Nitric oxide and major depression

Abstract

Nitric oxide has been known to play a significant role in the pathophysiology of various disorders of the body. Despite its very short half-life, nitric oxide is known to modulate various neurotransmitter system(s) in the body and thus is speculated to play an imperative role in the pathogenesis of neurological disorders. This “wonder” molecule has been often found to possess a “dual role” in many neurological disorders of the body. Evidences have shown its prominent role in the pathogenesis of major depression. Nitric oxide modulates norepinephrine, serotonin, dopamine, glutamate, the major neurotransmitters involved in the neurobiology of major depression. The nitric oxide modulatory activity of various new generations of antidepressants has been demonstrated. Clinical studies have also confirmed the nitric oxide modulatory activity of various antidepressants particularly belonging to the class of selective serotonin reuptake inhibitors. The present review attempts to discuss the role of nitric oxide in the pathophysiology of major depression. Further, the involvement of nitric oxide system in the mechanism of various antidepressants has been discussed in detail. Nitric oxide based antidepressants can be the future drugs of choice for major depression, particularly in the treatment of pharmacoresistant depression.

Introduction

Major depression is a debilitating disorder and is expected by the World Health Organization (WHO) to be the second most prevalent disorder (after ischemic heart disease) by 2020. Despite the availability of various antidepressant molecules belonging to diverse mechanisms of action, a sizeable population still continues to suffer from its ill-consequences. The reason for this pharmacoresistance is not clear, however, researchers are trying to explore all the possible drug targets to treat major depression. Recently, the role of nitric oxide in the pathophysiology of major depression has come to the forefront and the fact that paroxetine, a selective serotonin reuptake inhibitor (SSRI), is a nitric oxide synthase (NOS) inhibitor has encouraged the researchers to explore more about nitric oxide in the pathogenesis of major depression.

Nitric oxide has been considered as an important neurotransmitter substance involved in the pathophysiology of many neurological disorders, such as epilepsy, schizophrenia, drug addiction, anxiety, major depression, etc. Nitric oxide is a chemical messenger that possesses an ability to freely diffuse across the cell membranes and unlike other classical neurotransmitters, this molecule is neither stored in the synaptic vesicles nor released by the process of exocytosis [1]. The half life of nitric oxide is very small (3–6 s). Nitric oxide through modulating different biochemical reactions plays an important role in the physiological processes of the body. For example, in the brain, nitric oxide has been implicated in neurotransmission, neuromorphongenesis, synaptic plasticity, regulation of gene expression, modulating sexual and aggressive behaviors, learning, perception of pain, aggression and depression [2]. Since the designation of nitric oxide as “molecule of the year” by Science in 1962, a preponderance of the literature has brought insights into its innumerable roles in many brain related disorders including stress and major depression.

Nitric oxide is synthesized from l-arginine with the help of an NOS enzyme. NOS is a highly regulated enzyme with a heme domain that is linked to the flavin mononucleotide (FMN)/flavin adenine dinucleotide (FAD) reductase enzyme and transfers the electrons from nicotinamide adenine dinucleotide phosphate (NADPH) to the heme part [3].

Three forms of NOS viz. nNOS (neuronal NOS; type I), iNOS (inducible NOS; type II), eNOS (endothelial NOS; type III) are known to exist in mammals. All the three isoforms of NOS are known to express in different regions of the brain. Both nNOS and eNOS are constitutively expressed in the brain and are calcium/calmodulin dependent. However, studies have revealed that these two isoforms of NOS may also be induced under certain stressful conditions. On the contrary, the expression of iNOS is a highly regulated one and is calcium independent [1]. Within the brain, nNOS is found in many areas associated with stress and depression, namely hippocampus, hypothalamus, dorsal raphe nucleus, locus coeruleus [4].

There are various evidences in the literature that has demonstrated an imperative role of nitric oxide in major depression. These citations include:

• The level of plasma nitric oxide metabolites has been found to be significantly higher in suicidal patients than in nonsuicidal psychiatric patients or in normal control subjects [5]. Similarly, a clinical study has demonstrated an increased production of nitric oxide in depressed patients [6], suggesting that the levels of nitric oxide are altered in majorly depressed individuals.

• Decreasing the levels or blocking the synthesis of nitric oxide (blocking NOS) in brain can induce antidepressant-like effects, thus implicating the role of endogenous hippocampal nitric oxide in the pathophysiology of major depression [7], [8]. Various NOS inhibitors viz. l-NAME (a non-selective NOS inhibitor) or 7-nitroindazole (7-NI; a selective nNOS inhibitor) are known to reduce the immobility period and increase swimming behavior in the rat forced swim test, thus, displaying antidepressant-like activity [7], [9]. The NOS inhibitor 1-[2-(trifluoromethyl)phenyl] imidazole (TRIM) is found to be protective in unpredictable chronic mild stress procedure in mice [10] suggesting that NOS inhibitors could be the future drugs of choice for the treatment of stress and related disorders.

• The inhibitors of NOS are known to enhance the extracellular levels of serotonin and dopamine in the rat ventral hippocampus, one of the major brain areas involved in the pathophysiology of major depression. l-arginine has the opposite effect thus demonstrating that endogenous nitric oxide may exert a negative control over the levels of serotonin and dopamine in the hippocampus [11]. It is further confirmed from a study demonstrating that retrodialysis of the ventral hippocampus injected with 7-NI, a specific nNOS inhibitor induced a very large increase in extracellular dopamine and a small increase in serotonin [11].

• Evidences have also demonstrated that inhibiting the NOS enzyme could be used as a strategy to enhance the clinical efficacy of serotoninergic antidepressants [12]. Interestingly, Finkel et al. have reported that paroxetine, a selective serotonin reuptake inhibitor, is an NOS inhibitor [13]. In another study, paroxetine has shown to demonstrate an anti-compulsive effect through decreasing the central levels of nitric oxide [14]. Similar to this, one of the preclinical findings has demonstrated that N(G)-nitro-l-arginine (l-NNA), an NOS inhibitor, augmented the behavioral effect of imipramine or fluoxetine in the forced swim test [12].

• In one of the recent clinical studies, patients suffering from major depression and bipolar disorder demonstrated high immunoreactivity for nNOS in the CA1 and subiculum region of the hippocampus as compared to the control group [15].

• Chronic administration of nitric oxide synthase inhibitor, N(G)-nitro-l-arginine (l-NNA; 0.1, 0.3 mg/kg) for 21 days produced down-regulation of the cortical beta adrenoceptors. This effect is similar to that observed with the chronic treatment of imipramine, a tricyclic antidepressant [16]. This indicates the modulating effect of nitric oxide on various receptor systems of the body that are supposed to be involved in major depression.

• Animal studies have indicated that nitric oxide via modulating the level of cyclic guanosine monophosphate (cGMP) is known to produce a depression-like state in an animal model [17]. cGMP is degraded into GMP with the help of phosphodiesterase enzyme (PDE). It has been shown that the drugs affecting PDE influenced cyclic guanosine monophosphate functions have been found to be useful for the treatment of major depression [18]. This is explained in the next part of the review.

• Studies have shown that a deficiency in magnesium ion may be responsible for the pathophysiology of major depression. Deficiency in magnesium may result in an increased production of nitric oxide which may induce symptoms of major depression [19]. Magnesium treatment in majorly depressed patients has found to induce a rapid antidepressant effect [19].

• Further, melatonin is known to inhibit NOS in rat cerebellum [20]. Melatonin modulatory drugs are found to be useful antidepressants [21]. It has been found that N1-acetyl-5-methoxykynuramine, a brain metabolite of melatonin rather than melatonin, inhibits nNOS [22]. Agomelatine, a melatonergic agonist (at both MT₁ and MT₂ receptors) and serotonin 2C (5-HT_2C) receptor antagonist, has an antidepressant activity [23].

• The level of nNOS was found to be significantly lower in the locus coeruleus region of the brain of patients suffering from major depression as compared to the normal controls [24].

• In contrary to these studies, it has also been suggested that there is a decrease in the plasma nitric oxide levels in patients suffering from major depression that may pose a risk for the development of coronary artery diseases. Another study has indicated that the decreased production of nitric oxide by the vascular wall and platelets might contribute to the development of coronary heart diseases in patients suffering from major depression [25]. Also, milnacipran, a serotonin noradrenaline reuptake inhibitor, might increase the levels of nitric oxide in depressed patients [26].

Therefore, based on the above facts, the role of nitric oxide in the pathophysiology of major depression is still obscured. However, all the above evidences have pointed out an important role of nitric oxide in the pathophysiology of major depression and the drugs which affect the nitric oxide system may be useful for the treatment of this devastating disorder. Based on above evidences, we suppose that targeting the nitric oxide system may help the researchers and clinicians to treat the depressed patients who do not respond to conventional antidepressant molecules. However, this hypothesis requires further clinical evidences and proper efficacy versus safety ratio should be assessed. The inhibitors of NOS may produce cardiovascular complications, such as hypertension, coronary artery spasm, and platelet aggregation [27], and thus assessing risk/benefit ratio is utmost essential before these drugs are put into clinical practice for the treatment of major depression.