Ellagic acid-loaded galactosylated liposomes: an efficient strategy for counteracting senescence in mixed primary glial cells

Aging constitutes a multifaceted biological phenomenon with profound implications for the central nervous system. Astrocytes, which serve as vital homeostatic support cells, undergo a transition toward cellular senescence over time, thereby fueling the progression of neurodegenerative pathologies. Ellagic acid (EA) is a natural polyphenol present in various fruits and nuts that has recently garnered attention for its potential anti-aging and anti-senescence properties. It has beneficial effects in models of neurodegeneration, cardiovascular and renal aging, and oxidative stress. However, its clinical application is hindered by low water solubility, poor stability, low permeability, and limited bioavailability. To overcome these shortcomings and optimize its efficacy, galactosylated liposomes using galactosylceramide (Gal-LP-EA) were optimized. Liposomal encapsulation improved the water solubility of EA and they exhibited high encapsulation efficiency, good stability in the presence of human serum albumin and storage stability, and slow drug release profile. Gal-LP-EA improved EA permeability coefficient in BBB-PAMPA assay. The ability of EA and Gal-LP-EA to counteract the senescence induced by doxorubicin was analysed in mixed primary glial cells. The results demonstrated that doxorubicin treatment induced a senescent phenotype in mixed glial cells, characterized by increased expression of senescence markers such as p21 and by decrease of Ki67 and SIRT1 along with activation of the DNA damage response (γ-H2AX and p53). Also, EA and especially Gal-LP-EA were able to reduce this effect. The results of this multidisciplinary study underscore the potential of developing EA-loaded galactosyl-coated liposomes to modulate pathways involved in age-related neurodegeneration.