Cyclic GMP metabolism and its role in brain physiology. J Physiol Pharmacol

Department of Cellular Signaling, Medical Research Center, Polish Academy of Sciences, Warsaw, Poland.
Journal of physiology and pharmacology: an official journal of the Polish Physiological Society (Impact Factor: 2.39). 04/2005; 56 Suppl 2(2):15-34.
Source: PubMed


Cyclic GMP (cGMP) is synthesized by guanylyl cyclase (GC) in response to nitric oxide (NO) and carbon monoxide (CO) or natiuretic peptides (NPs); atrial, brain and C-type (ANP, BNP and CNP). cGMP is degraded by several cGMP-specific phosphodiesterases (PDEs). Guanylate cyclases (GC) are differentiated into: membrane-bound/particulate (pGC) and cytosolic/soluble (sGC). In recent years evidence has accumulated that NO is the main activator of sGC and NO/cGMP plays important role in glutaminergic, cholinergic and dopaminergic signaling pathways. cGMP in the nervous system is involved in long term potentiation and depression (LTP, LTD) suggesting its participation in learning and memory mechanism. cGMP regulates calcium homeostasis and phototransduction. Its level is regulated by PDEs and their specific inhibitors protect cGMP level in cells and are very important from clinical point of view.

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    • "Solis et al. have indicated the anxiolytic effect of chronic sildenafil treatment based on the results of open-field test, which pointed out an increased number of center entries and a prolonged time spent in the center of the open field apparatus [9]. Additionally, in some animal studies, it was indicated that sildenafil consolidated the memory [10] [11] [12] [13] [14], and reported that injection of a cGMP analog into rat hippocampus improved the results of object recognition test, which is associated with memory consolidation [5]. Stress is an inevitable element in human life that can be defined as disruption of homeostasis. "
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    ABSTRACT: There are contradictory results about the effects of exercise and sildenafil on cognitive functions. To investigate the effects of sildenafil pretreatment and chronic exercise on anxiety and cognitive functions. Wistar rats (n=42) were divided as sedentary and exercise groups. A moderate-intensity swimming exercise was performed for 6weeks, 5days/week, 1h/day. Some of the rats were administered orogastrically with sildenafil (25mg/kg/day) either acutely or chronically. Exposure to cat odor was used for induction of stress. The level of anxiety was evaluated by elevated plus maze test, while object recognition test was used to determine cognitive functions. Brain tissues were removed for the measurement of myeloperoxidase (MPO), malondialdehyde (MDA), nitric oxide levels, lucigenin-enhanced chemiluminescence, and for histological analysis. Increased MPO and MDA levels in sedentary-stressed rats were decreased with sildenafil applications. Chronic exercise inhibited the increase in MPO levels. Increased nitric oxide and lucigenin chemiluminescence levels in sedentary-stressed rats, were diminished with chronic sildenafil pretreatment. The time spent in the open arms of the plus maze was declined in sedentary-stressed rats, while chronic sildenafil pretreatment increased the time back to that in non-stressed rats.Acute sildenafil application to exercised rats prolonged the time spent in open arms as compared to non-treated exercise group. The time spent with the novel object, which was decreased in sedentary-stressed rats, was increased with sildenafil pretreatment. Our results suggest that sildenafil pretreatment or exercise exerts a protective effect against acute stress and improves cognitive functions by decreasing oxidative damage. Copyright © 2015. Published by Elsevier Inc.
    Physiology & Behavior 07/2015; 151. DOI:10.1016/j.physbeh.2015.07.030 · 2.98 Impact Factor
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    • "It has been reported that sGCα1 and sGCβ1 subunits are widely distributed in the human brain, consistent with a major role in NO signaling; the NO/cGMP pathway appears to be affected by aging in the human brain [8]. It has been reported that cGMP concentration in the rat brain decreases during development and aging, and the ability of the cholinergic system to synthesize cGMP decreases during the life span [9]. Also, it has been reported that sGC inhibitors suppress LTP and GC, and PKG contribute to LTP, possibly as activity-dependent presynaptic effectors of retrograde messengers [10]. "
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    ABSTRACT: Background The aim of this study was to investigate the effects of a potent nitric oxide-guanylate cyclase activator, 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1), on learning and memory functions in aged rats. Material/Methods Rats were divided into 2 groups as 4-month-old and 24-month-old rats. Rats received YC-1 (1 mg/kg/day) for 2 weeks long-term. Morris water maze (MWM) and passive avoidance (PA) tests were used to determine learning and memory functions. Results In the MWM test, there is a significant increase in the acquisition latency (1–4 days) of 24-month-old rats. There is a significant reduction in the “time spent in the escape platform’s quadrant” in 24-month-old rats compared to 4-month-old rats in the probe trial of the MWM test. YC-1 treatment reversed the reduction of the “time spent in the escape platform’s quadrant” of 24-month-old rats. In the PA test, there was no significant difference in the 1st-day latency of rats in all groups. On the 2nd day, retention latency significantly decreased in the 24-month-old rats compared to 4-month-olds. YC-1 reversed the diminished retention latency in 24-month-old rats. YC-1 treatment and aging did not affect results of the locomotor activity test or the foot-shock sensitivity test, suggesting our results were not due to a change in motor activity or disability of the animals. Conclusions Our findings suggest that activation of the NO-sGC-cGMP pathway plays an important role in spatial and emotional learning and memory functions in aged rats.
    08/2014; 20:130-137. DOI:10.12659/MSMBR.891064
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    • "Nitric oxide (NO) is an intercellular retrograde messenger in the central nervous systems which has been shown to involve in certain forms of long-term potentiation (LTP), expression and synaptic plasticity (Prast and Philippu, 2001; Domek-Łopacińska and Strosznajder, 2005; Koylu et al., 2005; Edwards and Rickard, 2007; Kleppisch and Feil, 2009; Cserép et al., 2011). "
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    ABSTRACT: In the present study, the effects of intra-dorsal hippocampal (intra-CA1) injections of nitric oxide (NO) agents on muscimol state-dependent memory were examined in mice. A single-trial step-down passive avoidance task was used for the assessment of memory retrieval in adult male NMRI mice. Post-training intra-CA1 administration of a GABAA receptor agonist, muscimol (0.05 and 0.1μg/mouse) dose dependently induced impairment of memory retention. Pre-test injection of muscimol (0.05 and 0.1μg/mouse) induced state-dependent retrieval of the memory acquired under post-training muscimol (0.1μg/mouse, intra-CA1) influence. Pre-test injection of a NO precursor, L-arginine (1 and 2μg/mouse, intra-CA1) improved memory retention, although the low dose of the drug (0.5μg/mouse) did not affect memory retention. Pre-test injection of an inhibitor of NO-synthase, L-NAME (0.5 and 1μg/mouse, intra-CA1) impaired memory retention, although the low dose of the drug (0.25μg/mouse) did not affect memory retention. In other series of experiments, pre-test intra-CA1 injection of L-arginine (0.25 and 0.5μg/mouse) 5min before the administration of muscimol (0.1μg/mouse, intra-CA1) dose dependently inhibited muscimol state-dependent memory. Pre-test intra-CA1 administration of L-arginine (0.125, 0.25 and 0.5μg/mouse) by itself cannot affect memory retention. Pre-test intra-CA1 injection of L-NAME (0.25μg/mouse, intra-CA1) reversed the memory impairment induced by post-training administration of muscimol (0.1μg/mouse, intra-CA1). Moreover, pre-test administration of L-NAME (0.125 and 0.25μg/mouse, intra-CA1) with an ineffective dose of muscimol (0.025μg/mouse, intra-CA1) significantly restored the retrieval and induced muscimol state-dependent memory. Pre-test intra-CA1 administration of L-NAME (0.0625, 0.125 and 0.25μg/mouse) by itself cannot affect memory retention. It may be suggested that the nitric oxide in the dorsal hippocampal area play an important role in muscimol state-dependent memory.
    Pharmacology Biochemistry and Behavior 12/2013; 117. DOI:10.1016/j.pbb.2013.12.010 · 2.78 Impact Factor
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