four hours later cell vitality was evaluated by the colorimetric MTT assay, whereas the neuroinflammation underling AD was observed by Western blot analysis for IκBα degradation and nuclear factor-κB traslocation, as well as glial fibrillary acidic protein expression. For the organotypic model of AD, hippocampal slice cultures were prepared from mice at postnatal day 6 and after 21 days of culturing the slices were pre-treated with co-ultraPEALut (reference concentrations: 27, 2.7 and 0.27 µM PEA) for 2 h and then incubated with Aβ₁₋₄₂ (1 µg/ml) for 24 h. Pre-treatment with co-ultraPEALut significantly reduced inducible nitric oxide synthase and glial fibrillary acidic protein expression, restored neuronal nitric oxide synthase and brainderived neurotrophic factor and reduced the apoptosis. Taken together our results clearly showed that co-ultraPEALut is able to blunt Aβ-induced astrocyte activation and to exert a marked protective effect on glial cells. These findings suggest that the association of co-ultraPEALut may provide an effective strategy for AD.
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Combination of luteolin with palmitoylethanolamide reduces iNOS and GFAP expression and protects glial cells against Aβ injury in in vitro and ex vivo models.
“the combination of luteolin with another anti-inflammatory compound, the palmitoylethanolamide is able to reduce iNOS and GFAP expression and protect glial cells against the Aβ injury in both in vitro and ex vivo experimental models (Paterniti et al., 2014)”
From Exploring the Therapeutic Potential of Phytochemicals in Alzheimer’s Disease: Focus on Polyphenols and Monoterpenes (2022) · cites this paper as Paterniti et al., 2014
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“Pretreatment with coultraPEALut significantly reduced iNOS, glial fibrillary acidic protein expression and apoptosis, and restored neuronal NO synthase as well as brain-derived neurotrophic factor (BDNF; Paterniti et al., 2014).”
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“Neuronal differentiation was achieved using retinoic acid (RA) as previously described [39]; differentiation of cell lines into neuronal-like cell lines is required to mimic the intracellular environment of a neuronal cell.”
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- Authors
- Paterniti, I., Cordaro, M., Campolo, M., Siracusa, R., Cornelius, C., Navarra, M., Cuzzocrea, S., & Esposito, E.
- Affiliations
- University of Messina (IT)
- ORCID
- Venue
- CNS & Neurological Disorders - Drug Targets
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2014-12-12
- Volume
- 13
- Issue
- 9
- Pages
- 1530-1541
- ISSN
- 1568-007X (ISSN-L)
- 1871-5273
- OpenAlex
- W2038183008
- Cited by
- 90
- References
- 0
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 13 · 2023: 5 · 2022: 6 · 2021: 9 · 2020: 11 · 2019: 7 · 2018: 7 · 2017: 11 · 2016: 7 · 2015: 7
- FWCI
- 5.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- CNS & Neurological Disorders - Drug Targets (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disorders and Treatments
- Keywords
- Alzheimer's disease, palmitoylethanolamide, luteolin, neuroprotection, neuroinflammation, amyloid-beta, oxidative stress, NF-κB signaling, IκBα degradation, organotypic hippocampal slice cultures, nitric oxide synthase, glial fibrillary acidic protein
- MeSH terms
- NF-KappaB Inhibitor alpha, Amides, Animals, DNA Damage, Dose-Response Relationship, Drug, Drug Interactions, Ethanolamines, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Hippocampus, Humans, Neuroblastoma, Nitrites, Organ Culture Techniques, Palmitic Acids, Peptide Fragments, Amyloid beta-Peptides, NF-kappa B, Neuroprotective Agents, Brain-Derived Neurotrophic Factor, I-kappa B Proteins, Cell Line, Tumor, Luteolin, Glial Cell Line-Derived Neurotrophic Factor, Mice, Caspase 3, In Vitro Techniques
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