Central Nervous System Agents in Medicinal Chemistry - Volume 8, Issue 2, 2008

Recent studies show that the behavioral changes associated with reward expectation may be underpinned by two different cognitive mechanisms: perceptual sensitivity on the one hand, and response bias on the other. Perceptual sensitivity refers to the quality of decision-making as a function of the ratio between signal and noise. The prospect of reward may improve the signal-to-noise ratio for stimuli with a high reward value. In contrast, response bias refers to the a priori likelihood of making one response rather than another, regardless of incoming perceptual information. The prospect of reward may create a response bias by increasing the likelihood of making a response with a high reward value. Thus reward value may be implemented in the control of action through two parallel systems, one system that influences perceptual sensitivity and one system that influences response bias. Electrophysiological recordings suggest that these two systems operate through parallel neural circuits. Evidence for a system that influences perceptual sensitivity is seen in frontal cortex, with neurons that fire differentially following a reliable prediction of reward. Evidence for a system that influences response bias on the basis of reward is seen in the basal ganglia. This system determines the baseline neuronal activity in advance of sensory information processing. Both systems send output to brainstem structures to increase the strength of action representations as a function of incentive. Both systems may be modulated by dopamine input. The cellular action of dopamine, however, depends on the type of receptor involved: Through D2-like receptors dopamine depresses the activity of target neurons, whereas through D1-like receptors dopamine interacts with other receptors. Here I review the evidence in relation to the proposal that the two reward systems - influencing perceptual sensitivity versus response bias - have distinguishable receptor profiles, with reward effects of sensitivity primarily dependent on D1-like receptors, and reward effects of bias mostly due to D2-like receptors.

The amino acid L-glutamate is generally recognized as the major excitatory neurotransmitter of the mammalian central nervous system (CNS) and glutamate receptors play a major role in fast excitatory synaptic transmission. Nmethyl- D-aspartate (NMDA)-type glutamate receptors are widely distributed throughout the CNS and operate ligandactivated ion channels. The activation and function of NMDA receptors are modulated by a variety of endogenous and exogenous compounds. Various anesthetic protocols have been used in pediatric medicine for many years in the absence of clear systematic assessment concerning drug exposure and possible adverse effects. It is known that most of the currently used anesthetic drugs have either NMDA receptor blocking or gamma-amino butyric acid (GABA) receptor activating properties. It has been reported that anesthetics such as ketamine, an NMDA receptor antagonist, cause neuronal cell death in rodents when administered during critical periods of development. The window of vulnerability to the neuronal effects of pediatric anesthetics seems to be restricted to the period of rapid synaptogenesis, also known as the brain growth-spurt period. Accentuated neurodegenerative mechanisms in the immature brain can thus increase neuronal susceptibility to exposure to anesthetic agents. Anesthetics that block NMDA or activate GABA receptors consistently increase cell death in the neonatal brain, suggesting that the physiological stimulation of NMDA receptors is necessary for normal neuronal synaptogenesis, differentiation, and survival during development. The main purposes of this review are to outline progress in the application of pharmacogenomic/systems approaches and animal models to systematically evaluate dose-response and time-course effects of anesthetic agents; to describe what is known about underlying mechanisms; and to define the relationship between altered NMDA receptor expression and the potential of anesthetics to cause toxicity during development. It should be mentioned that much of this discussion is based on experiments conducted only with ketamine. This is due in part to the use of ketamine in critical early studies and the volume of preclinical experimental work performed with this agent, and because comparative (rodent and nonhuman primates) data exist for this compound. The findings of the ketamine studies to date are sufficiently strong enough to cause concern for other agents which affect the same receptors.

West syndrome is a severe epilepsy, occurring in infancy, that comprises epileptic seizures known as spasms, in clusters, and a unique EEG pattern, hypsarrhythmia, with psychomotor regression. Maturation of the brain is a crucial component. The onset is within the first year of life, before 12 months of age. Patients are classified as cryptogenic (10 to 20%), when there are no known or diagnosed previous cerebral insults, and symptomatic (80 to 90%), when associated with pre-existing cerebral damages. The time interval from a brain insult to infantile spasms onset ranged from 6 weeks to 11 months. West syndrome has a time-limited natural evolutive course, usually disappearing by 3 or 4 years of age. In 62% of patients, there are transitions to another age-related epileptic encephalopathies, the Lennox-Gastaut Syndrome and severe epilepsy with multiple independent foci. Spontaneous remission and remission after viral infections may occur. Therapy with ACTH and corticosteroids are the most effective. Reports about intravenous immunoglobulins action deserve attention. There is also immune dysfunction, characterized mainly by anergy, impaired cell-mediated immunity, presence of immature thymocytes in peripheral blood, functional impairment of T lymphocytes induced by plasma inhibitory factors, and altered levels of immunoglobulins. Changes in B lymphocytes frequencies and increased levels of activated B cells have been reported. Sensitized lymphocytes to brain extract were also described. Infectious diseases are frequent and may, sometimes, cause fatal outcomes. Increase of pro-inflamatory cytokines in serum and cerebrospinal fluid of epileptic patients were reported. Association with specific HLA antigens was described by several authors (HLA-DR7, HLA-A7, HLA-DRw52, and HLA-DR5). Auto-antibodies to brain antigens, of several natures (N-methyl-d-aspartate glutamate receptor, gangliosides, brain tissue extract, synaptic membrane, and others), were described in epileptic patients and in epileptic syndromes. Experimental epilepsy studies with anti-brain antibodies demonstrated that epileptiform discharges can be obtained, producing hyperexcitability leading to epilepsy. We speculate that in genetically prone individuals, previous cerebral lesions may sensitize immune system and trigger an autoimmune disease. Antibody to brain antigens may be responsible for impairment of T cell function, due to plasma inhibitory effect and also cause epilepsy in immature brains.

Processing of information by the central nervous system (CNS) depends on the dendritic morphology of postsynaptic neurons. The patterning of dendrites is determined by extrinsic and intrinsic factors that promote the activation of cellular signaling pathways. These factors and signaling cascades may lead to the transcriptional activation of regulators of neuronal morphology. Interestingly, when there is an abnormal decrease in the number of dendrite branches and disruption of proper networks, neurodegenerative diseases, including Rett Syndrome, autism, and mental retardation, may result. In this review, we evaluate the potential of regulators of dendrite patterning as targets for drug design for the treatment of neurodegenerative diseases and altered neuronal growth in the CNS. Particular attention is directed towards a specific regulator of dendrite branching reported by our group, cypin (cytosolic PSD-95 interactor). We discuss this novel intrinsic regulator of dendrite branching as an innovative pharmacological target for the use of computer-aided rational drug design to control guanine levels, microtubule assembly, and neuronal differentiation during CNS development and in disease states.

Just a few short years ago, elevated homocysteine levels were widely considered to be a risk factor for a plethora of diseases from cardiovascular disorders to neurodegenerative conditions. Because of this there was a boom in research into this amino acid, with over 13 000 scientific papers published on it by January, 2008. It was hoped that simple pharmacological and dietary intervention to lower plasma homocysteine would offer a cost-effective solution to prevent the future development of disease in individuals with high homocysteine levels. However, trials of vitamin therapies to counteract elevated homocysteine, whilst successful in lowering plasma homocysteine, have not demonstrated any clinical benefit. Thus, many now believe that it is possible that elevated homocysteine levels are a consequence of, rather than a cause of, cardiovascular and neurodegenerative disorders. If this is so, then the value of homocysteine as a target for research and pharmacological intervention is greatly reduced. So, is the boom time for homocysteine research over? This review will consider the scientific studies relating to homocysteine and neurodegenerative conditions, with particular reference to Alzheimer's Disease and Parkinson's Disease, and will consider what is next for homocysteine research.

A novel class of therapeutic agents based on nucleic acids has emerged and shown very promising pre-clinical results, named small interfering RNAs (siRNAs) and microRNAs (miRNAs). siRNAs are small RNA duplexes capable of silencing undesired (i.e., mutant, exogenous or aberrant) gene expression with high specificity through a mechanism known as RNA interference. These agents have called special attention to neuroscience since they have been used to experimentally treat a variety of neurological diseases with distinct etiologies such as viral, prions, genetic disorders and others. siRNAs have also been used in other scenarios as: drug-receptor blockage, inhibition of pain signaling and regulation of behavior. Although in a very initial stage, miRNAs also promise novel therapeutic approaches. In this review article we intend to introduce clinicians and researchers to the novel field of si- and miRNA-mediated gene silencing strategies, its history, use in cell and animal models, delivery methods, current status and possible applications in future clinical practice.

For ages, the practice of drug discovery has relied heavily on the one-drug one-target design strategy of medicinal chemistry. However, despite the tremendous advances made in chemical and biological sciences and in the discovery technologies the number of drugs/drug candidates coming out from this one-drug one-target approach is paradoxically dwindling. It is now well recognized that the age old philosophy of medicinal chemistry lacks a fundamental conceptual framework. This is particularly so in disorders such as depression where a multiple of pathways are simultaneously deregulated and which basically result from multiple molecular abnormalities, not just from a defect in a single pathway. The recent times has seen a shift towards one drug-multiple target selective design strategy. This novel paradigm has already produced a diverse set of multiple acting structures for depression. Largely as a consequence of the unacceptable side effects, tolerability and low level of efficacy of the currently used drugs (tricyclic antidepressants, mono amine oxidase and selective serotonin reuptake inhibitors), other new generation agents are increasingly being identified that act at more than one target in depressive disorders. Multitarget selective antidepressant research has produced a number of diverse and novel chemistries with a huge potential for the treatment of this debilitating disorder. This manuscript reviews the latest developments surrounding multitarget selective agents for depression, the benefits of such multi acting agents and the implications for the future design of potent and selective dual, triple or even poly-target active antidepressants.