Microglia Determine Brain Region-Specific Neurotoxic Responses to Chemically Functionalized Carbon Nanotubes

• Published in: ACS nano 2015-08, Vol.9 (8), p.7815-7830
• Main Authors: Bussy, Cyrill, Al-Jamal, Khuloud T, Boczkowski, Jorge, Lanone, Sophie, Prato, Maurizio, Bianco, Alberto, Kostarelos, Kostas
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes - cytology; Astrocytes - drug effects; Astrocytes - metabolism; Biomarkers - metabolism; Brain; Brain Chemistry; Carbon nanotubes; CD11b Antigen - genetics; CD11b Antigen - metabolism; CD11c Antigen - genetics; CD11c Antigen - metabolism; Cell Survival - drug effects; Chemical Sciences; Coculture Techniques; Corpus Striatum - cytology; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Culture; Culture Media, Conditioned - pharmacology; Delivery systems; Drug Delivery Systems; Exposure; Fetus; Frontal Lobe - cytology; Frontal Lobe - drug effects; Frontal Lobe - metabolism; Gene Expression; Glial Fibrillary Acidic Protein - genetics; Glial Fibrillary Acidic Protein - metabolism; L-Lactate Dehydrogenase - metabolism; Medicinal Chemistry; Microglia - cytology; Microglia - drug effects; Microglia - metabolism; Multi wall carbon nanotubes; Nanomaterials; Nanostructure; Nanotubes, Carbon - chemistry; Nanotubes, Carbon - toxicity; Nitric Oxide - secretion; Organ Specificity; Primary Cell Culture; Rats
• ISSN: 1936-0851; 1936-086X
• DOI: 10.1021/acsnano.5b02358

Surface tunability and their ability to translocate plasma membranes make chemically functionalized carbon nanotubes (f-CNTs) promising intracellular delivery systems for therapeutic or diagnostic purposes in the central nervous system (CNS). The present study aimed to determine the biological impact of different types of multiwalled CNTs (MWNTs) on primary neuronal and glial cell populations isolated from fetal rat frontal cortex (FCO) and striatum (ST). Neurons from both brain regions were generally not affected by exposure to MWNTs as determined by a modified LDH assay. In contrast, the viability of mixed glia was reduced in ST-derived mixed glial cultures, but not in FCO-derived ones. Cytotoxicity was independent of MWNT type or dose, suggesting an inherent sensitivity to CNTs. Characterization of the cell populations in mixed glial cultures prior to nanotube exposure showed higher number of CD11b/c positive cells in the ST-derived mixed glial cultures. After exposure to MWNTs, CNT were uptaken more effectively by CD11b/c positive cells (microglia), compared to GFAP positive cells (astrocytes). When exposed to conditioned media from microglia enriched cultures exposed to MWNTs, ST-derived glial cultures secreted more NO than FCO-derived cells. These results suggested that the more significant cytotoxic response obtained from ST-derived mixed glia cultures was related to the higher number of microglial cells in this brain region. Our findings emphasize the role that resident macrophages of the CNS play in response to nanomaterials and the need to thoroughly investigate the brain region-specific effects toward designing implantable devices or delivery systems to the CNS.