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Spontaneous Expression of Inducible Nitric Oxide Synthase in the Hypothalamus and Other Brain Regions of Aging Rats¹

Departments of Urology and Medicine, UCLA School of Medicine, Harbor-UCLA Medical Center, Torrance, California 90509

Address all correspondence and requests for reprints to: Nestor Gonzalez-Cadavid, Ph.D., Harbor-UCLA Medical Center, Division of Urology, Department of Surgery, Bldg. F-6, 1000 West Carson St., Torrance, California 90509.

Our laboratory has demonstrated that aging in Brown-Norway rats is associated with decreased LH pulse amplitude and reduced GnRH and LH responsiveness to excitatory amino acids (EAA), presumably through the NMDA receptor (NMDAR). Nitric oxide (NO) is a neurotransmitter postulated to be involved in hypothalamic synaptic events required for normal GnRH regulation through the activation of neuronal nitric oxide synthase (nNOS). Paradoxically, excessive stimulation of nNOS by NMDAR or the expression of inducible nitric oxide synthase (iNOS) can lead to supraphysiological levels of NO acting as effector of apoptosis with resultant decreased regional neuronal function. The aims of this study were to determine: 1) whether aging in the preoptic area/medial basal hypothalamus is associated with altered NO synthesis; 2) the possible roles of the NMDAR/nNOS cascade and iNOS in this process; and 3) whether alterations in the levels of NOS isoforms are specific to this region of the brain. Brown Norway male rats (N = 5) at ages 1 (immature), 3 (adult), and 24 (old) months, were used for measuring NMDARs in hypothalamic membranes by the binding of a (3H)-NMDAR ligand. Another series of the same age groups of rats (N = 9) were used to determine by Western blot the contents of NMDAR, nNOS, and iNOS in the hypothalamus, and only iNOS in the frontal and parietal cortex, and cerebellum. NOS activity was measured in the hypothalamus by the arginine/citrulline assay. A significant decrease of NMDA analog binding was found in the hypothalamus from old rats as compared with adult (-66%) and immature animals (-57%), accompanied by a reduction in NMDAR content (-34% and -46%, respectively). NOS activity in the hypothalamus was 67% and 100% higher in old rats as compared with the other two groups, although no significant differences were observed in nNOS content. However, hypothalamic iNOS increased 3.8- and 7.6-fold in old rats, as compared with adult and immature, respectively. This increase in hypothalamic iNOS was paralleled by a rise of iNOS in other brain regions of old rats as compared respectively to adult and immature animals: 3.9- and 12.8-fold, in the frontal cortex; 2.8- and 2.5-fold, in the parietal cortex; and 3.1- and 4.8-fold, in the cerebellum. These results show that aging in this rat model is associated with high NO synthesis in the hypothalamus and other regions of the brain, which is independent of the NMDAR/nNOS cascade. We speculate that increased brain levels of iNOS may lead to neurotoxicity, which may be involved in GnRH impaired pulsatile secretion, as well as acting as a possible inducer of age associated neuronal loss in cognitive related brain areas.

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