Chair and Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Staszica 4, PL Lublin, Poland

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1 1 Chair and Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Staszica 4, PL Lublin, Poland JOLANTA ORZELSKA, SYLWIA TALAREK The current approach to the central effects of sildenafil role of nitric oxide:cgmp pathway. Aktualny pogląd na temat ośrodkowego działania sildenafilu rola drogi tlenek azotu:cgmp. INTRODUCTION Nitric oxide (NO) is an important bioregulatory molecule in the nervous, immune and cardiovascular systems. It is synthesized from L-arginine, which is converted to L-citrulline in the presence of O 2, NADPH and tetrahydrobiopterin by a nitric oxide synthase (NOS)- catalysed reaction [6,11]. There are four members of the NOS family: neuronal NOS (nnos), endothelial NOS (enos), inducible NOS (inos) and mitochondrial NOS (mnos). The last one is an isoform of nnos present in the inner mitochondrial membrane. The enzymes: nnos and enos are Ca 2+ - calmodulin-dependent, constitutively expressed in mammalian cells that generate increments of NO, lasting a few minutes. In contrast, inos is a Ca 2+ - calmodulin-independent enzyme and its regulation depends on de novo synthesis [1,23]. NO binds to a haem-containing enzyme called soluble guanylyl cyclase (sgc) and thus activates cellular signaling cascades. NO interacts with sgc allosterically to increase cyclic guanosine-3, 5 -monophosphate (cgmp) concentrations, leading to cgmp-dependent responses (Ryc.1.) [6,24]. cgmp in turn modulates the activity of cgmp-dependent kinases, cgmp-gated ion channels, and cgmp-regulated phosphodiesterases (PDE) [19]. The focus of early NO research was the endothelium, and the enzyme complex nitric oxide synthase was found as a constituent enzyme activity in these cells [44]. It soon became apparent that NO had functions outside its ability to cause vasodilatation of blood vessels and it functioned as a neurotransmitter in both central and peripheral nervous systems. Although there is considerable evidence that NO functions are a neurotransmitter, it is an unusual transmitter. It is a labile free-gas that is not stored in synaptic vesicles, does not undergo reversible interactions with receptors and its activation is not terminated by presynaptic reuptake or enzymatic degradation. Moreover, NO simply diffuses from nerve terminals, as

2 2 opposed to the exocytosis by which conventional neurotransmitters are released [11]. The range of this NO diffusion implies that structures in the vicinity of the producing cell, both neuronal and non-neuronal, are acting as a neurotransmitter [16]. In the central nervous system (CNS), NO is formed following the activation of glutamate receptors, mainly NMDA (N-methyl-D-aspartate) subtype. After this activation, Ca 2+ is transiently increased in the cytosol and forms a complex with calmodulin that binds to and activates constitutive nnos [37]. NO is supposed to play an important role in several brain functions and/or dysfunction, including regulation of neuronal excitability, synaptic plasticity- long term potentiation (LTP) and depression (LTD), neurotoxicity and neuroprotection [22]. Furthermore, NO has been implicated in other brain functions, such as nociception, learning and memory, anxiety, seizure activity, feeding, drinking [55], and regulation of the release and uptake of neurotransmitters such us dopamine, -aminobutyric acid (GABA), serotonin and glutamate [16]. Sildenafil is approved as the first oral drug to treat erectile dysfunction [39]. Initially, the focus of the scientist s research was to treat hypertension and angina pectoris. However, the phase I clinical trials did not yet prove conclusive with regard to the existence of the antihypertensive effect and sildenafil had little therapeutic potential for the treatment of angina. Interestingly enough, it exhibited a different pharmacological effect in these patients, namely marked penile erection [25]. Sildenafil is a potent phosphodiesterase 5 (PDE5) reversible and selective inhibitor, which blocks cgmp hydrolysis effectively, resulting in accumulation of cgmp and increasing biological effects of NO (Fig.1.) [21]. PDE5 belongs to an important family of proteins that specifically hydrolyses cgmp. There are eleven members of a superfamily PDEs, of which three types (PDE1, 5, 6) selectively hydrolyze cgmp. PDE5 is found in several parts of the body such as lungs, platelets, in various forms of smooth muscle and also in several brain regions. Latest studies revealed that sildenafil was more selective for PDE5 [27] and by inhibiting this enzyme it increases the level of cgmp leading to beneficial effects in targeting some organs (e.g. penis, lungs, heart and brain). The localization of PDE5 tin areas of the brain [3] provides for a possibility of CNS effects of sildenafil administration. Several direct effects of sildenafil administration on the CNS have been reported in both rodents and humans. Therefore this review provides an overview of such studies and presents potential mechanisms that may explain the pharmacological effects.

3 3 Fig.1. The L-arginine/NO/cGMP pathway and its modification by sildenafil. (based on: Bruckdorfer 2005 and Goldenberg 1998) SILDENAFIL AND ANXIETY The presence of NOS in brain regions connected with anxiety, especially the hypothalamus, amygdale and hippocampus, indicated that NO was implicated in the control of anxiety [59]. Several studies have implied that NO has some modulatory effect on anxiety, but the evidence is still contradictory. Both anxiolytic- [17] and anxiogenic-like [56] effects have been reported with NOS inhibitors, in elevated plus-maze test (an animal model of anxiety). The administration of L-G-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor, induced an anxiolytic-like effect. In addition, pretreatment with L-arginine (L-arg)

4 4 counteracted the anxiolytic-like effect in the elevated plus-maze test [60]. There are also results which have shown a role of the cgmp in the action of NO on anxiety [15, 61, 62]. Furthermore, it is known that an inhibition of PDE5 increases the release of glutamate in the nucleus accumbens, which is involved in anxiety [29]. Additionally, there are published studies which suggest that the augmentation of the NO-cGMP cascade by sildenafil induces anxiogenic-like effect in mice [30, 62]. However, the findings are still contradictory and further investigations are necessary to clarity this effect of sildenafil. SILDENAFIL AND AGGRESSIVE DISTURBANCES There is evidence that genetic or pharmacological inhibition of the synthetic enzyme that produces NO in neurons evokes elevated and sustained aggression in male mice. Male mice with targeted deletion of the genes encoding the neuronal (nnos -/- ) isoform of nnos display altered aggressive behaviors [40]. Administration of 7-nitroindazole (7-NI), specific inhibitor of nnos, evokes a substantial increase in aggressive behavior of male mice, resembling effects observed in nnos -/- animals [12]. Moreover, it is known that high densities of nnos positive cells are localized in the limbic system, which regulates emotional behavior and aggression [41]. Recently, the excessive aggressive and impulsive traits in nnos -/- mice have been shown to be caused by reductions in serotonine (5-HT) turnover in brain regions regulating emotions. It has been established that 5-HT is the key neurochemical involved in male-typical offensive aggression and, in addition, that NO plays an important role in normal 5-HT brain function [9]. Some recent studies have described neurological and emotional disturbances including increased aggressive behavior (e.g. rape, suicide, attempted suicide, or murder) in some men taking sildenafil [34, 35]. One possible mechanism of these effects of sildenafil is the inhibition of PDE5 and the subsequent accumulation of cgmp. Alternatively, accumulation of cgmp has potential to negatively feedback upstream mechanisms involved in NO production. Increased cgmp elevates aggression in mice, dogs, and elevated cgmp concentrations have been observed in humans classified as aggressive. Contradictory, there are studies showing that administration of sildenafil does not directly affect aggressive behavior in mice [28].

5 5 SILDENAFIL AND NEUROGENESIS Recent scientific studies have demonstrated that neurogenesis occurs not only in developing organisms but it also occurs continuously into and throughout adult life [52]. Ongoing neurogenesis is thought to be an important mechanism underlying neuronal plasticity, which influences learning and memory but generally declines with age and is associated with neurodegenerative diseases [54]. There is evidence indicating that nnos may play a role during neurogenesis as well as during differentiation of neuronal cells [8]. It is known that nnos is transiently expressed in the cerebral cortical plate and in hippocampus in embryonic rat brain during the period of peak cortical neurogenesis [5]. In addition, NO production is regulated in an activitydependent manner in the brain during the period of developmental synaptogenesis [10]. NO may also promote neurogenesis after brain injury because administration of a NO donor improves neurological functional recovery in young rats after stroke [64]. Moreover, it is known that cgmp is reduced with age [49]. Therefore, it is hypothesized that administration of sildenafil, which causes intracellular accumulation of cgmp, to rats subjected to stroke enhances improvement of neurological outcome during stroke recovery. Recent studies demonstrate that treatment of local cerebral ischemia in rats with sildenafil improved recovery of neurological outcome [64]. It is known that sildenafil promotes cell proliferation, increases angiogenesis, synaptogenesis and enhances brain plasticity in both young and aged rats [65]. Consequently, the use of PDE5 inhibitors such as sildenafil may offer an innovative approach to the improvement of brain function in the aged population [54]. SILDENAFIL AND MEMORY ENHANCEMENT AND ATTENTION The NO-cGMP pathway has been implicated in some forms of learning and memory [16]. In the CNS, NO is known to act as a retrograde messenger following glutamatergic NMDA neurotransmission by stimulating sgc in the presynaptic terminal [6]. The stimulation of sgc leads to the formation of cgmp, whose increased levels result in further release of glutamate, and hence may constitute a presynaptic mechanism contributing to the early phase of a long term potentiation (LTP) [3]. LTP is thought to be a synaptic correlate of learning and memory, and is present mostly in higher brain centers involved in cognitive functions, particularly in the cerebral cortex and hippocampus. There are studies showing that

6 6 induction of LTP is blocked by inhibition of NOS [4,16]. The results resonate with observations concerning the role of NO:cGMP pathway in certain types of learning behavior. Recent findings suggest that systemic administration of sildenafil has cognitiveenhancing effects in attenuating the complex maze learning impairment induced by blockade of muscarinic cholinergic receptor [13]. Moreover, there are studies that show the subthreshold effects of sildenafil on cognitive processing and suggest that the ability to focus attention can be enhanced [47]. Therefore sildenafil, a specific inhibitor of cgmp degrading enzyme, may offer a new strategy for memory improvement and a novel therapy for Alzheimer s disease in the future [54]. SILDENAFIL AND SUBSTANCE DEPENDENCE Drug addiction (substance dependence) is a chronic relapsing disease that is characterized by compulsion to seek and take the drug, loss of control in limiting the intake, emergence of negative emotional states (e.g., dysphoria, anxiety, irritability) when access to the drug is prevented [31]. It is the disease of the brain reward system, which is located predominantly in the limbic structures of the brain, and its main neurotransmitter is dopamine. The adaptation of an organism to a chronic intake of drugs involves development of adaptive changes, tolerance or sensitization [58]. Tolerance is defined as a need to increase doses of an abusive substance in order to experience the same reaction. One of the causes of tolerance is enzymatic induction, due to which a substance of abuse is eliminated more rapidly from the organism. The other type of tolerance is pharmacodynamic tolerance, which can be chronic or acute. Three mechanisms are believed to be involved: rapid desensitization linked with receptor phosphorylation, internalization of the receptor, and induction of genomic changes leading to a decrease in the rate of synthesis of receptor and in synthesis of defective forms of receptor [57]. A sensitization process is an increased response to a drug that follows its repeated intermittent administration. This process can be connected with liver damage and impairment of substance metabolism or with elevated reactivity of dopaminergic system [58]. There is a lot of evidence to support the hypothesis that NO may be involved in the development of dependence on some substances of abuse such as opioids, ethanol, nicotine and psychostimulants [55]. It has been demonstrated that inhibitors of NOS diminished signs of morphine abstinence and the development of tolerance to the analgesic effects of opioids [33, 55]. Moreover, there is data concerning the role of NO in the development of tolerance

7 7 following chronic ethanol administration. NOS inhibition by nonselective inhibitors NOS, L- NAME and L-NOARG, and also by selective inhibitor NOS, 7-nitroindazole, blocks the development of tolerance to the psychomotor impairment following ethanol administration [63]. Additionally, several reports indicate that decreased activity of NOS prevents sensitization to the locomotor effect produced by CNS stimulants [55]. In addition, several epidemiological studies imply that sildenafil is abused in a recreational fashion. Most of the nightclub customers report to take sildenafil simultaneously with illegal drugs (cocaine and cannabis), illicit drugs and alcohol [2]. Moreover, some of authors raises the hypothesis that sildenafil may exert rewarding effects. It has been shown that pretreatment with sildenafil results in the modification of several behavioral signs centrally evoked by dopamine agonists in experimentally naive male rats [18]. The findings of Tahsili-Fahadan et al. (2006) indicate that sildenafil with doses of 20 and 40 mg/kg induces a significant place preference. They have also shown that the rewarding effect of sildenafil is inhibited by both NOS inhibitor L-NAME and MB. Pretreatment with L-arginine potentiates the subthreshold effect and per se non-effective doses of sildenafil. These effects can suggest that the rewarding effect of sildenafil might be mediated through its capability of activating NO-cGMP signaling pathway [50]. SILDENAFIL AND PAIN Pain is a complex process, which involves modulation of both the peripheral and the CNS. It is also a self-protective mechanism which forces the body to move away from danger and, afterwards, to rest the injured part, giving the body a chance to heal itself [54]. The number of researches have demonstrated a role of the NO/cGMP signaling pathway in the processing of nociception. It has been shown that the local administration of L-arginine (a precursor of NO) produces antinociception in rats with carregeenin-induced hyperalgesia, and this effect has blocked by NO inhibitors and methylene blue, an inhibitor of sgc [14]. Moreover, it is shown that a NO donor and NO-synthase inhibitors reduce pain through a spinal mechanism that involves activation of sgc [48]. There are results which indicate that NO is connected, at least partly, with antinociception activity of benzodiazepines [51]. Therefore, it has been proposed that sildenafil, whose effect is closely connected with cgmp concentration, can be involved in nociceptive processes. It is suggested that the antinociceptive effect of sildenafil is due to a local action, as the contralateral administration of the drug is ineffective to reduce flinching. The data also indicate that the inhibition of

8 8 PDE5 and therefore the accumulation of cgmp is enough to produce antinociception [38]. Additionally, the current study provides evidence for a peripheral interaction between PDE5 inhibitor- sildenafil and morphine [26, 36]. Initially, it has been reported that local administration of either NO synthase inhibitors or sgc inhibitor blocks the antinociception produced by morphine [32]. There are studies which indicate that L-NAME blocks the antinociception produced by the morphine-sildenafil combination. Moreover, naloxone, the opioid receptor antagonist, does not modify the effect of sildenafil, indicating that sildenafil does not act on the opioid receptor. Jain et al. (2003) suggest that the activation of opiod receptors by morphine produces an increase in NO, which in turn activates cgmp to produce antinociception. SILDENAFIL AND SEIZURES It has been found that NO produced in response to NMDA receptor stimulation may be involved in the modulation of seizure [7]. NO is known to be a modulator of seizure activity with diverse anticonvulsant and proconvulsant effects based on the type of seizures, source of NO, and other neurotransmitter systems involved. Many studies have revealed that NOS inhibitors, can potentiate the effects of convulsant drugs [45, 53]. However, other studies indicate that NO has also proconvulsant effect [42, 43]. Interestingly, Gilard et al. (2002) have recently reported the occurrence of seizure attacks in two healthy men after using sildenafil. The authors of this study suggest that the activation of NO/cGMP pathway plays a crucial role in the lowering of seizure threshold by sildenafil. It has been shown that the proconvulsant effect of sildenafil can be blocked by either NOS inhibitor - L-NAME or sgc inhibitor - methylene blue, what suggests direct evidence in favor of a NO/cGMP mediated modulation of seizure threshold by sildenafil. However, L-arginine, a precursor of NO produces additive/synergestic interactions with the proconvulsant effect of sildenafil, further supporting the involvement of NO in this effect [46]. Therefore, alteration of seizure threshold by sildenafil may have clinical relevance and warrants further investigations. CONCLUSION Sildenafil is a drug widely used for male erectile dysfunction but it also has several direct effects on the CNS. Most studies indicate that there is indirect link between central effects of sildenafil and NO-cGMP pathway. With regard to the fact that NO-cGMP is

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14 Zhang R., Wang Y., Zhang L., Zhang Z., Tsang W., Lu M. et al. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke, 2002, 33, Zhang L., Zhang R.L., Wang Y., Zhang C., Zhang Z.G., Meng H., Chopp M. Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor. Stroke, 2005, 36, SUMMARY Sildenafil is a drug widely used for male erectile dysfunction but it has also several direct effects on the CNS. These effects in human include dizziness, depression, insomnia, abnormal dreams and nervousness. In rodents, sildenafil produces an antinociceptive effects, evokes neurogenesis, reduces neurological deficits after stroke, enhances the processes of memory and it is involved in the development of dependence on some addictive substances. It is generally known that sildenafil inhibits PDE5 and exerts the activation of NO in the CNS but can also use other mechanisms, for example dopaminergic system. The central effects of sildenafil and lines of its action are encouraging and need further investigation. Key words: sildenafil, nitric oxide, central effects. STRESZCZENIE Sildenafil jest lekiem stosowanym w zaburzeniach wzwodu ale wykazuje również szereg działań ośrodkowych. U ludzi może wywoływać zawroty głowy, depresję, bezsenność, nieprawidłowe sny i nerwowość. U gryzoni sildenafil wykazuje działanie antynocyceptywne, wywołuje neurogenezę, zmniejsza deficyty neurologiczne po udarze, poprawia procesy pamięci, a także włączony jest w procesy uzależnień lekowych. Wiadomo, że sildenafil hamuje PDE5 i zwiększa działanie NO w ośrodkowym układzie nerwowym ale może również działać poprzez inne, mało poznane mechanizmy, co wymaga dalszych badań. Słowa kluczowe: sildenafil, tlenek azotu, efekty ośrodkowe