Nerve growth factor rapidly suppresses basal, NMDA-evoked, and AMPA-evoked nitric oxide synthase activity in rat hippocampus in vivo

Abstract

In adult forebrain, nerve growth factor (NGF) inf luences neuronal maintenance and axon sprouting and is neuroprotective in several injury models through mechanisms that are incompletely understood. Most NGF signaling is thought to occur after internalization and retrograde transport of trkA receptor and be mediated through the nucleus. However, NGF expression in hippocampus is rapidly and sensitively regulated by synaptic activity, suggesting that NGF exerts local effects more dynamically than possible through signaling requiring retrograde transport to distant afferent neurons. Interactions have been reported between NGF and nitric oxide (NO). Because NO affects both neural plasticity and degeneration, and trk receptors can mediate signaling within minutes, we hypothesized that NGF might rapidly modulate NO production. Using in vivo microdialysis we measured conversion of L-[ C]arginine to L-[ C]citrulline as an accurate ref lection of NO synthase (NOS) activityin adult rat hippocampus. NGF significantly reduced NOS activity to 61% of basal levels within 20 min of onset of delivery and maintained NOS activity at less than 50% of baseline throughout 3 hr of delivery. This effect did not occur with control protein (cytochrome c) and was not mediated by an effect of NGF on glutamate levels. In addition, simultaneous delivery of NGF prevented significant increases in NOS activity triggered by the glutamate receptor agonists Nmethyl-D-aspartate (NMDA) and ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Rapid suppression by NGF of basal and glutamate-stimulated NOS activity may regulate neuromodulatory functions of NO or protect neurons from NO toxicity and suggests a novel mechanism for rapidly mediating functions of NGF and other neurotrophins.

p75 Neurotrophin receptor mediates neurotrophin activation of NF‐kappa B and induction of iNOS expression in P19 neurons

“…Thus, the potential for neurotrophin regulation of the biosynthetic enzymes iNOS and nNOS is important. NGF promotes increases in nNOS mRNA and in NOS activity in cholinergic neurons of the basal forebrain (Holtzman et al, 1994(Holtzman et al, , 1996, but NGF substantially inhibits basal and stimulated NOS activity in the hippocampus, microglia, and cultured dorsal root ganglia (Thippeswamy and Morris, 1997;Lam et al, 1998;Nakajima et al, 1998). The nNOS stimulation by NGF in the basal forebrain cholinergic system apparently is mediated by trkA receptors.…”

NO-cGMP Signaling and Regenerative Medicine Involving Stem Cells

“…In neurons, NO production is sensitive to a number of stimuli. Neurotrophic factors such as NGF may regulate NO synthesis by nNOS through mechanisms operating via TrkA receptors [47,65]. Other factors including glutamate, thrombin, histamine and acetylcholine, all have been shown to stimulate the production of NO under a variety of physiological or pathophysiological conditions.…”

Spatiotemporal pattern of nicotinamide adenine dinucleotide phosphate‐diaphorase reactivity in the developing central nervous system of premetamorphic Xenopus laevis tadpoles

“…NO also has been reported to cause growth cone collapse and the retraction of axons (Hess et al, 1993;Renteria and Constantine-Paton, 1996;Van Wagenen and Rehder, 1999) and has been linked to a number of neurotrophic factors (Lam et al, 1998;Estevez et al, 1998;Klöcker et al, 1998;Xiong et al, 1999;Ernst et al, 2000), suggesting that NO may be involved in the organisation of axonal projections during development. Recently, three bilaterally symmetric populations of putative nitrergic neurons were identified in the hindbrain of Xenopus larvae (stage 42; Nieuwkoop and Faber, 1956) using nicotinamide adenine dinucleotide phosphatediaphorase (NADPH-d) histochemistry .…”