Elsevier

Experimental Gerontology

Volume 32, Issues 4–5, July–October 1997, Pages 431-440
Experimental Gerontology

The nitric oxide hypothesis of brain aging

https://doi.org/10.1016/S0531-5565(96)00154-4Get rights and content

Abstract

Nitric oxide synthase (NOS)-containing neurons are found in many loci throughout the central nervous system, which include the cerebral cortex, the cerebellum, the hippocampus, and the hypothalamus. NO plays a very important role in control of neuronal activity in all of these areas by diffusing into neurons where it activates soluble guanylate cyclase (sGC) leading to generation of cyclic guanosine monophosphate (cGMP) and cyclo-oxygenase 1 leading to generation of prostaglandins. Both of these active agents are involved in mediating the actions of NO, the first gasseous transmitter. In the cerebellum, NO is extremely important and it is also thought to mediate long-term potentiation in the hippocampus. Various stresses and corticoids have been shown in monkeys and also in rodents to cause neuronal cell death. This may be via the stimulation of glutamic acid release, which by N-methyl-D-aspartate (NMDA) receptors causes release of NO, which can lead to neuronal cell death. In the hypothalamus, NO stimulates corticotropin-releasing hormone (CRH), prolactin releasing factor, growth hormone-releasing hormone (GHRH), and somatostatin, lutenizing hormone-releasing hormone (LHRH), but not follicle stimulating hormone-releasing factor (FSHRF) release. In situations of increased release of NO in the hypothalamus, it could cause neuronal cell death. Following bacterial or viral infections, toxic products of the inffective agents, such as bacterial lipopolysaccharide (LPS), circulate to the brain, where they induce interleukin-1 and iNOS mRNA and synthesis. After several hours delay, massive quantities of NO are released. Induction of iNOS occurs in the choroid plexus, meninges, in circumventricular organs, and in large numbers of iNOS neurons in the arcuate and paraventricular nuclei. The large amounts of NO released by iNOS may well produce death not only of neurons but also glial. Repeated bouts of systemic infection even without direct neural involvement could result in induction of iNOS in the central nervous system and lead to large fall out of neurons in hippocampus to impair memory, hypothalamus to decrease fever, and neuroendocrine response to infection, and could play a role in the pathogenesis of degenerative neuronal diseases of aging, such as Alzheimers. The largest induction of iNOS occurs in the anterior pituitary and pineal glands. The damage to the pituitary could also impair responses to stress and infection, and the release of NO during infection could be responsible for the degenerative changes in the pineal and diminished release of melatonin, an antioxident, and consequently, an antiaging hormone, that occur with age.

References (25)

  • A. Kamat et al.

    Glutamic acid stimulated lutenizing-hormone releasing hormone release is mediated by alpha adrenergic stimulation of nitric oxide release

    Brain Res. Bull.

    (1995)
  • M.C. Aguila

    Growth hormone-releasing factor increases somatostatin release and mRNA levels in the rat periventricular nucleus via nitric oxide by activation of guanylate cyclase

  • W.A. Banks et al.

    Passage of cytokines across the blood-brain barrier

    Neuroimmunomodulation

    (1995)
  • D.S. Bredt et al.

    Localization of nitric oxide synthase I indicating a neural role for nitric oxide

    Nature

    (1990)
  • G. Canteros et al.

    Ethanol inhibits lutenizing hormone-releasing hormone (LHRH) secretion by blocking the response of LHRH neuronal terminals to nitric oxide

  • B.H. Duvilanski et al.

    Role of nitric oxide in control of prolactin release by the adenohypophysis

  • S. Griffin
  • S. Karanth et al.

    Role of nitric oxide in interleukin 2-induced corticotropin-releasing factor release from incubated hypothalami

  • J. Knoll

    Sexual performance and longevity

  • S.K. Mani et al.

    Nitric oxide mediates sexual behavior in female rats by stimulating LHRH release

  • S.M. McCann et al.

    The role of nitric oxide in reproduction

  • L.J. McDonald et al.

    Nitric oxide and cyclic GMP signaling

  • Cited by (105)

    • The role of arginase in aging: A systematic review

      2019, Experimental Gerontology
      Citation Excerpt :

      Neurological diseases, particularly neurodegenerative diseases such as Alzheimer's disease (AD), are a major problem of public health in elderly people (Qiu et al., 2007). Arginase activity is critical for the synthesis of polyamines, NO, agmatine and L-ornithine (as precursor of glutamate and γ-aminobutyric acid), which play a crucial role in normal brain cell functioning and neurotransmission (Morris Jr, 2016; Gupta et al., 2012; Minois et al., 2011; McCann, 1997). As a time-dependent decrease in Arg1 expression was found in cultured neurons (Cai et al., 2002), age-related changes in arginase activity could alter central nervous system (CNS) functions by restricting L-arginine-derived biomolecules production or promoting oxidative stress or apoptosis.

    • Ageing alters behavioural function and brain arginine metabolism in male Sprague-Dawley rats

      2012, Neuroscience
      Citation Excerpt :

      However, it can be neurotoxic when present in excessive amount due to its properties as a free radical (Calabrese et al., 2007). It has, therefore, been proposed that NO is critically involved in the ageing process, the so-called NO hypothesis of ageing (McCann, 1997; McCann et al., 1998, 2005), as well as the neurodegenerative process in Alzheimer’s disease (Law et al., 2001; Malinski, 2007). Previous research has demonstrated altered NOS activity and expression during ageing in memory-related brain structures and the correlations with age-related cognitive impairments (Sugaya et al., 1996; Law et al., 2000, 2002; Necchi et al., 2002; Liu et al., 2003a,b, 2004a,b, 2005, 2009b).

    View all citing articles on Scopus
    View full text