■ REVIEW : Glial NO: Normal and Pathological Roles

Abstract

All nervous system cell types can be induced with cytokines or bacterial products to make nitric oxide, at least in culture. The signaling pathways invoked by inducers that result in transcriptional activation of the nitric oxide synthase gene are becoming clear, and modulators of this induction have been discovered. Much suggestive and, recently, more definitive evidence has accumulated for induction of nitric oxide synthase in glial cells in vivo associated with viral infection, as well as in animal models of trauma, ischemia, and autoimmunity. Whether nitric oxide from this source contributes to or limits the attendant conditions is not yet clear. The Neuroscientist 2: [90][91][92][93][94][95][96][97][98][99] 1996 It is overly simplistic but convenient to divide the parenchymal, non-neuronal CNS cells into astrocytes, oligodendrocytes, and microglia. Each glial cell type contributes more or less extensively to the development of the CNS and to its steady state functions (for the &dquo;compleat&dquo; account, see reference 1 ). In particular neuropathologies, microglia and astrocytes are activated and contribute to oligodendrocyte and neuron damage and recovery (2-4). One novel but increasingly common currency for intercellular signaling in the CNS is nitric oxide (-NO) (5), a relatively benign and not very reactive gas with a biological half-life of seconds to minutes (6). However, -NO becomes highly reactive through secondary reactions (for example, with O2--) that produce more toxic species (ONOO-and -OH).Three isoforms of NO synthase (NOS) sharing considerable sequence homology catalyze the formation of NO in the nervous system (7). These are designated Types I (NOS 1 ), II (NOS2), and III (NOS3) (the order in which the cDNAs were cloned, not historically according to when their existence was first mooted). NOS3 (&dquo;endothelial&dquo; NOS) is a constitutive and largely membrane-bound enzyme dependent on calcium and calmodulin for activity. NOS is activated by intracellular calcium transients and found constitutively in particular neurons. The suggestion of a constitutive NOS in glial cells arose from observations of the production of a nitrosyl factor from stimulated astrocytes (8). With a variety of antibodies raised against NOS I and also NADPH diaphorase (NADPH-d) histochemistry (an indication of NOS activity under stringent conditions), the presence of NOS I in astrocytes has been verified (9-12).Questions about the nature of this constitutive astrocyte NOS and its role in vivo remain to be answered. In particular, and related to the growing interest in NOS 1 expression during the development of the nervous system (13), such roles for glial-derived NO may include programmed cell death, as well as neuronal guidance and differentiation.NOS2, a dimeric, heme-containing, soluble protein, is independent of calcium for activity (14). First described in activated macrophages, it has now been reported in a wide variety of normal and neoplastic cell types. In the CNS, all parenchymal and cerebrovascular cel...

Intrathecal HIV-1 Envelope Glycoprotein gp120 Induces Enhanced Pain States Mediated by Spinal Cord Proinflammatory Cytokines

“…Neurons (Murphy and Grzybicki, 1996), astrocytes (Murphy and Grzybicki, 1996;Togashi et al, 1997), and microglia all basally express cNOS. Indeed, cNOS is the principal isoform of NOS in both neurons (Murphy and Grzybicki, 1996) and astrocytes (Togashi et al, 1997).…”

“…Although classic views of pain facilitation have only focused on neurons, these neuroactive substances also activate glia (Hartung et al, 1988;Marriott et al, 1991;Murphy, 1993;Kreutzberg, 1996). As a result, microglia and astrocytes release a wide variety of neuroactive substances, including several known to activate spinal cord pain transmission neurons (Hartung et al, 1988;Marriott et al, 1991;Dutton, 1993;Kreutzberg, 1996;Murphy and Grzybicki, 1996).…”

“…Direct in vitro antigen stimulation of glia by substances such as bacterial cell walls [lipopolysaccharide (LPS)] and viral envelope proteins (gp120) activates these cells, causing release of glutamate and NO, as well as release of proinflammatory cytokines including interleukin-1␤ (IL-1␤) (Murphy, 1993;Kettenmann and Ransom, 1995;Kreutzberg, 1996;Murphy and Grzybicki, 1996). Although glutamate and NO have long been known to facilitate pain (Meller et al, 1992a), spinal IL-1 has only been recently recognized as exerting such effects.…”

Glia in pathological pain: A role for fractalkine

“…Additionally, glia produce and release proinflammatory cytokines, including interleukin-1 (IL1), tumor necrosis factoralpha (TNF) and interleukin-6 (IL6) (Benveniste, 1997), that further stimulate glial cells and neurons (Halassa et al, 2007, Nguyen et al, 2002. In the CNS, astrocytes and microglia express receptors for IL1, TNF andIL6 (Halassa et al, 2007, Hanisch, 2002), and respond to these cytokines by releasing NO (Burgher et al, 1997, Murphy andGrzybycki, 1996), EAAs and prostaglandins (Halassa et al, 2007, Pocock andKettenmann, 2007), increasing substance P release from primary afferent neurons (Inoue et al, 1999), and by up-regulating enzymes such as cyclooxygenase-2 characterized to produce prostaglandins that facilitate pain transmission (Samad et al, 2001). Thus, understanding pain mechanisms from a perspective that includes spinal cord glial stimulation has contributed to our knowledge about potential mechanisms that underlie the shift from adaptive pain to pathological pain (DeLeo et al, 2007).…”

The Oct DNA motif participates in the alcohol inhibition of the inducible nitric oxide synthase gene promoter in rat C6 glioma cells

“…Transactivation of the Nos2 gene, expression of inducible nitric-oxide synthase (iNOS) and the resulting production of nitric oxide (NO) is an integral inflammatory response in the CNS (Murphy and Grzybicki, 1996). Nitric oxide generated from iNOS has been implicated in many CNS pathologies including brain infections, and neurological disorders such as acquired immunodeficiency syndrome and multiple sclerosis (Adamson, et al, 1996, Bagasra, et al, 1995.…”