Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 6, Issue 3, 2006

Since the human erythropoietin (EPO) gene was cloned in 1983, use of recombinant human EPO (rh-EPO) has become widespread for treating anemia in patients with end stage renal failure. Rh-EPO has a direct effect on haematopoiesis, reflected by increased hemoglobin levels. However, recent studies have shown that nerve cells also have erythropoietin receptors and that this cytokine is made in the nervous system and can function as a neuroprotective agent. In the last decade, it has been shown that EPO exerts general tissue protection including anti-apoptotic, antioxidant and angiogenesis effects. Perhaps best characterized is the mechanism whereby EPO inhibits apoptosis, with the effect believed to occur mostly by activation of the PI-3K-Akt axis or JAK2-STAT5 axis. This anti-apoptotic mechanism is not only important for erythropoiesis, but also appears to play an important role in other processes with high apoptotic activity, such as in stroke, retinal diseases and possibly chronic heart failure and myocardial infarction. Experimental studies in rats have shown that administration of EPO after six hours of arterial occlusion of the middle cerebral artery provided a 50% reduction in infarct size. Moreover, a recent phase 1-2 clinical trial has suggested that EPO can ameliorate neural damage in patients who have had a stroke. In this review, we discuss the neuroprotective properties and the future of rh- EPO therapy in patients with ischaemic stroke.

Since proteins and peptides play critical roles in many biological phenomena, their use as drugs is of great interest. However, their development is limited due to their poor bioavailability, antigenicity and unfavorable pharmacokinetics. In the majority of cases, not all domains of proteins are essential protein-protein interactions necessary for biological activities but only small regions of their folded structure, perform the interactions. Usually, these particular secondary structures are β-turns, occurring on the exposed surface of proteins, constitute the functional elements involved in molecular recognition processes between proteins, and in interactions between ligands and receptors. Moreover, there are also several examples of the design of modified peptides as therapeutic agents by mimicking β-turn structures. In view of this, this review will be focused on the importance of β-turn in some biological phenomena, such as prohormone proteolytic processing. This report will also address the use of β-turn mimicking strategies and its application in the design of potent peptide analogues which play an equally important role. Due to the optimal surface conformation, β-turn mimetics lead to productive interaction with receptors and antibodies.

The ultimate aim of many researchers is to design a drug, which could arrest or delay specifically the clinical evolution of symptoms of Alzheimer's disease (AD). The association of increased activity of glycogen synthase kinase-3 (GSK-3) with neuronal apoptosis, amyloid metabolism, and hyperphosphorylation of protein tau makes this kinase an attractive target for the therapy of neurodegenerative diseases. Lithium has been shown to be an important inhibitor of GSK-3 activity and therefore recently suggested as one of the treatment of AD. For some time, the most widely accepted mechanism of action of lithium was its inhibitory effect on inositol monophosphatase, resulting in depletion of inositol with profound effects on phosphoinositide signaling system. Although much evidence has not supported the inositol depletion hypothesis subsequently, the important role of inositol and inositides in the CNS, in addition to their role in phosphoinositide signaling pathways, has been discussed. A new perspective on the role of glucose in neurodegenerative changes in the CNS has been emerging from several lines of evidence. These accumulated observations may improve our understanding of the links between deficient glucose metabolism in the aging brain and the events leading to the onset of AD. The impairment of glucose utilization might act as the common denominator for the development of pathological hallmarks of AD.

NAD+ is as abundant as ATP in neuronal cells. NAD+ functions not only as a coenzyme but also as a substrate. NAD+ metabolism in neuronal cells is tightly controlled under physiological conditions, since NAD+ has a great impact on functional activity of neurons upon stimulation. NAD+-utilizing enzymes is involved in signal transduction. We focus on ADP-ribosyl cyclase/CD38 which synthesizes cyclic ADP-ribose (cADPR), a Ca2+ mobilizing messenger. Structural analysis defined the active site of the enzyme. ADP-ribosyl cyclase associated with CD38 was detected in the central nervous system (CNS) where its activity and expression were developmentally regulated. CD38 has been reported to have different subcellular locations either in neurons or in glial cells, suggesting multiple roles. cADPR, acts as a universal calcium mobilizer from intracellular stores independently from inositol trisphosphate which acts through activation/ modulation of ryanodine receptor channels involving FKBP12.6. cADPR was also involved in the regulation of some potassium currents in synaptic activity. cADPR synthesis in neuronal cells is stimulated or modulated via different pathways and various factors. Subtype-specific coupling of various neurotransmitter receptors with ADP-ribosyl cyclase confirms the involvement of the enzyme in signal transduction in neurons and glial cells. Therefore, it is possible that pharmacological manipulation of intracellular cADPR levels through ADP-ribosyl cyclase activity or expression, in the CNS may provide new therapeutic opportunities for treatment of neurological disorders.

Brazil possesses great biological and cultural diversity, above all, in view of the great number of indigenous ethnic groups - 218 in all - that inhabit the five main biomas in Brazil. The purpose of this review is to analyze the relationship between chemical constituents of species utilized by several groups of Brazilian Indians and the uses/indications made of the species by these same groups using ethnopharmacological surveys by different researchers, as from the seventies. The 34 publications selected, involving 26 indigenous ethnic groups, showed a total of 307 species utilized for 67 different diseases or effects possibly related to the Central Nervous System (CNS). These plants belong to 85 taxonomic families, mostly Fabaceae, Asteraceae, Rubiaceae, Poaceae, Apocynaceae, Bignoniaceae, Euphorbiaceae, and Solanaceae. The chemical constitution of these plants was researched as from the Pubmed and Web of Science and the information obtained was crossed with different indigenous uses, grouped in 12 categories according to similarities between their expected effects on the CNS: analgesics, to counteract fever, tonics and/or adaptogens, hallucinogens, anxiolytics, anticonvulsants, head illnesses, hypnotics, stimulants, weight control, memory enhancers, and others. Some phytochemical classes were observed to be more common among plants utilized for certain purposes: flavonoids (analgesia, fever, anxiety, hypnotic, weight control, and as a stimulant), alkaloids (hallucinogens, head illnesses, and as a stimulant), essential oils (fever and anxiety), lignans (hallucinogen), tannins (anxiety), triterpenes and saponins (hypnotic). These data suggest that these phytochemical classes possibly possess a greater number of chemical constituents that perform the effects described or that, in some way, assist in determining the use of the plant by the Indians.