Pervasive Genomic Damage in Experimental Intracerebral Hemorrhage: Therapeutic Potential of a Mechanistic-Based Carbon Nanoparticle.

Abstract

Therapy for intracerebral hemorrhage (ICH) remains elusive, in part dependent on the severity of the hemorrhage itself as well as multiple deleterious effects of blood and its breakdown products such as hemin and free iron. While oxidative injury and genomic damage have been seen following ICH, the details of this injury and implications remain unclear. Here, we discovered that, while free iron produced mostly reactive oxygen species (ROS)-related single-strand DNA breaks, hemin unexpectedly induced rapid and persistent nuclear and mitochondrial double-strand breaks (DSBs) in neuronal and endothelial cell genomes and in mouse brains following experimental ICH comparable to that seen with γ radiation and DNA-complexing chemotherapies. Potentially as a result of persistent DSBs and the DNA damage response, hemin also resulted in senescence phenotype in cultured neurons and endothelial cells. Subsequent resistance to ferroptosis reported in other senescent cell types was also observed here in neurons. While antioxidant therapy prevented senescence, cells became sensitized to ferroptosis. To address both senescence and resistance to ferroptosis, we synthesized a modified, catalytic, and rapidly internalized carbon nanomaterial, poly(ethylene glycol)-conjugated hydrophilic carbon clusters (PEG-HCC) by covalently bonding the iron chelator, deferoxamine (DEF). This multifunctional nanoparticle, DEF-HCC-PEG, protected cells from both senescence and ferroptosis and restored nuclear and mitochondrial genome integrity in vitro and in vivo. We thus describe a potential molecular mechanism of hemin/iron-induced toxicity in ICH that involves a rapid induction of DSBs, senescence, and the consequent resistance to ferroptosis and provide a mechanistic-based combinatorial therapeutic strategy.

• Authors: Prakash Dharmalingam, Girish Talakatta, Joy Mitra, Haibo Wang, Paul J Derry, Lizanne Greer Nilewski, Emily A McHugh, Roderic H Fabian, Kimberly Mendoza, Velmarini Vasquez, Pavana M Hegde, Eugenia Kakadiaris, Trenton Roy, Istvan Boldogh, Venkatesh L Hegde, Sankar Mitra, James M Tour, Thomas A Kent, Muralidhar L Hegde
• Journal: ACS nano (ACS Nano) Vol. 14 Issue 3 Pg. 2827-2846 (03 24 2020) ISSN: 1936-086X [Electronic] United States
• PMID: 32049495 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Reactive Oxygen Species
• Polyethylene Glycols
• Hemin
• Carbon
• Iron
• Deferoxamine

Topics

• Animals
• Carbon (pharmacology)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Cellular Senescence (drug effects)
• Cerebral Hemorrhage (drug therapy, genetics, metabolism)
• DNA Breaks, Single-Stranded (drug effects)
• DNA Damage
• Deferoxamine (pharmacology)
• Hemin (antagonists & inhibitors, pharmacology)
• Humans
• Iron (pharmacology)
• Mice
• Mitochondria (drug effects)
• Nanoparticles (chemistry)
• Polyethylene Glycols (pharmacology)
• Reactive Oxygen Species (metabolism)