CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 10, Issue 7, 2011

As with most areas of pharmacotherapeutics, a significant percentage of patients are not fully served by existing medicines in the area of major depressive disorder (MDD) [1, 2]. Only about one third of patients respond to current antidepressants and less than one third display symptom remission. Another third of the patients do not respond to multiple therapeutic interventions (treatment resistant depression or TRD) leaving a huge unmet medical need in a disease area that affects millions of people each year [2]. A report by Berman and colleagues [3] and its subsequent replication by Zarate et al. [4] have inspired new ideas about antidepressant drug action. In patients that did not respond to at least two adequate antidepressant regimens, the dissociative anesthetic, ketamine, produced immediate and relatively long-lasting relief of mood symptoms after a single intravenous dose. The work has been systematically replicated in different cohorts of TRD patients including those suffering with bipolar depression [5, 6]. The idea that blockade of N-methyl-D-asparte (NMDA) receptors by ketamine would be antidepressant was deduced from connections of NMDA receptors, long-term potentiation, and electroconvulsive therapy by Trullas and Skolnick in 1990 [7]. Additional clinical validation came with the finding that an NMDA receptor antagonist selective for NR2B receptors was also effective in TRD patients [8]. Given the efficacy of ketamine and the difficulties of using ketamine as a prescription drug (it is abused and produces marked central nervous system side effects as do other NMDA receptor antagonists [9]), finding novel agents that can mimic the antidepressant effects without the safety issues becomes a goal of those seeking improved therapeutic options for TRD patients. A large clue already in hand in the new discovery effort is that ketamine is known to block NMDA receptors. In this vein, other NMDA receptor blockers might be viable treatment agents without the side effects. Zn2+ also blocks NMDA receptors and is antidepressant; work in TRD patients has shown it to be effective as an adjunct with imipramine [10]. Other ways of producing functional dampening of NMDA receptor function are already being explored. GLYX-13, a putative glycine-site functional partial agonist, has preclinical antidepressant-like activity and is being funded now for Phase II clinical investigation [11]. The vigorous activity in the area of TRD therapeutics is a testament to the mood that shines over many laboratory benches as answers to important questions seem within reach. What are the key biological actions of ketamine that enable relief from TRD? One of the first clues came from the preclinical laboratory. Ketamine and other NMDA receptor antagonists produced effects in the mouse-forced swim test that were comparable to those of other antidepressant drugs; these behavioral effects of ketamine were prevented by an alpha-amino-3-hydroxy-5- methylisoxazole-4-propionic acid (AMPA) receptor antagonist [12]. Thus, ketamine, by virtue of its glutamate releasing effects, produces activation of AMPA receptors that is responsible for the antidepressant-like signatures observed. Convergent biochemical, neurobiological, and behavioral data implicate AMPA receptor amplification as a core feature of antidepressant drug action [13]. It is not unreasonable to speculate that other methods of increasing AMPA receptor function would also produce fast-acting antidepressant response in TRD patients. What drugs exist that most directly facilitate AMPA receptor function? Positive allosteric modulators of AMPA receptors are one such possibility and display robust antidepressant effects in rodent models [13, 14] but have yet to be put to clinical proof of concept in TRD [14]. Zn2+, with augmenting effects in TRD patients [10], is also AMPA antagonist sensitive [15]. Antagonists of metabotropic mGlu2/3 receptors also engender antidepressant-like neurochemical and behavioral effects in a host of preclinical models and a number of these effects are prevented by AMPA receptor antagonists [1, 14]....

More the 100,000 papers have been published about nitric oxide (NO) since its discovery 24 years ago. NO is a distinct cell-to-cell signalling molecule which is found in nearly all the tissues of the body and central nervous system (CNS). Interest in NO grew when its release from endothelial cells lining blood vessels was shown to cause relaxation of the underlying smooth muscle, thereby affecting blood flow and pressure. When, in 1998, Furchgott, Ignarro and Murad won the Nobel Prize for Physiology or Medicine for their contribution to the study of NO its fame peaked. Also in 1998, NO was identified as the mysterious substance produced following activation of N-methyl-D-aspartic acid (NMDA) glutamatergic receptors. An enormous amount of data on the role of NO has been collected since then. Indeed, it is hard to find a disease which is not associated with altered NO homeostasis. NO is a gas produced from the amino acid L-arginine by members of the NO synthase (NOS) family of proteins, respectively, as endothelial, neuronal, and inducible NO synthases. NO is involved in smooth muscle relaxation, neural communication, and immune defence. In the CNS, NO is a key physiological signalling molecule. A number of studies have identified high levels of nNOS in many areas of the brain. It occurs also in astrocytes and cerebral blood vessels. Some of the NO effects are mediated by stimulation of soluble guanylyl cyclase and it product cyclic guanosine monophosphate (cGMP). However, it has also been clearly shown that NO becomes noxious if produced in excess. Toxic compounds can be formed as a result of NO undergoing oxidative-reductive reactions when a cell is in a pro-oxidant state. Both NO and these toxic compounds have been implicated in the pathogenesis of neurodegenerative disorders. Indeed, the cellular damage in neurodegenerative disorders could be caused by NO and peroxynitrites, the latter formed by the reaction between NO and a superoxide anion. This scenario is common to Alzheimer's disease (AD) and Parkinson's disease (PD), pain, atherosclerosis, epilepsy and septic shock. NO has also been suggested to have a significant role in many different psychiatric disorders such as depression, anxiety, schizophrenia. Despite the enormous amount of progress we have made in terms of understanding the aetiology of NO-related diseases in the last twenty years, important questions about the role of NO in the CNS remain unanswered. Given the broad range of functions of NO, this Special Issue will concentrate on some of the physiological and pathological implications of NO activity in the regulation of the CNS. In particular, it focuses on the multifaceted functions of NO in various neuropsychiatric disorders. This Special Issue deals with this hot topic and it is produced by leading groups in the neuroscience field with the aim of summarizing recent advances in genetic, epidemiological, molecular and cellular biology research that have increased our knowledge of the mechanisms by which NO gives rise to degenerative processes and, in general, to alterations of nervous system structure and function. While covering the latest research in schizophrenia, AD, PD, epilepsy and brain tumours, for obvious reasons, this special issue cannot be exhaustive. Indeed, it is impossible to include reviews highlighting all the vast number of different CNS diseases in which NO seems to play a role. I hope that more volumes on the subject will be possible in the future.....

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe cognitive impairment due to neuronal death. Although the lost of cognitive function is the main problem for AD subjects, death occurs due to secondary issues such as concomitant infections, respiratory complications or multi-organ failure. Current drugs used in AD are acetylcholinesterase inhibitors and antagonists of the N-methyl-D-aspartate receptor. These drugs may only slightly improve cognitive functions but have only very limited impact on the clinical course of the disease. Over the last 5 years, new targets were identified and innovative drugs against AD have been designed and developed. Worthy of mention are β-secretase inhibitors, monoclonal antibodies against amyloid-β-peptide and tau inhibitors. However, although promising beneficial effects were highlighted in the data from preclinical studies, only few of these new drugs improved cognitive functions for a significant time frame in AD subjects. Controversial is the therapeutic effect on AD obtained through the manipulation of the nitric oxide synthase/nitric oxide system since the potential toxic effects on brain function could overcome the beneficial effects. The aim of this review is to analyze from a pharmacologic point of view both old and new drugs developed for the treatment of AD. In addition, the risk/benefit ratio related to the modulation of the nitric oxide synthase/nitric oxide system in AD brain will be analyzed.

Several recent studies have emphasized a crucial role for the nitrergic system in movement control and the pathophysiology of the basal ganglia (BG). These observations are supported by anatomical evidence demonstrating the presence of nitric oxide synthase (NOS) in all the basal ganglia nuclei. In fact, nitrergic terminals have been reported to make synaptic contacts with both substantia nigra dopamine-containing neurons and their terminal areas such as the striatum, the globus pallidus and the subthalamus. These brain areas contain a high expression of nitric oxide (NO)-producing neurons, with the striatum having the greatest number, together with important NO afferent input. In this paper, the distribution of NO in the BG nuclei will be described. Furthermore, evidence demonstrating the nitrergic control of BG activity will be reviewed. The new avenues that the increasing knowledge of NO in motor control has opened for exploring the pathophysiology and pharmacology of Parkinson's disease and other movement disorders will be discussed. For example, inhibition of striatal NO/guanosine monophosphate signal pathway by phosphodiesterases seems to be effective in levodopa-induced dyskinesia. However, the results of experimental studies have to be interpreted with caution given the complexities of nitrergic signalling and the limitations of animal models. Nevertheless, the NO system represents a promising pharmacological intervention for treating Parkinson's disease and related disorders.

Schizophrenia is a devastating, chronic brain disorder afflicting about 1% percent of the population. The etiology, neuropathology, and pathophysiology of schizophrenia remain elusive. Intense research has been conducted in order to identify specific biological markers of schizophrenia. The gas nitric oxide (NO) is an important signaling molecule involved in many cellular events that take place in the cardiovascular, immune and nervous systems of animals. This present review aims to show that NO and its metabolites play eminent roles in schizophrenia and have a significant influence on our understanding of the development, progression and, possibly, treatment of the disease. Special emphasis is given to aspects of genetic linkage between NO generating and modulating proteins and schizophrenia, and the impact of NO metabolism on processes known to be disturbed in this neuropsychiatric disorder (i. e., nerve cell migration, formation and maintenance of synapses, N-methyl-D-aspartic acid receptor mediated neurotransmission, adult hippocampal neurogenesis, membrane pathology and cognitive abilities). Although certain alterations of brain NO metabolism are not unique to, or indicative of, schizophrenia, their modulation might be a promising therapeutic option for the future.

Nitric oxide (NO) plays a variety of physiological and pathological roles in mammalian cells. In the central nervous system NO may behave as a second messenger, neuromodulator, and neurotransmitter, which may suggest an essential role of this gaseous molecule in epilepsy and epileptogenesis. The aim of this review is to survey the current literature in terms of experimental and clinical evidence of anti- or proconvulsive properties of NO and its implications in the anticonvulsive action of antiepileptic drugs. Up-to-date multiple NO synthase (NOS) inhibitors and donors of NO were used in a plethora of seizure models (e.g. electrically and pharmacologically-evoked convulsions, amygdala-kindled seizures). Reported results vary depending on the seizure model, kind and doses of pharmacological tools used in experiments, and route of drug administration. The most thoroughly tested NOS inhibitor was 7- nitroindazole (7-NI), which presented anticonvulsive properties in most known models of seizures. The clear-cut proconvulsant action of 7-NI was observed only in kainate-, nicotine-, and soman-induced convulsions in rodents. This NOS inhibitor enhanced the anticonvulsant action of almost all available classic and second-generation antiepileptic drugs except tiagabine, felbamate, and topiramate. The effect of NG-nitro-L-arginine methyl ester was not so unambiguous. In pentylenetetrazole, pictotoxin, and N-methyl-Daspartate seizure models the inhibitor exhibited dose-dependent bidirectional action. NG-nitro-L-arginine methyl ester potentiated the efficacy of diazepam and clonazepam, diminished that of valproate and phenobarbital, but did not affect the anticonvulsant action of phenytoin and ethosuximide. On the other hand, NG-nitro-L-arginine, was anticonvulsant in nicotine-, glutamate-, and hyperbaric O2- evoked seizures, and proconvulsant in pilocarpine-, kainate-, bicuculline-, aminophylline-, and 4-aminopyridine-induced convulsions. NG-nitro-L-arginine remained without effect on the anticonvulsant action of both classic (valproate, phenobarbital, diazepam) and new generation (oxcarbazepine, felbamate, and ethosuximide) antiepileptic drugs. The action of ethosuximide was even impaired. Summing up, in the present state of knowledge the only reasonable conclusion is that NO behaves as a neuromodulator with dual - proconvulsive or anticonvulsive - action.

Gliomas, defined as tumors of glial origin, represent between 2-5% of all adult cancer and comprise the majority of primary brain tumors. Infiltrating gliomas, with an incidence of more than 40% of brain tumors, are the most common and destructive primary brain tumors for which conventional therapies have not significantly improved patient outcome. In fact, patients suffering from malignant gliomas have poor prognoses and the majority have local tumor recurrence after treatment. Tumor growth and spread of tumor cells depend basically upon angiogenesis and on functional abnormalities of tumor cells in the control of apoptosis, as they are paradigmatic for their intrinsic resistance to multiple pro-apoptotic stimuli. Therefore, promising strategies for treatment of brain cancer would be directed to appropriate neutralization of angiogenesis and sensibilization of cancer cells to undergo apoptosis. However, despite advances in this field, high-grade gliomas remain incurable with survival often measured in months. Therefore there is a need to discover new and more potent cocktails of drugs to target the key molecular pathways involved in glioma angiogenesis and apoptosis. This review deals with the effects of two groups of molecules closely linked to neural tissue, which have been implicated in brain cancer: nitric oxide and peptides of the adrenomedullin family. These molecules exert vasodilatory and proangiogenic actions. Adrenomedullin also has antiapoptotic functions at appropriate concentrations. The inhibition of these functions, in the case of cancer, may provide new pharmacological strategies in the treatment of this disease.

Background and objectives: Cerebral vasospasm is an important cause of poor outcomes in subarachnoid haemorrhage patients. This study was designed to assess the effectiveness and safety of nimodipine in the prevention of cerebral vasospasm in aneurysmal subarachnoid haemorrhage patients. Methods: We searched Pubmed, OVID, Embase, the Cochrane library, the stroke clinical trial registry, and the National Science and Technology Library database and collected prospective, randomised, controlled clinical trials of the prophylactic use of nimodipine for aneurismal subarachnoid haemorrhage patients. A meta-analysis was performed on the studies that met the criteria for inclusion. Results: Eight studies met the inclusion criteria, and 1514 patients finished trial observation for the different indicators. Compared with the placebo group, fully recovered (all cases) patients increased 64% in the nimodipine group (P = 0.0002, OR = 1.64, 95% CI 1.26-2.13, NNT=-1.048), fully recovered or moderately disabled (all cases) patients increased 79% (P = 0.0007, OR = 1.79, 95% CI 1.28-2.51, NNT = -5.889), patient death (in cerebral vasospasm cases) decreased 74% (P = 0.008, OR = 0.26, 95% CI 0.09-0.71, NNT = 2.298), the incidence of symptomatic cerebral vasospasm decreased 46% (P < 0.00001, OR = 0.54, 95% CI 0.42-0.69, NNT = 1.952), the incidence of delayed neurological function deficits (all cases) decreased 38% (P < 0.0001, OR = 0.62, 95% CI 0.50-0.78, NNT = 1.078), the occurrence of cerebral infarction (on CT scan) decreased 58% (P = 0.001, OR = 0.58, 95% CI 0.42-0.81, NNT = 3.314), the occurrence of cerebral infarction (in cerebral vasospasm cases) decreased 65% (P = 0.003, OR = 0.35, 95% CI 0.17-0.69, NNT = 3.688), the occurrence of cerebral infarction (all cases) decreased 48% (P < 0.00001, OR = 0.52, 95% CI 0.41-0.66, NNT = 1.196), and the difference in recurrent haemorrhage and adverse reactions between the nimodipine and placebo groups was not statistically significant (nimodipine group versus placebo group, recurrent haemorrhage P = 0.15, OR = 0.75, 95% CI 0.50-1.11; adverse reaction P = 0.59, OR = 1.13, 95% CI 0.71-1.81). Conclusion: Compared with placebo, nimodipine can significantly improve clinical outcomes, as assessed by self-formulated standards and Glasgow outcome scores, and it can significantly reduce the occurrence of symptomatic cerebral vasospasm and delayed neurological function deficits (all cases), as well as cerebral infarction, although the incidence rate of recurrent haemorrhage and adverse reactions is not significantly reduced by nimodipine.

This study describes the interaction between human acetylcholinesterase (AChE), a key regulator of central and peripheral cholinergic function, and the widely used nitrogen mustard alkylating agent, cyclophosphamide (CP). Modeling of the AChE sequence (NCBI Accession No: AAI05061.1) was performed using ‘Swiss Model Workspace’. The protein-model was submitted to the Protein Model Database and was assigned accession number PM0077393. A plot showing normalized QMEAN scores versus protein size was made to compare the model with a non-redundant set of Protein Data Bank structures, which gave a Z-score QMEAN as -0.58. The predicted local error for the modeled structure was found to be well within tolerable limits. Z-score values for Cβ interaction, all atom interaction, solvation and torsion were found to be -1.10, -0.90, -0.06 and -0.40, respectively. Docking between CP and AChE was performed using ‘Autodock4.2’. Apart from other interaction-types, six carbon atoms of CP (C1, C2, C3, C4, C6 and C7) were determined to be involved in hydrophobic interactions with amino acid residues Y121, W233, L323, F331, F335 and Y338 of the ‘acyl pocket’ within AChE. Five carbon atoms of CP (C2, C4, C5, C6 and C7) were involved in hydrophobic interactions with 3 amino acid residues within the enzyme's ‘catalytic site’. In conclusion, hydrophobic interactions play a major role in the appropriate positioning of CP within the ‘acyl pocket’ as well as ‘catalytic site’ of AChE to permit suitable orientation and allow docking. This information may aid the design of more potent and versatile AChE-inhibitors as pharmacologic tools and drugs to characterize and treat neurological disorders, and additionally provides a model whose value can be quantitatively assessed by X-ray crystallographic analysis of the AChECP three-dimensional structure.

Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in several areas of the central nervous system (CNS). Substantial evidence has documented a common inflammatory mechanism in neurodegeneration. It is known that classical anti-inflammatory agents, steroids and nonsteroidal anti-inflammatory drugs, have not played a major role in the management of CNS inflammatory conditions. This may be partly due to the natural compartmentation of the brain by the blood-brain barrier. Thus, there is much interest in developing novel anti-inflammatory drugs that may help to prevent or ameliorate CNS inflammation. Resveratrol (RSV) has received considerable attention over the last several decades. Experimental studies have revealed its benefits in several human disease models, including cardio- and neuro-protection, immune regulation and cancer chemoprevention. The broad action spectrum of RSV is explained by the involvement of numerous signaling networks and cellular effector mechanisms. Among them, apoptotic and antioxidant targets have been implicated. Recently, also anti-neuroinflammatory activity has been observed. A number of studies demonstrated that RSV mediates the downregulation of various inflammatory biomarkers such as tumor necrosis factor, cyclooxygenase 2, inducible nitric oxide synthase and interleukins. This activity seems to depend on some structural features of RSV such as the number and the position of hydroxyl groups. In this review, a comprehensive account of multiple intracellular RSV targets involved in neuroinflammation and its analogues design will be treated, pointing to structure/activity relationships.