The nitric oxide hypothesis of brain aging.

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 cyclooxygenase 1 leading to generation of prostaglandins. Both of these active agents are involved in mediating the actions of NO, the first gaseous 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 ineffective 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.