Eicosanoids and nitric oxide influence induction of reactive gliosis from spreading depression in microglia but not astrocytes

Abstract

Microglia and astrocytes are transformed into reactive glia (RG) by brain disease and normal function. Eicosanoids and nitric oxide (NO), two intercellular mediators, may influence gliosis. We investigated how drugs that alter production of these paracrine signals effect induction of glial reactivity from spreading depression. Unilateral (left) neocortical spreading depression was induced in 95 halothane anesthetized rats by intracortical injections of 0.5 M KCl, with or without drug treatment (five animals/group). Immunohistochemical staining (IS) intensity using the OX-42 and anti-glial fibrillary acidic protein (GFAP) antibodies determined reactivity in microglia and astrocytes, respectively. After 3 days, brains were processed for OX-42 and GFAP-IS and mean optical densities (OD) of IS were measured. Average OD's (for OX-42) and the log ratio (left/right) of OD's (OX-42 and GFAP) were compared to normal animals. Spreading depression induced significant log ratios for both OX-42- and GFAP-IS (P's < 0.01). However, dexamethasone (a glucocorticoid), nordihydroguaiaretic acid (a lipoxygenase inhibitor), and nitroprusside (a NO donor) prevented significant left sided and log ratio OD values for microglia (P's > 0.05). L-Name, a NO synthase inhibitor, caused significant increases in left and right OD's for microglia (P's < 0.05). Mepacrine, a phospholipase A2 inhibitor, Indomethacin, a cyclooxygenase inhibitor, and phenylephrine, an adrenergic agonist, did not prevent induction of significant OX-42 log ratios (P's < 0.01, 0.05, 0.01), and resulted in increases in left side OD's (P's < 0.01, 0.05, 0.05). Significant GFAP log ratios occurred after spreading depression in all drug groups, P's < 0.01. Thus, induction of reactivity in microglia is more sensitive to eicosanoids and NO than in astrocytes.

Chemical and mechanical nerve root insults induce differential behavioral sensitivity and glial activation that are enhanced in combination

“…This is in agreement with studies demonstrating that microglia respond to minor changes in their environment (Caggiano and Kraig, 1996;Kreutzberg, 1996). The apparent disparity in responses between microglia and astrocytes for different types of stimuli may be due to their varying roles in the central nervous system.…”

“…Although little is known about what triggers glial activation, it has been shown that both microglia and astrocytes can be activated by depolarization of neighboring neurons, consistent with a tetrapartite model of the synapse (Kreutzberg, 1996;DeLeo et al, 2006). Yet, microglia may respond to these neuronal changes before astrocytes, and may be more sensitive to changes in neurotransmitters (Caggiano and Kraig, 1996). It is likely that in our combined injury microglia in the contralateral dorsal horn respond to small perturbations in extracellular ion homeostasis and this microglial activation then leads to further neuronal sensitization.…”

Differential activation of subtype purinergic receptors modulates Ca2+ mobilization and COX‐2 in human microglia

“…This study also demonstrated LPS activation of PLA 2 and that inhibition of COX-2 blocked LPS-evoked activation of cells. Interestingly, inhibition of PLA 2 and blockade of cyclooxygenase have also been shown to induce reactivity in microglia, but not astrocytes, in spreading depression induced in rat brain (Caggiano and Kraig, 1996).…”

Multiplexed Cytokine Protein Expression Profiles from Spreading Depression in Hippocampal Organotypic Cultures

“…In addition, we performed labeling studies with the microglial marker OX-42 to determine if SD in HOTCs induced activation of microglia similar to that seen in vivo (Caggiano and Kraig, 1996;Gehrman et al, 1993). In normal HOTCs, OX-42 positive microglia typically displayed a small soma from which extended numerous finely branched processes (Fig.…”