# Standardized Hydroxytyrosol-Enriched Olive Pomace Juice Modulates Metabolic and Neurotrophic Signaling Pathways to Attenuate Neuroinflammation and Protect Neuronal Cells

## TL;DR

This study shows that olive pomace juice, rich in hydroxytyrosol, protects neurons and reduces inflammation, offering potential for neurodegenerative disease treatments.

## Contribution

The study identifies hydroxytyrosol as the key compound in olive pomace juice responsible for neuroprotection and anti-inflammatory effects.

## Key findings

- OPJ reduced H2O2-induced neuronal cell death and inhibited amyloid fibril formation.
- Hydroxytyrosol showed greater neuroprotective and anti-inflammatory effects than tyrosol.
- OPJ modulated antioxidant, anti-apoptotic, and neurotrophic pathways via Nrf2, AMPKα–SIRT1–PGC1α, and CREB–BDNF–TrkB signaling.

## Abstract

Olive pomace (OP), a by-product of olive oil production, is a sustainable resource rich in bioactive compounds with potential applications in cosmetics and pharmaceuticals. This study investigates the protective effects of olive pomace juice (OPJ) against H2O2-induced neuronal damage and LPS-induced inflammatory responses in HT22 and BV2 cells, respectively. OPJ suppressed H2O2-induced cell death and exerted anti-apoptotic effects by reducing the BAX/BCL2 ratio and caspase-3 cleavage. OPJ also mitigated neurodegenerative hallmarks by decreasing amyloid fibrils formation and inhibiting β-secretase and acetylcholinesterase (AChE) activity. Mechanistically, OPJ enhanced antioxidant response by upregulating Nrf2 and its downstream molecule HO-1, along with increasing mRNA levels of antioxidant enzymes, including catalase, SOD1, and GPx. OPJ further activated AMPKα–SIRT1–PGC1α signaling and CREB–BDNF–TrkB signaling, suggesting modulation of key antioxidant, anti-apoptotic, and neurotrophic pathways. In BV2 cells, OPJ downregulated pro-inflammatory cytokines (IL-6 and IL-1β) and decreased iNOS and COX-2 expression through suppression of NF-κB and MAPK signaling pathways. HPLC analysis identified hydroxytyrosol (10.92%) as the major active compound in OPJ, which compared with tyrosol (2.18%), and hydroxytyrosol exhibited greater neuroprotective and anti-inflammatory effects than tyrosol. This study highlights the potential of OPJ and its major compound, hydroxytyrosol, as functional agents for mitigating neurodegeneration-related cellular response, supporting its application in the food and pharmaceutical industries.