Abstract
RNA sequencing (RNAseq) can be a powerful tool in the identification of transcriptional changes after drug treatment. RNAseq was utilized to determine expression changes in Fluorescence-activated cell sorted (FACS) CD11b/c+ cells from the striatum (STR) and prefrontal cortex (PFC) of male Sprague-Dawley rats after a methamphetamine (METH) binge dosing regimen. Resident microglia and infiltrating macrophages were collected 2 h or 3 days after drug administration. Gene expression changes indicated there was an increase toward an overall pro-inflammatory state, or M1 polarization, along with what appears to be a subset of cells that differentiated toward the anti-inflammatory M2 polarization. In general, there were significantly more mRNA expression changes in the STR than the PFC and more at 2 h post-binge METH than at 3 days post-binge METH. Additionally, Ingenuity® Pathway Analysis along with details of RNA expression changes revealed cyclo-oxygenase 2 (COX2)-driven prostaglandin (PG) E2 synthesis, glutamine uptake, and the Nuclear factor erythroid2-related factor 2 (NRF2) canonical pathway in microglia were associated with the binge administration regimen of METH.
Highlights
Methamphetamine (METH) is known to induce neuroinflammation
Of the 7601 genes significantly changed by METH at the 2 h time point in the combined STR and prefrontal cortex (PFC), 2483 genes were common to both regions, with 1255 of those genes significantly upregulated in both STR and PFC and 1223 significantly downregulated in both regions, considering all significant fold-changes (Figure 2a)
The present RNA sequencing results indicate that CD11b/c+ cells isolated from rat STR and PFC
Summary
Methamphetamine (METH) is known to induce neuroinflammation. Resident glial cells, including microglia [1,2,3] and astrocytes [4,5,6] in the brain are implicated in contributing to this METH-induced neuroinflammation via production and release of a variety of inflammatory mediators, such as interleukin (IL) 1β [7,8], IL6 [9,10], tumor necrosis factor (TNF) α [11], C-C motif chemokine ligand 2(CCL2) [12], reactive oxygen species (ROS) [13,14], and nitric oxide [15]. The canonical role of central nervous system (CNS)-resident microglia is to serve as sentinels to detect disturbances in the chemical environment around neurons and to respond to these disturbances. In their response to locally detected lipopolysaccharide (LPS) or interferon-gamma (INF-γ), microglia can take on the role known as the M1 phenotype. Microglia can take on an M2 phenotype if stimulated locally by IL4 or IL13 In this state of activation, the microglial cell produces and releases mediators such as IL10, which can serve as an anti-inflammatory signal to initiate recovery from an insult
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