Protective Effect of Semisynthetic and Natural Flavonoid on Aged Rat Microglia–enriched Cultures
The ROS-mediated lysosomal dysfunction and coinciding deterioration of mitochondrial function are thought to be the prominent mechanisms responsible for aging. Microglia, the resident macrophages in the central nervous system, were postulated to belong to the major targets vulnerable to these detrimental processes, acting as principal drivers in brain aging. The present study investigated the potential protective effect of the semisynthetic flavonoid 3′-O-(3-chloropivaloyl) quercetin (CPQ) and quercetin (Q) on microglia-enriched mixed brain cultures (MBCs) established from aged Wistar rats. Both flavonoids tested suppressed the development of lipofuscin-related autofluorescence in aged cells. Further ensuing protective effects included reduction of protein oxidation markers in aged cells. Moreover, unlike Q, CPQ significantly suppressed sensitivity of aged cells to stimulation of superoxide burst. Other activation markers, cellular hypertrophy and isolectin B4 binding, were also downregulated by treatment with both CPQ and Q. In conclusion, results of our study suggest that both flavonoids tested may protect microglia with a quite comparable efficacy against aging-related accumulated alterations. The protective mechanism can include interference with the ROS-mediated vicious cycles involving lysosomal dysfunction. Nevertheless, the lipophilized quercetin, CPQ, a compound with proposed enhanced biological availability compared to parent molecule, can represent an agent potentially useful for new effective pharmaceutical intervention against brain aging, overcoming the limitations of clinical applicability of quercetin.
KeywordsMicroglia Aging Flavonoids Lipofuscin Mitochondria ROS
The study was supported by VEGA 2/0041/17, VEGA 2/0031/12, VEGA 2/0029/16, APVV-18-0336, APVV-15-0308. The work was supported by The Agency of the Ministry of Education of the Slovak Republic for the Structural Funds of EU, OP R&D of ERDF as a part of the Project: “Evaluation of natural substances and their selection for prevention and treatment of lifestyle diseases” (ITMS 26240220040).
Compliance with Ethical Standards
The study was performed in compliance with the Principles of Laboratory Animal Care and was approved by the institutional ethics committee and by the State Veterinary and Food Administration of the Slovak Republic (Act No. Ro-2590/11-221).
Conflict of Interest
The authors declare that there is no conflict of interest.
- Choi DY, Lee YJ, Hong JT, Lee HJ (2012) Antioxidant properties of natural polyphenols and their therapeutic potentials for Alzheimer’s disease. Brain Res Bull 87:144–153. https://doi.org/10.1016/j.brainresbull.2011.11.014 CrossRefPubMedGoogle Scholar
- Ginhoux F, Lim S, Hoeffel G, Low D, Huber T (2013) Origin and differentiation of microglia. Front Cell Neurosci 7. https://doi.org/10.3389/fncel.2013.00045
- Giulian D, Baker TJ (1986) Characterization of ameboid microglia isolated from developing mammalian brain. J Neurosci 6:2163–2178. https://doi.org/10.1523/JNEUROSCI.06-08-02163.1986 CrossRefPubMedPubMedCentralGoogle Scholar
- Ma W, Coon S, Zhao L, Fariss RN, Wong WT (2013) A2E accumulation influences retinal microglial activation and complement regulation. Neurobiol Ageing 34:943–960. https://doi.org/10.1016/j.neurobiolageing.2012.06.010 CrossRefGoogle Scholar
- Mangold CA, Wronowski B, Du M, Masser DR, Hadad N, Bixler GV, Brucklacher RM, Ford MM, Sonntag WE, Freeman WM (2017) Sexually divergent induction of microglial-associated neuroinflammation with hippocampal ageing. J Neuroinflammation 14(1):141. https://doi.org/10.1186/s12974-017-0920-8 CrossRefPubMedPubMedCentralGoogle Scholar
- Marschallinger J, Irving Mosher I, Wyss-Coray T (2017) Microglial dysfunction in brain ageing and neurodegeneration. In: Fulop T, Franceschi C, Hirokawa K, Pawelec G (eds) Handbook of immunosenescence, basic understanding and clinical implications. Springer, Cham, pp 1–15. https://doi.org/10.1007/978-3-319-64597-1_149-1 CrossRefGoogle Scholar
- Mellou F, Lazari D, Skaltsa H, Tselepis AD, Kolisis FN, Stamatis H (2005) Biocatalytic preparation of acylated derivatives of flavonoid glycosides enhances their antioxidant and antimicrobial activity. J Biotechnol 116(3):295–304. https://doi.org/10.1016/j.jbiotec.2004.12.002 CrossRefPubMedGoogle Scholar
- Paolicelli RC, Bisht K, Tremblay M-È (2014) Fractalkine regulation of microglial physiology and consequences on the brain and behaviour. Front Cell Neurosci 8. https://doi.org/10.3389/fncel.2014.00129
- Rook GA, Steele J, Umar S, Dockrell HM (1985) A simple method for the solubilisation of reduced NBT, and its use as a colorimetric assay for activation of human macrophages by gamma-interferon. J Immunol Methods 82(1):161–167. https://doi.org/10.1016/0022-1759(85)90235-2 CrossRefPubMedGoogle Scholar
- Shamsi FA, Boulton M (2001) Inhibition of RPE lysosomal and antioxidant activity by the age pigment lipofuscin. IOVS 42:3041–3046Google Scholar
- Stolzing A, Widmer R, Jung T, Voss P, Grune T (2006) Tocopherol-mediated modulation of age-related changes in microglial cells: turnover of extracellular oxidized protein material. Free Radic Biol Med 40:2126–2135. https://doi.org/10.1016/j.freeradbiomed.2006.02.011 CrossRefPubMedGoogle Scholar
- Sun GY, Chen Z, Jasmer KJ, Chuang DY, Gu Z, Hannink M, Simonyi A (2015) Quercetin attenuates inflammatory responses in BV-2 microglial cells: role of MAPKs on the Nrf2 pathway and induction of heme oxygenase-1. PLoS One 10:e0141509. https://doi.org/10.1371/journal.pone.0141509 CrossRefPubMedPubMedCentralGoogle Scholar
- von Leden RE, Khayrullina G, Moritz KE, Byrnes KR (2017) Age exacerbates microglial activation, oxidative stress, inflammatory and NOX2 gene expression, and delays functional recovery in a middle-aged rodent model of spinal cord injury. J Neuroinflammation 14:161. https://doi.org/10.1186/s12974-017-0933-3 CrossRefGoogle Scholar
- Wong WT (2013) Microglial ageing in the healthy CNS: phenotypes, drivers, and rejuvenation. Front Cell Neurosci. https://doi.org/10.3389/fncel.2013.00022