Nitric Oxide (NO) Synthase Inhibitors: Potential Candidates for the Treatment of Anxiety Disorders?

Close to 19% of the world population suffers from anxiety. Current medications for this chronic mental disorder have improved treatment over the last half century or more, but the newer anxiolytics have proved disappointing, and enormous challenges remain. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, is involved in the pathogenesis of anxiety. In particular, excessive NO production might contribute to its pathology. This implies that it might be useful to reduce nitrergic activity; therefore, molecules aiming to downregulate NO production such as NO synthase inhibitors (NOSIs) might be candidates. Here, it was intended to critically review advances in research on these emerging molecules for the treatment of anxiety disorders. Current assessment indicates that, although NOSIs are implicated in anxiety, their potential anti-anxiety action remains to be established.

The role of nitric oxide (NO) modulators in obsessive-compulsive disorder (OCD).

Obsessive-compulsive disorder (OCD) is as serious devastating anxiety disorder. Selective serotonin reuptake inhibitors (SSRIs) are largely used for the treatment of this mental disease. This pharmacological approach presents consistent limitations including modest efficacy and important side effects. There is pressing need, therefore, to develop new molecules with higher efficacy and safety. Nitric oxide (NO) is an intra-and inter-cellular messenger in the brain. Its involvement in the pathogenesis of OCD has been proposed. In a series of preclinical studies, the anxiolytic profile of NO modulators has been emerged. In the present review I intended to critically evaluate advances in research of these molecules as potential novel agents for the treatment of OCD, comment their advantages over currently used pharmacological therapy as well remaining challenges. Up to now, few preclinical studies have been carried out to this end. Nonetheless, experimental evidence proposes a role for NO and its modulators in OCD. Additional research is mandatory aiming to definitively determine a role for NO modulators for the treatment of OCD. A note of caution, however, is needed on account of potential neurotoxicity and narrow therapeutic window of NO compounds.

The Nitric Oxide (NO) Donor Molsidomine Counteract Social Withdrawal and Cognition Deficits Induced by Blockade of the NMDA Receptor in the Rat.

The deficiency of the gaseous molecule nitric oxide (NO) seems to be critically involved in the pathogenesis of schizophrenia. Thus, molecules that can normalize NO levels, as are NO donors, might be of utility for the medication of this psychiatric disease. The aim of the present study was to detect the ability of the NO donor molsidomine to reduce schizophrenia-like impairments produced by the blockade of the N-methyl-D-aspartate (NMDA) receptor in rats. Molsidomine's ability to attenuate social withdrawal and spatial recognition memory deficits induced by the NMDA receptor antagonist ketamine were assessed using the social interaction and the object location test, respectively. Further, the efficacy of the combination of sub-effective doses of molsidomine with sub-effective doses of the atypical antipsychotic clozapine in alleviating non-spatial recognition memory deficits was evaluated utilizing the object recognition task. Molsidomine (2 and 4 mg/kg) attenuated social withdrawal and spatial recognition memory deficits induced by ketamine. Co-administration of inactive doses of molsidomine (1 mg/kg) and clozapine (0.1 mg/kg) counteracted delay-dependent and ketamine-induced non-spatial recognition memory deficits. The current findings suggest that molsidomine is sensitive to glutamate hypofunction since it attenuated behavioral impairments in animal models mimicking the negative symptoms and cognitive deficits of schizophrenia. Additionally, the present results support the potential of molsidomine as an adjunctive drug for the therapy of schizophrenia.

The Nitric Oxide (NO) Donor Molsidomine Attenuates Memory Impairments Induced by the D1/D2 Dopaminergic Receptor Agonist Apomorphine in the Rat.

Several lines of evidence suggest that scarcity of the gaseous molecule nitric oxide (NO) is associated with the pathogenesis of schizophrenia. Therefore, compounds, such as NO donors, that can normalize NO levels might be of utility for the treatment of this pathology. It has been previously shown that the NO donor molsidomine attenuated schizophrenia-like behavioral deficits caused by glutamate hypofunction in rats. The aim of the current study was to investigate the efficacy of molsidomine and that of the joint administration of this NO donor with sub-effective doses of the non-typical antipsychotics clozapine and risperidone to counteract memory deficits associated with dysregulation of the brain dopaminergic system in rats. Molsidomine (2 and 4 mg/kg) attenuated spatial recognition and emotional memory deficits induced by the mixed dopamine (DA) D1/D2 receptor agonist apomorphine (0.5 mg/kg). Further, the joint administration of sub-effective doses of molsidomine (1 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted non-spatial recognition memory impairments caused by apomorphine. The present findings propose that molsidomine is sensitive to DA dysregulation since it attenuates memory deficits induced by apomorphine. Further, the current findings reinforce the potential of molsidomine as a complementary molecule for the treatment of schizophrenia.

Effects of low doses of different nitric oxide (NO) donors in rat models of obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD).

Several lines of evidence suggest that the intra- and inter-cellular messenger nitric oxide (NO) is critically involved in anxiety. Contrasting findings are reported, however, regarding the effects of NO donors in preclinical models of anxiety. Previous research has shown that challenge with a low dose range of the NO donors sodium nitroprusside (SNP) and molsidomine induce anti-anxiety-like effects in rodents. There is poor information concerning the effects of these NO donors on preclinical models mimicking the obsessive-compulsive disorder (OCD) and the post-traumatic stress disorder (PTSD). The present research was designed to investigate this issue in the rat. To this end, the mCPP-induced excessive self-grooming and the contextual fear conditioning (CFC) test which are behavioural paradigms resembling OCD and PTSD respectively in rodents were used. Acute administration of SNP (1 mg/kg) and molsidomine (4 mg/kg) attenuated excessive self-grooming induced by the 5-HT2C receptor agonist mCPP (0.6 mg/kg). Further, at the same dosage, both these NO donors reduced freezing behaviour evidenced in the CFC test. The present results suggest that NO donors are efficacious in attenuating abnormal behaviours revealed in animal models of OCD and PTSD which are among the most severe pathologies of anxiety.

Crocus sativus L. Extracts and Its Constituents Crocins and Safranal; Potential Candidates for Schizophrenia Treatment?

Schizophrenia is a chronic mental devastating disease. Current therapy suffers from various limitations including low efficacy and serious side effects. Thus, there is an urgent necessity to develop new antipsychotics with higher efficacy and safety. The dried stigma of the plant Crocus sativus L., (CS) commonly known as saffron, are used in traditional medicine for various purposes. It has been demonstrated that saffron and its bioactive components crocins and safranal exert a beneficial action in different pathologies of the central nervous system such as anxiety, depression, epilepsy and memory problems. Recently, their role as potential antipsychotic agents is under investigation. In the present review, I intended to critically assess advances in research of these molecules for the treatment of schizophrenia, comment on their advantages over currently used neuroleptics as well-remaining challenges. Up to our days, few preclinical studies have been conducted to this end. In spite of it, results are encouraging and strongly corroborate that additional research is mandatory aiming to definitively establish a role for saffron and its bioactive components for the treatment of schizophrenia.

The Nitric Oxide (NO) Donor Sodium Nitroprusside (SNP) and Its Potential for the Schizophrenia Therapy: Lights and Shadows.

Schizophrenia is a severe psychiatric disorder affecting up to 1% of the worldwide population. Available therapy presents different limits comprising lack of efficiency in attenuating negative symptoms and cognitive deficits, typical features of schizophrenia and severe side effects. There is pressing requirement, therefore, to develop novel neuroleptics with higher efficacy and safety. Nitric oxide (NO), an intra- and inter-cellular messenger in the brain, appears to be implicated in the pathogenesis of schizophrenia. In particular, underproduction of this gaseous molecule is associated to this mental disease. The latter suggests that increment of nitrergic activity might be of utility for the medication of schizophrenia. Based on the above, molecules able to enhance NO production, as are NO donors, might represent a class of compounds candidates. Sodium nitroprusside (SNP) is a NO donor and is proposed as a promising novel compound for the treatment of schizophrenia. In the present review, we intended to critically assess advances in research of SNP for the therapy of schizophrenia and discuss its potential superiority over currently used neuroleptics.

Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential.

Natural products or organic compounds isolated from natural sources as primary or secondary metabolites have inspired numerous drugs [...].

Crocins, the Bioactive Components of Crocus sativus L., Counteract the Disrupting Effects of Anesthetic Ketamine on Memory in Rats.

Consistent experimental evidence suggests that anesthetic doses of the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine cause severe memory impairments in rodents. Crocins are among the various bioactive ingredients of the plant Crocus sativus L., and their implication in memory is well-documented. It has not yet been elucidated if crocins are able to attenuate the memory deficits produced by anesthetic ketamine. The present study was undertaken aiming to clarify this issue in the rat. For this aim, the object recognition, the object location and the habituation tests, reflecting non-spatial recognition memory, spatial recognition memory and associative memory, respectively, were utilized. A post-training challenge with crocins (15-30 mg/kg, intraperitoneally (i.p.), acutely) counteracted anesthetic ketamine (100 mg/kg, i.p.)-induced performance impairments in all the above-mentioned behavioral memory paradigms. The current findings suggest that crocins modulate anesthetic ketamine's amnestic effects.

Repeated but not acute exposure with a low dose range of the nitric oxide (NO) donor sodium nitroprusside (SNP) induces anxiolytic-like behaviour in a dose-independent manner in two different rat models of anxiety.

Sodium nitroprusside (SNP) is a nitric oxide (NO) donor which actually is under assessment as a potential candidate for the treatment of schizophrenia. It is well documented that anxiety symptoms are a prominent future in various psychiatric diseases comprising schizophrenia. Prior research has shown that acute challenge with SNP (1-3 mg/kg) induced anti-anxiety effects in rats but these effects at high doses were confounded by sedation and were disappeared after repeated application of it. It is still unknown if administration of a lower SNP dose range, either acutely or sub-chronically, could induce anxiolytic-like behaviour. The present study was designed to investigate this issue in rats. For this aim, the light/dark and the open field tests were used. Acute challenge with SNP (0.1 and 0.3 mg/kg, 30 min before testing) did not affect rodents' performance in the above mentioned behavioural paradigms. Conversely, rats treated sub-chronically with SNP (0.1 and 0.3 mg/kg, once per day, for 5 consecutive days), displayed longer time spent in the light chamber of the light/dark box and in the central area of the open field with respect to their vehicle-treated counterparts. Interestingly, SNP did not influence the first latency to enter the dark chamber and the number of transitions between the light and dark compartments of the apparatus in the light/dark test and did not modify the number of squares crossed, grooming episodes and rearings in the open field test. Finally, acute administration of SNP (0.1, 0.3 and 1 mg/kg, 10 min before testing) also did not influence rats' performance in the light/dark test. The present results indicate that short-term repeated but not acute application of a range of low doses of the NO donor SNP in a dose-independent manner induced an anti-anxiety behaviour in the rat which was not accompanied by undesired effects.

The GABAA-Benzodiazepine Receptor Antagonist Flumazenil Abolishes the Anxiolytic Effects of the Active Constituents of Crocus sativus L. Crocins in Rats.

Anxiety is a chronic severe psychiatric disorder. Crocins are among the various bioactive components of the plant Crocus sativus L. (Iridaceae) and their implication in anxiety is well-documented. However, which is the mechanism of action underlying the anti-anxiety effects of crocins remains unknown. In this context, it has been suggested that these beneficial effects might be ascribed to the agonistic properties of these bioactive ingredients of saffron on the GABA type A receptor. The current experimentation was undertaken to clarify this issue in the rat. For this research project, the light/dark and the open field tests were used. A single injection of crocins (50 mg/kg, i.p., 60 min before testing) induces an anti-anxiety-like effect revealed either in the light-dark or open field tests. Acute administration of the GABAA-benzodiazepine receptor antagonist flumazenil (10 mg/kg, i.p., 30 min before testing) abolished the above mentioned anxiolytic effects of crocins. The current findings suggest a functional interaction between crocins and the GABAA receptor allosteric modulator flumazenil on anxiety.

Effects of Anesthetic Ketamine on Anxiety-Like Behaviour in Rats.

There is scarce information regarding the effects of anesthetic doses of the non-competitive N-methyl-D-aspartate receptor antagonist ketamine on anxiety. The current study evaluated the acute effects of intraperitoneally (i.p.) administered anesthetic ketamine (100 mg/kg) i.p. on anxiety in rats. For this purpose, the light/dark and the open field tests were utilized. The effects of anesthetic ketamine on motility were also examined using a motility cage. In the light/dark test, anesthetic ketamine, administered 24 h before testing reduced the number of transitions between the light and dark compartments and the time spent in the light compartment in the rats compared with their control cohorts. In addition, ketamine was found to exert a depressive effect on rats' motility. In the open field test, animals treated with anesthetic ketamine 24 h before testing spent essentially no time in the central area of the apparatus, decreased horizontal ambulatory activity, and preserved to a certain extent their exploratory behaviour compared to their control counterparts. The results suggest that, in spite of its hypokinetic effect, a single anesthetic ketamine administration apparently induces an anxiety-like state, while largely preserving exploratory behaviour in the rat. These effects were time-dependent they since they were extinguished when testing was carried out 48 h after anesthetic ketamine administration.

The role of nitric oxide (NO) donors in anxiety. Lights and shadows.

Anxiety-related disorders are a common public health issues. Current medication for this affective disorder involves the GABA-ergic or the serotonergic transmission. Different forms of anxiety, however, are resistant to treatment with GABA-ergic or serotonergic agents and the use of these compounds can be associated with severe side effects. Thus, almost 60 years after the discovery of the benzodiazepines there is need not only for fresh medications but also alternative targets. The nitrergic system has emerged as a promising target since several lines of evidence suggest that nitric oxide (NO), an intra- and inter-cellular messenger in the brain, is implicated in anxiety. Therefore, NO modulators might be beneficial. Here I critically review advances in research of agents acting on the nitrergic system, such as the NO donors, for the treatment of anxiety. Present analysis suggests that although NO donors are involved in anxiety their potential anxiolytic effect remains to be established.

Effects of the active constituents of Crocus sativus L. crocins and their combination with memantine on recognition memory in rats.

Crocus sativus L., is a plant cultivated in many countries of the world. Crocins are among the active constituents of C. sativus and their implication in cognition has been proposed. The present study was designed to investigate in the rat the effects of crocins on distinct recognition memory components (encoding, storage and retrieval). Subsequently, the potential use of crocins as adjunctive agents for the treatment of memory disorders was examined. Thus, the effects exerted by a combination of subthreshold doses of crocins and memantine on recognition memory were evaluated. To assess the effects of compounds on memory, the novel object-recognition task (NORT) was used. In a preliminary study, the influence of the retention time (the delay between the two trials) on the performance of rats was assessed. Rats' recognition memory abilities remained intact up to 6 h, but were extinguished when a delay of 24 h was utilized. Crocins, at any dose tested (5, 15, and 30 mg/kg), did not affect rats' performance, whereas administration of higher doses (15 and 30 mg/kg) reversed delay-dependent deficits in the NORT. The combination of subthreshold doses of crocins (5 mg/kg) and memantine (3 mg/kg) did not influence the performance, but counteracted delay-dependent deficits in the NORT. These findings suggest that crocins counteract natural forgetting and may modulate different aspects of recognition memory, and that the combined use of crocins and memantine might represent a novel strategy to treat memory disorders.

The novel dehydroepiandrosterone (DHEA) derivative BNN27 counteracts delay-dependent and scopolamine-induced recognition memory deficits in rats.

Experimental evidence indicates that the neurosteroids dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) are involved in cognition. BNN27 is a novel 17C spiroepoxy-DHEA derivative, which devoid of steroidogenic activity. The neuroprotective effects of BNN27 have been recently reported. The present study was designed to investigate the effects of BNN27 on recognition memory in rats. For this purpose, the novel object task (NOT), a procedure assessing non-spatial recognition memory and the novel location task (NLT), a procedure evaluating spatial recognition memory were used. Intraperitoneal (i.p.) administration of BNN27 (3 and 10mg/kg) antagonized delay-dependent deficits in the NOT in the normal rat, suggesting that this DHEA derivative affected acquisition, storage and retrieval of information. In addition, BNN27 (3 and 10mg/kg, i.p.) counteracted the scopolamine [0.2mg/kg, subcutaneously (s.c.)]-induced non-spatial and spatial recognition memory deficits. These findings suggest that BNN27 may modulate different aspects of recognition memory, potentially interacting with the cholinergic system, relevant to cognition.

Acute and repeated exposure with the nitric oxide (NO) donor sodium nitroprusside (SNP) differentially modulate responses in a rat model of anxiety.

The nitric oxide (NO) donor sodium nitroprusside (SNP) actually is under investigation for the treatment of schizophrenia. That anxiety disorders are noted to occur commonly in schizophrenia patients is known. Contradictory results were reported however, concerning the effects of SNP in animal models of anxiety disorders. The present study investigated the effects of acute and repeated administration of SNP on anxiety-like behaviour in rats assessed in the light/dark test. The effects of SNP on motility in a locomotor activity chamber were also investigated in rats. Acute administration of 1 mg/kg SNP 30 but not 60 min before testing induced anxiolytic-like behaviour which cannot be attributed to changes in locomotor activity. Conversely, a single injection of 3 mg/kg SNP at 30 min before testing depressed rats' general activity, while at 60 min this dose did not influence performance of animals either in the light/dark or in the motor activity test. Repeated application of SNP (1 and 3 mg/kg, for 5 consecutive days) did not alter rodents' performance in the above described behavioural paradigms. The present results suggest that the effects exerted by SNP in the light/dark test in rats are dose, time and treatment schedule-dependent. The current findings propose also a narrow therapeutic window for SNP in this animal model of anxiety.

Constituents of Saffron (Crocus sativus L.) as Potential Candidates for the Treatment of Anxiety Disorders and Schizophrenia.

Anxiety disorders and schizophrenia are common public health issues. The dried stigma of the plant Crocus sativus L., (C. sativus) commonly known as saffron are used in folk medicine for various purposes. Several lines of evidence suggest that C. sativus, crocins and safranal are implicated in anxiety and schizophrenia. Here, I intend to critically review advances in research of these emerging molecules for the treatment of anxiety and schizophrenia, discuss their advantages over currently used anxiolytics and neuroleptics, as well remaining challenges. Current analysis shows that C. sativus and its components might be a promising class of compounds for the treatment of the above mentioned psychiatric diseases.

Effects of low doses of the novel dehydroepiandrosterone (DHEA) derivative BNN27 in rat models of anxiety.

RATIONALE: Several lines of evidence indicate that the neurosteroid dehydroepiandrosterone (DHEA) is involved in anxiety. BNN27 is a new DHEA derivative lacking steroidogenic effects. The beneficial effects exerted by BNN27 in preclinical models of schizophrenia and memory disorders have been recently reported. OBJECTIVES: The present study was designed to investigate the effects of this DHEA novel analog on anxiety-like behavior in rats. METHODS: To this end, the light/dark box, the open field, the contextual fear conditioning, and the excessive self-grooming induced by the serotonin 5-HT2c receptor agonist mCPP tests were utilized. RESULTS: Animals treated acutely with BNN27 (1, 3, and 6 mg/kg) dose dependently spent more time in the bright compartment of the light/dark box and in the central zone of the open field with respect to their vehicle-treated cohorts. Further, BNN27 reduced freezing behavior and weakened the mCPP-induced excessive self-grooming. CONCLUSIONS: Our data indicate that BNN27 is a highly potent anxiolytic agent, as in all studied paradigms it showed anxiolytic-like effects in male rats.

The novel dehydroepiandrosterone derivative BNN27 counteracts the impairing effects of anesthetic ketamine on rats' non-spatial and spatial recognition memory.

Conspicuous experimental evidence indicates that anesthetic doses of the non-competitive NMDA receptor antagonist ketamine disrupt memory abilities in rodents. BNN27 is a synthetic analogue of dehydroepiandrosterone (DHEA) with potent antioxidant properties and its involvement in cognition has recently been shown. It is not yet clarified whether BNN27 can attenuate the cognition deficits induced by anesthetic ketamine. The present study was designed to elucidate this issue in the rat. For this purpose, the object recognition and the object location tests which are behavioral procedures evaluating non-spatial and spatial recognition memory respectively in rodents were used. The effects of compounds on motility were also tested utilizing a motor activity cage. Post-training administration of BNN27 (3 and 6 mg/kg, intraperitoneally) counteracted anesthetic ketamine (100 mg/kg, intraperitoneally)-induced non-spatial and spatial recognition memory deficits. Further, these effects cannot be attributed to changes to locomotor activity. Our findings clearly show the protective role of BNN27, on recognition memory impairment induced by anesthetic ketamine, indicating a functional interaction following co-administration of synthetic microneurotrophins and ketamine.

Anesthetic ketamine impairs rats' recall of previous information: the nitric oxide synthase inhibitor N-nitro-L-arginine methylester antagonizes this ketamine-induced recognition memory deficit.

BACKGROUND: There is poor experimental evidence concerning the effects of anesthetic doses of the noncompetitive N-methyl-D-aspartate receptor antagonist ketamine on rodents' memory abilities. The current study was designed (1) to investigate the consequences of posttraining administration of anesthetic ketamine (100 mg/kg intraperitoneally) on rats' recognition memory and (2) to evaluate the ability of the nitric oxide synthase inhibitor N-nitro-L-arginine methylester (L-NAME; 1, 3, and 10 mg/kg intraperitoneally) to counteract the expected behavioral deficits produced by anesthetic ketamine. Finally, in an attempt to clarify if the expected memory impairments produced by anesthetic ketamine were related to the anesthesia, we also tested the effects of a subanesthetic dose of it (3 mg/kg intraperitoneally) on rats' recognition memory. METHODS: The novel object recognition test, a procedure assessing recognition memory in rats, was selected. RESULTS: Posttraining administration of anesthetic (but not of subanesthetic) ketamine disrupted rats' performance in the novel object recognition paradigm. The discrimination index (D) was decreased by ketamine from 0.415 (using saline) to 0.128, thus indicating that the anesthetic dose of ketamine impaired recognition memory. L-NAME (1-3, but not 10, mg/kg) reversed this memory deficit produced by ketamine; the D index of 0.128 using ketamine treatment was increased by 1 and 3 mg/kg L-NAME to 0.427 and 0.478, respectively. CONCLUSIONS: The current results indicate that anesthetic ketamine impaired rats' posttraining memory components (storage and/or retrieval of information) and that a nitric oxide component modulates its behavioral effects.