Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 9, Issue 4, 2009

Serotonin, a biogenic amine, is present in significant amounts in many structures of the CNS. It is involved in regulation of a wide variety of physiological functions, such as sensory and motor functions, memory, mood, and secretion of hormones including reproductive hormones. It has also been implicated in the etiology of a range of psychiatric disorders such as anxiety, depression, and eating disorders, along with other conditions such as obesity and migraine. While some drugs that affect serotonin, such as fenfluramine and fluoxetine, have been successfully used in treatment of a range of psychiatric diseases, others, such as the amphetamine analogues MDMA and METH, are potent psychostimulant drugs of abuse. Alterations in serotonergic neurons caused by many of these drugs are well characterized; however, little is known about the reproductive consequences of such alterations. This review evaluates the effects of drugs such as MDMA, pCA, fenfluramine, and fluoxetine on serotonergic transmission in the brain, examines the relationships of these drug effects with the neuroendocrine mechanisms modulating reproductive events such as gonadotropin secretion, ovulation, spermatogenesis, and sexual behavior in animal models, and discusses possible reproductive implications of these drugs in humans.

Chronic ethanol ingestion, mostly in young adults, constitutes a frequent drug-abuse situation, which is associated to a wide variety of pathological disturbance affecting a number of organs, including liver, kidney, heart, pancreas and brain. The ethanol effects are more prominent when occurring at the perinatal period of life, generating, among other disabilities, brain developmental and functional impairments, as well as the so-called “fetal alcoholic syndrome”. However, low doses of ethanol, although not producing conspicuous signs of physiological impairment, may affect the developing organism, impairing the renal and cardiovascular system, among others. As a consequence of increased oxidative stress produced by ethanol intake and its subsequent oxidation, lipid peroxidation increases, enhancing reactive oxygen species formation, which is potentially injurious to the brain tissue. When occurring during gestation, lipid peroxidation may occur in the placenta, an event that would partially be responsible for fetal nutrition disturbance and consequently late physiological impairment. In this short review, data on ethanol effects on the nervous and cardiorenal structure and function are analyzed at the light of the most relevant hypotheses concerning ethanol mechanisms of action. Additionally, experimental data from the authors' laboratories are presented and discussed, focusing particular attention to the possibility of differential neural and cardiorenal ethanol effects as a function of the dose used in distinct experimental models.

The present review describes the role of the putative cross-talk between two neurotransmitters, nitric oxide (NO) and D-serine, in the brain. Under physiological conditions NO homeostasis guarantees the correct function of NO in a number of events in the brain such as neurotransmission and vascular tone regulation. D-serine, produced in astrocytes, acts synergistically with glutamate at NMDA receptors on postsynaptic neurons. Neuronal and endothelial NO synthase (nNOS and eNOS) in astrocytes cross-talk with serine racemase (SR) and D-amino acid oxydase (DAAO), catalyzing the synthesis and degradation of D-serine, respectively. SR is inhibited by NO which activates DAAO. D-serine inhibits nNOS but not eNOS and activates SR. Astrocytes and neurons also cross-talk through NO/D-serine system. D-serine released from astrocytes induces a rapid increase in NO contents in postsynaptic neurons. Overall, D-serine production in astrocytes is negatively regulated by NO. Under inflammatory conditions, pro-inflammatory cytokines or Aβ induce, first, a drop in NO contents and an increase in the amounts of D-serine in astrocytes. Together with enhanced glutamate release from presynaptic neurons, D-serine induces an increase in Ca2+ up-take into presynaptic neurons. In astrocytes an initial drop in NO contents triggers NF-κB activation followed by inducible NOS (iNOS) expression. iNOS-derived massive amounts of NO may potentially be toxic. Under schizophrenic conditions, D-serine production is down-regulated. Together with reduced glutamate release, this situation leads to the decreased NO production in postsynaptic neurons. In astrocytes induction of iNOS expression becomes predominant. Initial drop in nNOS-derived NO is potentially toxic in this scenario.

A series of 4-aryl substituted semicarbazones of pyridyl carbaldehyde and pyridyl methyl ketone were designed and synthesized to meet the structural requirements essential for anticonvulsant activity. The structure of synthesized compounds were confirmed by IR spectroscopy, PMR spectroscopy and nitrogen estimation. All the compounds were evaluated for anticonvulsant activity and neurotoxicity. Anticonvulsant activity was determined after intraperitoneal (i.p.) administration to mice by maximal electroshock (MES) and subcutaneous metrazol (ScMet) induced seizure methods and minimal motor impairment was determined by rotorod test. Majority of compounds exhibited significant anticonvulsant activity after intraperitoneal administration. The results obtained showed that 85.7 % of the compounds afforded protection in the MES test and 64.2 % of the total compounds afforded protection in ScPTZ test. Some of them also showed good activity after oral administration. In this study (Methyl-4- pyridyl) ketone -N4- (p- chloro phenyl) substituted semicarbazone emerged as most active derivative showing activity at 100 mg/kg in both the test with prolonged duration of action. In the present study semicarbazones of pyridyl containing carbonyl compounds emerges as the lead molecule, showing broad spectrum of activity with low neurotoxicity and prolong duration of action on oral administration. Thus these may be utilized for the future development of novel anticonvulsants with broad spectrum of anticonvulsant activity.

Hepatocyte growth factor (HGF) was originally identified as a molecule that could stimulate DNA synthesis in rat and human hepatocytes by autophosphorylation of the proto-oncogene c-met, which is a high-affinity receptor for HGF. Although it was at first considered that HGF could exert biological effects only on specific target cells, it has since been demonstrated that HGF mediates inflammatory responses to tissue injury and also regulates cell growth, cell motility, and morphogenesis in a wide variety of cell types, including cells within the nervous system. In the nervous system, HGF plays a role as a potent neurotrophic and angiogenetic factor. This factor promotes both the survival of neurons and the regeneration of injured nerves, and may also function as target-derived axonal chemoattractants, guiding axons to their target. These observations raised hopes that HGF protein might be useful for the clinical treatment of nervous system disorders. However, administration of HGF as a recombinant protein is still beset by a number of problems, such as a short serum half-life and poor access to the central nervous system by the systemic route because of the presence of the bloodbrain barrier. These problems can be major obstacles to the clinical use of this factor in a recombinant protein form, and has highlighted the need to develop innovative therapeutic strategies for more efficient delivery into the nervous system. Gene transfer into the nervous system has enormous therapeutic potential for a wide variety of disorders. It appears to have advantages over the administration of single or multiple bolus doses of a recombinant protein because gene transfer can achieve an optimally high, local concentration within the nervous system. In this article, we demonstrate the efficacy of HGF gene transfer and provide an overview of ideal treatment regimes for various nervous injuries and disorders.

Microglial cells, in contrast to other central nervous system cell types such as neurons and macroglia, are of myeloid origin. They constitute the immune cells of the brain and are involved in neuroinflammatory and neurodegenerative processes. Moreover, diseases of the central nervous system with an inflammatory component are characterized by the migration of bone marrow-derived monocytes into the brain where they differentiate into microglia, the “tissue macrophages” of the nervous system, bearing a therapeutic potential for certain diseases by transplantation of bone marrow- derived hematopoietic stem and progenitor cells. Due to their common origin, microglial cells and monocytes/ macrophages share expression of many surface receptors and signalling proteins. Moreover, there is overlap in the expression of many genes related to Alzheimer's disease. Activation of resident and blood-derived microglia in diseases of the central nervous system can be both beneficial, e.g. by degradation of protein aggregates, and detrimental, e.g. by secretion of neurotoxic factors. This review summarizes the current knowledge about the role of microglia in neurodegenerative diseases with a focus on Alzheimer's disease. Moreover, we present data how neuroinflammation is reflected by cellular changes in peripheral blood enabling the use of blood monocytes/macrophages for diagnosis, therapeutic target finding and outcome monitoring of neurodegenerative disorders. In summary, blood monocytes as microglia orthologues are an important model system to study the role of microglia in the pathogenesis of neurodegenerative diseases. They are suitable biomarker targets for diagnosis and prognosis and maybe also therapy of central nervous system disease.

One of the more fascinating recent discoveries in neuroscience is the widespread influence of hormones on brain regions and functions underlying pathological behaviors. A story is unfolding that points to critical roles played by hypothalamic - pituitary - gonadal (HPG) and hypothalamic - pituitary - adrenal (HPA) axes on a startling array of mental disorders, from depression to dementia. The influence of peptides and steroids does not end with hormones released from the two axes, however. It is now clear that the brain has adapted, “highjacked” is more descriptive, HPG and HPA hormones for uses unrelated to their original functions in reproduction and responses to stress. Findings of neuromodulatory effects of HPA and HPG hormones on monoamine, GABA, glutamate and opioid pathways and of hormone receptors and enzymes involved in hormone synthesis, particularly of steroids, in the hippocampus, amygdala and other subcortical brain regions provide the brain with multiple evolutionary means to adapt to new functions. The complexity of the metabolic cascade for the steroids also leaves open mechanisms by which endogenous errors and exogenous chemicals could be involved in the etiology of psychopathologies. The planned review will examine the recent literature for evidence of steroidal and peptidergic influences on basic biological functions and on mood disorders, anxiety and PTSD, schizophrenia, substance abuse and dementia. Emphasis will be placed on animal models, although findings with patient populations will be prominently included. Special attention will be paid to novel pathways by which the precursors and metabolites of sex steroids can influence psychopathologies. We also will speculate on promising treatments with hormone modulators that may be useful in mollifying the symptomology of the mental disorders.