Indomethacin treatment reduces microglia activation and increases numbers of neuroblasts in the subventricular zone and ischaemic striatum after focal ischaemia

Abstract

Neuroblasts from the subventricular zone (SVZ) migrate to striatum following stroke, but most of them die in the ischaemic milieu and this can be related to exacerbated microglial activation. Here, we explored the effects of the non-steroidal anti-inflammatory indomethacin on microglial activation, neuronal preservation and neuroblast migration following experimental striatal stroke in adult rats. Animals were submitted to endothelin-1 (ET-1)-induced focal striatal ischaemia and were treated with indomethacin or sterile saline (i.p.) for 7 days, being perfused after 8 or 14 days. Immunohistochemistry was performed to assess neuronal loss (anti-NeuN), microglial activation (anti-Iba1, ED1) and migrating neuroblasts (anti-DCX) by counting NeuN, ED1 and DCX-positive cells in the ischaemic striatum or SVZ. Indomethacin treatment reduced microglia activation and the number of ED1+ cells in both 8 and 14 days post injury as compared with controls. There was an increase in the number of DCX+ cells in both SVZ and striatum at the same survival times. Moreover, there was a decrease in the number of NeuN+ cells in indomethacin-treated animals as compared with the control group at 8 days but not after 14 days post injury. Our results suggest that indomethacin treatment modulates microglia activation, contributing to increased neuroblast proliferation in the SVZ and migration to the ischaemic striatum following stroke.

Neurodegeneration and Glial Response after Acute Striatal Stroke: Histological Basis for Neuroprotective Studies

“…Activated microglia/macrophages were labeled using the antibody anti-rat CD68 (clone ED1, 1 : 500, Serotec, UK), which binds to an epitope on the lysosomal membrane of activated macrophages/microglia [38–40], rabbit anti-Iba1 (1 : 1000, WAKO), an antibody that recognizes a calcium binding protein present in the cytoplasm of microglia [41–43], and mouse anti-MHC-II (1 : 100, Serotec), an antibody that recognizes the major histocompatibility complex class II molecule [7]. …”

Regulation of microglial activation in stroke

“…Probucol, another lipid-lowering agent, inhibited microglial release of NO, PGE 2 , IL-1β and IL-6 by down-regulating the NF-κB, MAPK and AP-1 signaling pathways in LPS-stimulated primary mouse and BV2 microglia; the in vivo pre-administration of probucol reduced microglial production of pro-inflammatory mediators (iNOS, COX-2, IL-1, IL-6) and improved outcomes after MCAO [149] . Treatment with indomethacin, one of the non-steroidal antiinflammatory drugs, remarkably reduced the number of Iba-1 cells and microglia activation but increased neuroblast proliferation 7 d after stroke [150] . Noggin, an endogenous antagonist of bone morphogenetic proteins, can protect against ischemic brain injury [151] , and this effect may be related to the regulation of M1/M2 microglial activation.…”

Post-Ischaemic Immunological Response in the Brain: Targeting Microglia in Ischaemic Stroke Therapy

“…Indomethacin is a non-steroidal inflammatory drug that is indicated for osteoarthritis and rheumatoid arthritis. Lopes et al [129] found that indomethacin treatment in rats with endothelin-1 (ET-1)-induced focal striatal ischaemia inhibited microglial activation at 8-and 14-d post-injury. Indomethacin administration was correlated with increased numbers of neuroblasts in the subventricular zone (SVZ) post-stroke mainly at 14 d post-stroke but did not significantly affect neuronal density or increase the neuroblast population in the infarct area.…”