Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 8, Issue 1, 2008

The effect of morphine on the expression on COX-2 and iNOS was considered by evaluating: a) the effects of COX1 and COX2 inhibitors on morphine withdrawal in vitro. Tolmetin (selective COX-1 inhibitor) and meloxicam (selective COX-2 inhibitor) treatment before or after morphine were able of both preventing and reversing the naloxone-induced contracture after exposure to morphine in a concentration-dependent fashion. b) the role of NF-kB in the expression of morphine withdrawal by using the PDTC, an inhibitor of NF-kB activation. PDTC was able to reduce the naloxone-induced contracture after exposure to the morphine in a concentrationdependent fashion. c) the role of NO in the expression of morphine withdrawal. L-NAME was able dose dependently to reduce the naloxone-induced contraction after exposure to morphine whereas D-NAME at the same concentrations did not affect it. The inhibitory effect of L-NAME on morphine withdrawal was dose dependently reversed by L-arginine not by Darginine. Finally, GTN on its own significantly increased the naloxone-induced contraction after exposure to morphine and it was also able to reverse the inhibition of morphine withdrawal caused by L-NAME. d) the effect of morphine on COX-2 protein expression in LPS-stimulated J774 macrophages. Treatment of J774 macrophages with LPS caused an accumulation of PGs. The addition of morphine to the cells 30 min before LPS challenge increased significantly PGs production. The COX-2 immunofluorescence study indicated that the control cells showed only background staining, cell stimulated with LPS alone revealed a diffuse accumulation of COX-2 immunostaining in the cytoplasm: this accumulation of COX-2 immunostaining increase significantly in cells stimulated with LPS+Morphine. This effect was reverted by naloxone. e) the effect of morphine on NO production by LPS-stimulated J774 macrophages. Treatment of J774 macrophages with LPS caused an significant increase of NO Morphine added to the cells 0.5 h before activation with LPS, further increased NO production. This effect was reverted by naloxone. Morphine was not able to increase NO production when added after LPS challenge. The present paper provides a strong evidence that both PGs and NO are involved in the development of morphine withdrawal further indicating that during morphine withdrawal the opioid induces the expression of the COX-2 and iNOS enzymes.

Negative and cognitive symptoms of schizophrenia remain difficult to treat. Many add-on medications to alleviate these symptoms have been proposed and investigated. In this inventory the various treatment strategies published since 1990 are being reviewed and categorised according to the pharmacological mechanism putatively involved. Notwithstanding the problems one experiences when comparing the applied measures for negative and cognitive symptoms, three clear recommendations for future research can be made viz. modulation of glutamatergic systems, blockade of serotonin 5-HT2 receptors and modulation of histaminergic systems. Strategies aimed at nAChR subtypes may also hold some promise.

A series of semicarbazones and thiosemicarbazones were designed and synthesized to meet the structural requirements essential for anticonvulsant activity. All the compounds were evaluated for anticonvulsant activity 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. Semicarbazones and thiosemicarbazones of lipophillic carbonyl groups (citral and carvone) showed excellent activity while semicarbazone and thiosemicarbazone of levulinic acid were found to be inactive. Results of the present study show that lipophilic aryl ring could be replaced with non-cyclic lipophillic groups but could not be replaced with hydrophilic substituents.

The last 20 years of the twentieth century witnessed a dramatic increase in research aimed at determining the mechanisms that regulate feeding behavior. Researchers, prompted by the alarming increase in the prevalence of obesity have identified many brain neuropeptides, especially in the hypothalamus that promote or inhibit food intake. How the complex interactions of these peptides leads to obesity has been clarified somewhat; unfortunately, this has not led to major advances in anti-obesity drug discovery. Continued effort during the first years of the new millennium has led to the discovery of new peptides mainly through inverse pharmacology techniques. In this article, we update information on obestatin, a closely related companion of ghrelin, on neuropeptide S, neuropeptide W, and others. These peptides use both classical and independent regulatory pathways to modulate feeding but often have additional biological activities. Strong arguments support a role in feeding regulation for some peptides. For others, this role remains controversial and further research is needed to clarify their exact effects.

Postoperative cognitive dysfunction (POCD) describes a decline in cognitive function for weeks or months after surgery with a prevalence in the elderly patient. Numerous methodological limitations make the interpretation of this clinical syndrome, based on the available literature on POCD, difficult, particularly the different definitions of POCD, the lack of control groups and the relative inconsistency in the occurrence of memory deficits. Several theories have been advanced to explain these observations, but although there is general agreement that POCD is likely to be multifactorial, whether its occurrence is a result of the effects of surgery or general anesthesia remains unclear. This review provides a synopsis of the available clinical and preclinical data and summarizes recent research relevant to the occurrence of POCD and possible pharmacologic algorithms for its prevention and treatment. The effects of volatile and intravenous anesthetics on synaptic transmission and synaptic plasticity, which might be related to cognitive dysfunction in the postoperative period, will be discussed. Unraveling these mechanisms should provide helpful indices for the identification, synthesis and development of new chemical entities suitable for therapeutic use.

Understanding the molecular mechanisms of neurodegeneration represents a scientific priority as it will allow scientists to more specifically target and simultaneously interrupt the multiple pathologic mechanisms that contribute to the progression of dementia in Alzheimer's disease (AD). Oxidative stress represents one of the key processes in AD pathogenesis, related to formation of both amyloid plaques and neurofibrillary tangles as well as to alteration of many biomolecules. For this reason several antioxidant molecules have been tested in in vitro and in vivo studies in order to detect more efficacious treatments. Dietary antioxidants seem also to have an important role in AD prevention, as shown by several epidemiological studies. Ongoing clinical trials to assess whether antioxidant supplementation has a role in primary prevention of AD or in delaying the progression of disease in individuals with Mild Cognitive Impairment (MCI), are in progress or planned. Thus, research involving new antioxidants and their potential clinical applications will provide new insights into the molecular basis of neuroprotective mechanisms that may be relevant to AD and other age-related neurodegenerative disorders.

Depressive disorder is a common illness that affects millions of people worldwide and the patients often suffer from symptoms such as depressed mood, sleep disturbances, and suicidal ideation. Since the approval of fluoxetine in the United States nearly 20 years ago, the annual prescription of antidepressants has increased rapidly. However, despite the increasing number of new antidepressants introduced to the clinic, the quality of treatment still remains poor due to the delayed response or low efficacy often associated with these synthetic antidepressants. Thus, there have been a growing number of patients turning to alternative medicine treatments for a more effective cure. To date, one of the most frequently used and well-studied herbal preparation for mild and moderate depression is the extract of St John's wort. However, recent report has indicated that drug interaction of this herb with other antidepressants may result in severe clinical consequences. Traditional Chinese medicine (TCM) has a long history of use in China with a proven record of high efficacy and low toxicity. It is also an excellent source of diverse and complex chemicals that possess a wide variety of biological activities. In recent years, TCM has received growing attention as an alternative or adjuvant therapy to Western medicine treatments and a large volume of efforts have been directed towards the identification of potential antidepressive phytomedicine from TCM. Potential TCM-derived therapeutics including herbal formulations, extracts, and individual active constituents have been evaluated with behavioral animal models and clinical studies. This article will review the recent development in the search for effective antidepressive therapeutics using TCM. Literatures published in Chinese will also be reviewed to include the recent advances in this area. Moreover, our group has been using a knowledge-based approach to identify active ingredients for the treatment of neurological disorders. The workflow of our approach will also be discussed.