NO and CO are unstable gases that play important roles as neural messenger molecules, either by themselves or in concert with each other. NO was initially characterized on the basis of its influence on cardiovascular epithelium and blood pressure, while the sources and biochemical pathways leading to CO formation, which is a product of hemoglobin catabolism that is formed in response to oxidative challenges, have been known for over three decades. Despite the original paradox that such highly toxic compounds could exert biological effects in the brain, both gases were subsequently shown to have pleiotropic effects in the CNS. Originally, much emphasis was put on their role in long-term potentiation and memory but by now, hundreds of articles attest to the ability of these gases to modify multiple brain functions. While these functions are generally considered to be linked to increased production of neurotransmitters, the precise mechanisms through which NO and CO influence brain activity remain surprisingly elusive. We know that through the release of cGMP, NO and CO can influence channel gating and activate cGMP-dependent protein kinases as well as cAMP-mediated effects, though the mechanisms leading to these effects may be different. This represents a potentially vast array of effects, and indeed the list of neurotransmitters presently thought to be under the influence of NO and/or CO includes acetylcholine, norepinephrine, dopamine, glutamate, prostaglandins and GABA. NO may also modulate gene transcription and translation, and has been shown to potentiate the effects of calcium on c-fos promoter-linked gene expression and to stimulate the expression of some immediate early genes. That both gases are capable of altering the activity of hypothalamic neurons should therefore not come as a surprise. On the other hand this discovery, which is relatively recent, has provided a new view of the organization of central neuroendocrine circuits.
NO exerts a dual action on the HPA axis, a phenomenon apparently not shared by CO. In the periphery (i.e. at the level of the median eminence and pituitary), NO inhibits the response of the HPA axis to blood-borne cytokines and to VP. In contrast, both NO and CO exert a stimulatory influence on brain structures protected by the blood-brain barrier. This concept is based on the observation that compounds that inhibit the activity of the enzymes responsible for NO or CO formation, called respectively NO synthase (NOS) and heme oxygenase (HO), blunt the HPA axis response to neurogenic or immune stressors. Additional evidence for the stimulatory effect of NO comes from our observation that the injection of NO donors into the brain releases ACTH and upregulates CRF and VP synthesis. Both in the periphery and the brain, the influence of NO is due to changes in the activity of the constitutive (c) isoform of NOS. It is presently assumed that the role of CO on the HPA axis is also due to gas synthesis under the control of constitutive HO, but this has not yet been demonstrated experimentally.
An interesting recent observation is that the intracerebroventricular injection of CRF or VP significantly increases PVN transcripts of cNOS, the enzyme responsible for NO formation in the brain. There is abundant evidence that not only immune, but also physico-emotional stresses such as shocks and restraint, upregulate NO formation in the endocrine hypothalamus. This type of stimuli also increases CRF and VP levels in the PVN. Collectively, these results led us to predict the existence of a functional connection between the cells that produce NO/CO, and those that produce CRF or VP. We propose that this relationship, which represents a novel concept in the regulation of the HPA axis, is crucial for health maintenance. We also propose that when this relationship becomes imbalanced, it can account for conditions associated with abnormal activity of the HPA axis and pathological NO/CO levels. By determining the consequence, on brain NO production, of blocking CRF or VP receptors, we may be able to gain more knowledge into functional connections between NO and CRF/VP.
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