Current Neuropharmacology (v.9, #4)

Neurotrophins are important proteins that regulate survival, development and function of neurons. They are produced by avariety of cells and exert their effects upon binding to specific tyrosine kinase receptors. The first neurotrophin to be identifiedwas Nerve Growth Factor (NGF). From the pioneer studies performed by Rita-Levi Montalcini, awarded with the Nobel Prize,other neurotrophins have been identified and this family of neurotrophic factors now includes Brain Derived NeurotrophicFactor (BDNF), Neurotrophin 3 and Neurotrophin 4. Their function as pro-survival proteins has been consolidated butsubsequent studies have demonstrated that neurotrophins may also play a role in some pathological conditions. This is the focusof this special issue of Current Neuropharmacology.The paper by Allen et al., addresses the involvement of neurotrophins, NGF and BDNF in particular, in Alzheimer’s diseaseand the possibility of using neurotrophin-based therapies.Frias et al., summarize studies that support the involvement of neurotrophins in the lower urinary tract (LUT) dysfunction andsuggest the use of urinary neurotrophins as biomarkers of LUT pathologies.The paper by Neto et al., addresses the involvement of neurotrophins in depression, a poorly understood pathology with anincreasing prevalence in Western countries.The paper by Siniscalco et al., addresses the involvement of neurotrophins in neuropathic pain, a complex pathology difficult totackle with, and its importance as targets for neuropathic pain treatment.Teng et al., summarize the clinical uses of stem cell-based administration of neurotrophins for the treatment of spinal cordinjury.This issue is published in memory of David Dawbarn, who passed away unexpectedly in January 2010. David dedicated mostof his work at the Bristol University to understanding the importance of neurotrophic factors in Alzheimer’s disease, unravelingthe molecular interactions between neurotrophins and their high-affinity receptors. His research was a key factor to the designof new therapies for the treatment of Alzheimer’s disease, pain and asthma. He is greatly missed by the scientific community,friends and family.

Role of Neurotrophins in Neuropathic Pain by Dario Siniscalco, Catia Giordano, Francesco Rossi, Sabatino Maione, Vito de Novellis (523-529).
Neurotrophins (NTs) belong to a family of structurally and functionally related proteins, they are the subsets ofneurotrophic factors. Neurotrophins are responsible for diverse actions in the developing peripheral and central nervoussystems. They are important regulators of neuronal function, affecting neuronal survival and growth. They are ableto regulate cell death and survival in development as well as in pathophysiologic states. NTs and their receptors areexpressed in areas of the brain that undergo plasticity, indicating that they are able to modulate synaptic plasticity.Recently, neurotrophins have been shown to play significant roles in the development and transmission of neuropathicpain. Neuropathic pain is initiated by a primary lesion or dysfunction in the nervous system. It has a huge impact onthe quality of life. It is debilitating and often has an associated degree of depression that contributes to decreasing human wellbeing. Neuropathic pain ranks at the first place for sanitary costs.Neuropathic pain treatment is extremely difficult. Several molecular pathways are involved, making it a very complexdisease. Excitatory or inhibitory pathways controlling neuropathic pain development show altered gene expression, causedby peripheral nerve injury. At present there are no valid treatments over time and neuropathic pain can be classified as anincurable disease.Nowadays, pain research is directing towards new molecular methods. By targeting neurotrophin molecules it may bepossible to provide better pain control than currently available.

Neurotrophins Role in Depression Neurobiology: A Review of Basic and Clinical Evidence by Fani L. Neto, Gisela Borges, Sonia Torres-Sanchez, Juan A. Mico, Esther Berrocoso (530-552).
Depression is a neuropsychiatric disorder affecting a huge percentage of the active population especially indeveloped countries. Research has devoted much of its attention to this problematic and many drugs have been developedand are currently prescribed to treat this pathology. Yet, many patients are refractory to the available therapeutic drugs,which mainly act by increasing the levels of the monoamines serotonin and noradrenaline in the synaptic cleft. Even inthe cases antidepressants are effective, it is usually observed a delay of a few weeks between the onset of treatment andremission of the clinical symptoms. Additionally, many of these patients who show remission with antidepressant therapypresent a relapse of depression upon treatment cessation. Thus research has focused on other possible molecular targets,besides monoamines, underlying depression. Both basic and clinical evidence indicates that depression is associated withseveral structural and neurochemical changes where the levels of neurotrophins, particularly of brain-derived neurotrophicfactor (BDNF), are altered. Antidepressants, as well as other therapeutic strategies, seem to restore these levels. Neuronalatrophy, mostly detected in limbic structures that regulate mood and cognition, like the hippocampus, is observed indepressed patients and in animal behavioural paradigms for depression. Moreover, chronic antidepressant treatmentenhances adult hippocampal neurogenesis, supporting the notion that this event underlies antidepressants effects. Here wereview some of the preclinical and clinical studies, aimed at disclosing the role of neurotrophins in the pathophysiologicalmechanisms of depression and the mode of action of antidepressants, which favour the neurotrophic/neurogenic hypothesis.

Neurotrophins in the Lower Urinary Tract: Becoming of Age by Barbara Frias, Tiago Lopes, Rui Pinto, Francisco Cruz, Celia Duarte Cruz (553-558).
The lower urinary tract (LUT) comprises a storage unit, the urinary bladder, and an outlet, the urethra. Thecoordination between the two structures is tightly controlled by the nervous system and, therefore, LUT function is highlysusceptible to injuries to the neuronal pathways involved in micturition control. These injuries may include lesions to thespinal cord or to nerve fibres and result in micturition dysfunction. A common trait of micturition pathologies, irrespectiveof its origin, is an upregulation in synthesis and secretion of neurotrophins, most notably Nerve Growth Factor (NGF) andBrain Derived Neurotrophic Factor (BDNF). These neurotrophins are produced by neuronal and non-neuronal cells andexert their effects upon binding to their high-affinity receptors abundantly expressed in the neuronal circuits regulatingLUT function. In addition, NGF and BDNF are present in detectable amounts in the urine of patients suffering fromvarious LUT pathologies, suggesting that analysis of urinary NGF and BDNF may serve as likely biomarkers to bestudied in tandem with other factors when diagnosing patients. Studies with experimental models of bladder dysfunctionusing antagonists of NGF and BDNF receptors as well as scavenging agents suggest that those NTs may be key elementsin the pathophysiology of bladder dysfunctions. In addition, available data indicates that NGF and BDNF might constitutefuture targets for designing new drugs for better treatment of bladder dysfunction.

The Neurotrophins and Their Role in Alzheimer’s Disease by Shelley J. Allen, Judy J. Watson, David Dawbarn (559-573).
Besides being essential for correct development of the vertebrate nervous system the neurotrophins also play avital role in adult neuron survival, maintenance and regeneration. In addition they are implicated in the pathogenesis ofcertain neurodegenerative diseases, and may even provide a therapeutic solution for some. In particular there have been anumber of studies on the involvement of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in thedevelopment of Alzheimer’s disease. This disease is of growing concern as longevity increases worldwide, with littletreatment available at the moment to alleviate the condition. Memory loss is one of the earliest symptoms associated withAlzheimer’s disease. The brain regions first affected by pathology include the hippocampus, and also the entorhinal cortexand basal cholinergic nuclei which project to the hippocampus; importantly, all these areas are required for memoryformation. Both NGF and BDNF are affected early in the disease and this is thought to initiate a cascade of events whichexacerbates pathology and leads to the symptoms of dementia. This review briefly describes the pathology, symptoms andmolecular processes associated with Alzheimer’s disease; it discusses the involvement of the neurotrophins, particularlyNGF and BDNF, and their receptors, with changes in BDNF considered particularly in the light of its importance insynaptic plasticity. In addition, the possibilities of neurotrophin-based therapeutics are evaluated.

Functional Multipotency of Stem Cells: A Conceptual Review of Neurotrophic Factor-Based Evidence and Its Role in Translational Research by Yang D. Teng, Dou Yu, Alexander E. Ropper, Jianxue Li, Serdar Kabatas, Dustin R. Wakeman, Junmei Wang, Maryrose P. Sullivan, D. Eugene Redmond Jr., Robert Langer, Evan Y. Snyder, Richard L. Sidman (574-585).
We here propose an updated concept of stem cells (SCs), with an emphasis on neural stem cells (NSCs). Theconventional view, which has touched principally on the essential property of lineage multipotency (e.g., the abilityof NSCs to differentiate into all neural cells), should be broadened to include the emerging recognition of biofunctionalmultipotency of SCs to mediate systemic homeostasis, evidenced in NSCs in particular by the secretion of neurotrophicfactors. Under this new conceptual context and taking the NSC as a leading example, one may begin to appreciate andseek the “logic” behind the wide range of molecular tactics the NSC appears to serve at successive developmental stagesas it integrates into and prepares, modifies, and guides the surrounding CNS micro- and macro-environment towardsthe formation and self-maintenance of a functioning adult nervous system. We suggest that embracing this view of the“multipotency” of the SCs is pivotal for correctly, efficiently, and optimally exploiting stem cell biology for therapeuticapplications, including reconstitution of a dysfunctional CNS.

In 1907 Alois Alzheimer, a Bavarian psychiatrist, published a seminal two-page article, entitled A Characteristic Disease ofthe Cerebral Cortex[1], followed by the publication of his second article On Certain Peculiar Diseases of Old Age, thatdetailed the clinical, biographical, and neuropathological history of two patients admitted under his care for pre-senile dementia[2]. In these reports, Alzheimer described these patients as suffering from a state of profound mental impairment withprominent agnostic, aphasic, and apractic disturbances, which he brilliantly attributed to small miliary foci and/or densebundles of fibrils [1,2]. Even after a century of research, we continue to use the association between cognitive decline andproteinaceous deposits as classic hallmarks of Alzheimer’s disease.With the spectacular advancements in medicine and technology in recent decades, life expectancy has significantly increased,and diseases once deemed untreatable can now be prevented or even cured. Nevertheless, even with the progress that has beenmade in improving human health, this shift in demographics has been accompanied by the increased appearance of chronicdiseases associated with ageing. Among such disorders, Alzheimer’s disease remains one of the most feared, as it is anirreversible, largely age-related neurodegenerative brain disorder that is responsible for the gradual and insidious failure ofcognitive function. Ageing is one of the most well-established risk factors for Alzheimer’s disease [3]; this disorder hasemerged as the predominant form of dementia in the elderly, affecting one person in ten over the age of 65, and 50 percent ofindividuals over the age of 85 [4,5].Although the specific causes of idiopathic Alzheimer’s disease remain unknown, the vast majority of genetic and pathologicalobservations made over that the past two decades suggests that an initial and critical accumulation of amyloid-beta (Aβ) is akey initiating factor in the pathogenesis of this disease [6], leading to a variety of biochemical changes that includeneuroinflammation, synaptic dyfunction, and tauopathy, eventually resulting in cell death, a process that has been dubbed theamyloid cascade hypothesis. Nevertheless, in the earliest stages of Alzheimer’s disease, β-amyloidosis correlates poorly withthe degree of cognitive decline, implying that other of factors may contribute to AD progression. Recent reports show that asmany as 30% of individuals older than age 75 who are considered clinically normal at the time of death, have neuropathologicalhallmarks of AD when autopsied. Despite the substantial AD lesions in these individuals, a lack of apparent dysfunction mayreflect compensatory mechanisms that prevent cognitive decline [7-9].In this Hot Topic issue of Current Neuropharmacology, we have asked notable experts in the field to comment on some of thepromising directions in Alzheimer’s disease research that appear to be amenable to pharmacological intervention. In this issue,Niedowicz provides an insightful evaluation of AD therapeutics in light of the recent results from human clinical trials. Martinprovides a review on the use of the aged canines as a powerful model of Alzheimer’s disease. Our experts also cover notableadvances in drug targets, including the development of a unique class of high potency gamma secretase modulatory compounds(Bulic), the impact of calcineurin hyperactivity (Reese), and the pharmacological manipulation of heat shock proteins (Dickey)in Alzheimer’s disease. Together, we hope these reviews will provide important insights into the molecular pathwaysunderlying the pathogenesis of this disorder, and the potential counter-measures that may serve as future therapeutic strategiesfor the treatment of Alzheimer’s disease.

Environmental factors including chronic stress may play a critical role in the manifestation of Alzheimer’sdisease (AD).This review summarizes our studies of the aggravation of the impaired cognitive ability and its cellularand molecular correlates by chronic psychosocial stress and prevention by nicotine in an Aβ rat model of AD. Weutilized three approaches: learning and memory tests in the radial arm water maze, electrophysiological recordings ofthe cellular correlates of memory, long-term potentiation (LTP) and long-term depression (LTD), in anesthetized rats, andimmunoblot analysis of synaptic plasticity- and cognition-related signaling molecules. The Aβ rat model, representing thesporadic form of established AD, was induced by continuous i.c.v. infusion of a pathogenic dose of Aβ peptides via a 14-day osmotic pump. In this AD model, chronic stress intensified cognitive deficits, accentuated the disruption of signalingmolecules levels and produced greater depression of LTP than what was seen with Aβ infusion alone. Chronic treatmentwith nicotine was highly efficient in preventing the effects of Aβ infusion and the exacerbating impact of chronic stress.Possible mechanisms for the effect of chronic stress are discussed.

Chemical Biology, Molecular Mechanism and Clinical Perspective of γ - Secretase Modulators in Alzheimer’s Disease by Bruno Bulic, Julia Ness, Stefanie Hahn, Andreas Rennhack, Thorsten Jumpertz, Sascha Weggen (598-622).
Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides inbrain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer’s disease. Imaging studies indicatethat the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegenerationand cognitive decline may proceed independently of Aβ. This implies the necessity for early intervention in cognitivelynormal individuals with therapeutic strategies that prioritize safety. The aspartyl protease γ-secretase catalyses the last stepin the cellular generation of Aβ42 peptides, and is a principal target for anti-amyloidogenic intervention strategies. Due tothe essential role of γ-secretase in the NOTCH signaling pathway, overt mechanism-based toxicity has been observed withthe first generation of γ-secretase inhibitors, and safety of this approach has been questioned. However, two new classes ofsmall molecules, γ-secretase modulators (GSMs) and NOTCH-sparing γ-secretase inhibitors, have revitalized γ-secretaseas a drug target in AD. GSMs are small molecules that cause a product shift from Aβ42 towards shorter and less toxic Aβpeptides. Importantly, GSMs spare other physiologically important substrates of the γ-secretase complex like NOTCH.Recently, GSMs with nanomolar potency and favorable in vivo properties have been described. In this review, we summarizethe knowledge about the unusual proteolytic activity of γ-secretase, and the chemical biology, molecular mechanismsand clinical perspective of compounds that target the γ-secretase complex, with a particular focus on GSMs.

Exploiting the Diversity of the Heat-Shock Protein Family for Primary and Secondary Tauopathy Therapeutics by Jose F. Abisambra, Umesh K. Jinwal, Jeffrey R. Jones, Laura J. Blair, John Koren III, Chad A. Dickey (623-631).
The heat shock protein (Hsp) family is an evolutionarily conserved system that is charged with preventingunfolded or misfolded proteins in the cell from aggregating. In Alzheimer’s disease, extracellular accumulation of theamyloid β peptide (Aβ) and intracellular aggregation of the microtubule associated protein tau may result from mechanismsinvolving chaperone proteins like the Hsps. Due to the ability of Hsps to regulate aberrantly accumulating proteinslike Aβ and tau, therapeutic strategies are emerging that target this family of chaperones to modulate their pathobiology.This article focuses on the use of Hsp-based therapeutics for treating primary and secondary tauopathies like Alzheimer’sdisease. It will particularly focus on the pharmacological targeting of the Hsp70/90 system and the value of manipulatingHsp27 for treating Alzheimer’s disease.

Progranulin is a widely expressed protein that is involved in the regulation of multiple biological processes,including embryogenesis, host defense, and wound repair. In the central nervous system, progranulin is constitutivelyexpressed at modest levels in neurons and microglia, but shows dramatic microglial immunoreactivity in degenerativediseases that exhibit prominent neuroinflammation. In addition to the role that PGRN plays in the periphery, its expressionis of critical importance in brain health, as demonstrated by recent discovery that progranulin haploinsufficiency results infamilial frontotemporal lobar degeneration. Since progranulin deficiency was first described, there has been an intenseongoing effort to decipher the mysterious role that this protein plays in dementia. This review provides an update on ourunderstanding of the possible neuronal function and discusses the challenging problems related to progranulin expressionwithin genetics, cell biology, and neurodegeneration.

Impact and Therapeutic Potential of PPARs in Alzheimer’s Disease by Michael T. Heneka, Elisabet Reyes-Irisarri, Michael Hull, Markus P. Kummer (643-650).
Peroxisome proliferator activated receptors (PPARs) are well studied for their role of peripheral metabolism,but they also may be involved in the pathogenesis of various disorders of the central nervous system (CNS) includingmultiple sclerosis, amyotrophic lateral sclerosis, Alzheimer’s and, Parkinson’s disease. The observation that PPARsare able to suppress the inflammatory response in peripheral macrophages and in several models of human autoimmunediseases, lead to the idea that PPARs might be beneficial for CNS disorders possessing an inflammatory component.The neuroinflammatory response during the course of Alzheimer’s disease (AD) is triggered by the deposition of theγ-amyloid peptide in extracellular plaques and ongoing neurodegeneration. Non-steroidal anti-inflammatory drugs(NSAIDs) have been considered to delay the onset and reduce the risk to develop Alzheimer’s disease, while they alsodirectly activate PPAR.γ This led to the hypothesis that NSAID protection in AD may be partly mediated by PPAR.γSeveral lines of evidence have supported this hypothesis, using AD related transgenic cellular and animal models.Stimulation of PPARγ by synthetic agonist (thiazolidinediones) inducing anti-inflammatory, anti-amyloidogenic andinsulin sensitizing effects may account for the observed effects. Several clinical trials already revealed promising resultsusing PPARγ agonists, therefore PPAR.. represents an attractive therapeutic target for the treatment of AD.

The brain is a highly metabolically active organ producing large amounts of reactive oxygen species (ROS).These ROS are kept in check by an elaborate network of antioxidants. Although ROS are necessary for signaling andsynaptic plasticity, their uncontrolled levels cause oxidation of essential macromolecules such as membrane lipids, nucleicacids, enzymes and cytoskeletal proteins. Indeed, overproduction of ROS and/or failure of the antioxidant network leadto neuronal oxidative stress, a condition associated with not only aging but also Alzheimer’s disease (AD). However,the specific source of excessive ROS production has not yet been identified. On one hand, amyloid beta (Aβ) has beenextensively shown to act as an oxidant molecule. On the other hand, oxidative stress has been shown to precede andexacerbate Aβ pathology. This review will address the involvement of oxidative stress in the context of neuronal as wellas vascular dysfunction associated with AD.

Alzheimer’s Disease: Pathological Mechanisms and Recent Insights by Dana M. Niedowicz, Peter T. Nelson, M. Paul Murphy (674-684).
Amyloidopathies cause neurodegeneration in a substantial portion of the elderly population. Improvements inlong term health care have made elderly individuals a large and growing demographic group, marking these diseases asa major public health concern. Alzheimer’s Disease (AD) is the most studied form of neurodegenerative amyloidopathy.Although our understanding of AD is far from complete, several decades of research have advanced our knowledge tothe point where it is conceivable that some form of disease modifying therapy may be available in the near future. Theseadvances have been built on a strong mechanistic understanding of the disease from its underlying genetics, molecularbiology and clinical pathology. Insights derived from the study of other neurodegenerative diseases, such as some formsof frontotemporal dementia, have been critical to this process. This knowledge has allowed researchers to construct animalmodels of the disease process that have paved the way towards the development of therapeutics. However, what was oncethought to be a straightforward problem has evolved into a series of disappointing outcomes. Examination of pathwayscommon to all neurodegenerative diseases, including the cellular mechanisms that clear misfolded proteins and theirregulation, may be the best way to move forward.

A Role for Calcineurin in Alzheimer’s Disease by Lindsay C. Reese, Giulio Taglialatela (685-692).
Alzheimer’s disease (AD) is an incurable age-related neurodegenerative disorder characterized by profoundmemory dysfunction. This bellwether symptom suggests involvement of the hippocampus -- a brain region responsible formemory formation -- and coincidentally an area heavily burdened by hyperphosphorylated tau and neuritic plaques ofamyloid beta (Aβ). Recent evidence suggests that pre-fibrillar soluble Aβ underlies an early, progressive loss of synapsesthat is a hallmark of AD. One of the downstream effects of soluble Aβ aggregates is the activation of the phosphatase calcineurin(CaN). This review details the evidence of CaN hyperactivity in normal aging, models of AD, and actual diseasepathogenesis; elaborates on how this could manifest as memory impairment, neuroinflammation, hyperphosphorylatedtau, and neuronal death.

There is an urgent need for new ways to treat Alzheimer’s disease (AD), the most common cause of dementiain the elderly. Current therapies are modestly effective at treating the symptoms, and do not significantly alter the courseof the disease. Over the years, a range of epidemiological and experimental studies have demonstrated interactionsbetween diabetes mellitus and AD. As both diseases are leading causes of morbidity and mortality in the elderly and arefrequent co-morbid conditions, it has raised the possibility that treating diabetes might be effective in slowing AD. This iscurrently being attempted with drugs such as the insulin sensitizer rosiglitazone. These two diseases share many clinicaland biochemical features, such as elevated oxidative stress, vascular dysfunction, amyloidogenesis and impaired glucosemetabolism suggesting common pathogenic mechanisms. The main thrust of this review will be to explore the evidencefrom a pathological point of view to determine whether diabetes can cause or exacerbate AD. This was supported bya number of animal models of AD that have been shown to have enhanced pathology when diabetic conditions wereinduced. The one drawback in linking diabetes and insulin to AD has been the postmortem studies of diabetic brainsdemonstrating that AD pathology was not increased; in fact decreased pathology has often been reported. In addition,diabetes induces its own distinct features of neuropathology different from AD. There are common pathological featuresto be considered including vascular abnormalities, a major feature arising from diabetes; there is increasing evidence thatvascular abnormalities can contribute to AD. The most important common mechanism between insulin-resistant (type II)diabetes and AD could be impaired insulin signaling; a form of toxic amyloid can damage neuronal insulin receptors andaffect insulin signaling and cell survival. It has even been suggested that AD could be considered as type 3 diabetessince insulin can be produced in brain. Another common feature of diabetes and AD are increased advanced glycationendproduct-modified proteins are found in diabetes and in the AD brain; the receptor for advanced glycation endproductsplays a prominent role in both diseases. In addition, a major role for insulin degrading enzyme in the degradation of Aβpeptide has been identified. Although clinical trials of certain types of diabetic medications for treatment of AD have beenconducted, further understanding the common pathological processes of diabetes and AD are needed to determine whetherthese diseases share common therapeutic targets.

Acetylcholine (ACh) is probably the oldest signalling neurotransmitter which appeared in evolution before thenervous system. It is present in bacteria, algae, protozoa and plants. In insects and mammals it is involved in cell-to-cellcommunications in various neuronal and non-neuronal tissues. The discovery of nicotinic acetylcholine receptors(nAChRs) as the main receptors involved in rapid cholinergic neurotransmission has helped to understand the role of AChat synaptic level. Recently, several lines of evidence have indicated that extrasynaptically expressed nAChRs display distinctpharmacological properties from the ones expressed at synaptic level. The role of both nAChRs at insect extrasynapticand/or synaptic levels has been underestimated due to the lack of pharmacological tools to identify different nicotinicreceptor subtypes. In the present review, we summarize recent electrophysiological and pharmacological studies on theextrasynaptic and synaptic differences between insect and mammalian nAChR subtypes and we discuss on the pharmacologicalimpact of several drugs such as neonicotinoid insecticides targeting these receptors. In fact, nAChRs are involvedin a wide range of pathophysiological processes such as epilepsy, pain and a wide range of neurodegenerative andpsychiatric disorders. In addition, they are the target sites of neonicotinoid insecticides which are known to act as nicotinicagonists causing severe poisoning in insects and mammals.

cGMP Signaling, Phosphodiesterases and Major Depressive Disorder by Gillian W. Reierson, Shuyu Guo, Claudio Mastronardi, Julio Licinio, Ma-Li Wong (715-727).
Deficits in neuroplasticity are hypothesized to underlie the pathophysiology of major depressive disorder(MDD): the effectiveness of antidepressants is thought to be related to the normalization of disrupted synaptic transmissionand neurogenesis. The cyclic adenosine monophosphate (cAMP) signaling cascade has received considerableattention for its role in neuroplasticity and MDD. However components of a closely related pathway, the cyclic guanosinemonophosphate (cGMP) have been studied with much lower intensity, even though this signaling transduction cascade isalso expressed in the brain and the activity of this pathway has been implicated in learning and memory processes. CyclicGMP acts as a second messenger; it amplifies signals received at postsynaptic receptors and activates downstream effectormolecules resulting in gene expression changes and neuronal responses. Phosphodiesterase (PDE) enzymes degradecGMP into 5’GMP and therefore they are involved in the regulation of intracellular levels of cGMP. Here we review agrowing body of evidence suggesting that the cGMP signaling cascade warrants further investigation for its involvementin MDD and antidepressant action.