Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 7, Issue 4, 2007

The uridine nucleotides UTP, UDP and UDP-sugars produce a variety of effects by activating specific G protein- coupled P2Y receptors, i.e., the P2Y2, P2Y4, P2Y6 and P2Y14 variants. Except for P2Y14 which has recently been defined, stimulation of P2Y receptors by UTP and/or UDP augments proliferation of adult multipotent neural stem cells; stimulates dopaminergic differentiation in human mesencephalic neural stem cells; and enhances neurite outgrowth in nerve growth factor-differentiated PC12 cells and cultured DRG neurons. UTP and/or UDP have been shown to affect neuronal function by depolarizing neurons from cultured amphibian sympathetic ganglia; increasing firing rates of neurons; enhancing presynaptic glutamate release and promoting long-term potentiation; and by stimulating noradrenaline release from cultured sympathetic neurons. Furthermore, by activating P2Y receptors, UTP and/or UDP exhibit neuroprotective effects via induction of microglial convergence and reactive astrogliosis; protection from serum starvation-induced apoptosis; and stimulation of α-secretase-dependent APP processing and sAPPα release. Antagonism of uridine- nucleotide- stimulated P2Y receptors or the second messengers they generate, or degradation of extracellular uridine nucleotides, can block the effects mediated by these receptors. These observations suggest that uridine-nucleotide-stimulated P2Y receptors may constitute possible therapeutic targets for diseases affecting neuronal survival or function.

An extract from the leaves of the Ginkgo biloba tree, labeled EGb761, is one of the most widely used medicinal products in the West for cardiovascular and brain related diseases. In particular, it has been used frequently for the treatment and prevention of neurodegenerative diseases such as mild cognitive impairment or Alzheimer's disease. The drug is relatively safe and has been used widely by healthy individuals as an alternative medicine, even for anti-normal aging. EGb761 consists of two major substances, the flavone glycosides (flavonoid fraction, 24%) and the terpene lactones (terpenoid fraction, 6%), which might possess the function of neuroprotection. Possible mechanisms suggested include interactions with the mitochondria and apoptosis, platelet aggregation antagonism, free radicals and nitric oxide scavenging, modulation of neurotransmitters, and induction of growth factors. However, the mechanism of its therapeutic effect on the central nervous system remains inconclusive. In this review article, we will attempt to summarize the molecular evidence of the neuroprotective mechanism of Ginkgo, and to explain its possible neuroprotective effect on the central nervous system. By choosing a suitable biochemical marker, the neuroprotective effect of Ginkgo could be studied, quantified, and compared in different studies of the central nervous system as well as in other organ systems. This would lead to a better understanding of the mystified anti-aging role of Ginkgo in human.

Proteasomes (including constitutive proteasome, immunoproteasome, and their regulatory complexes) are multicatalytic complexes crucial for cell and body homeostasis and survival, being responsible for a consistent part of protein degradation. In the central nervous system (CNS), the activity of proteasomes affects a variety of crucial brain activities. While proteasome alteration (content and activity) during aging has been studied in several tissues and cellular models, few data are available regarding human CNS, and the identification of an appropriate and reliable model for the role of proteasome in human brain aging is still lacking. In this review, the available data on proteasome and brain aging in rodents, as well as the few data on non human primates, are critically revised. On the whole, the data regarding changes of proteasome activity and content with age are far from being clear, not only due to the heterogeneity of the models (differences between species, among strains of the same species) but also due to the brain areas considered. We paid particular attention to recent data obtained in human brain of non-demented donors and subjects affected by Alzheimer Disease (AD) demented subjects, as well as to new data on non human primate brain. The study of the possible role of proteasomes in brain aging, and the identification of reliable animal models, is pivotal for the development of possible ad hoc therapeutic interventions capable of retarding/counteracting brain aging and age-related brain pathologies. The therapeutic capability and limits of Vitamin E, the possible set up of proteasome modifiers (activators) as well as the effects on proteasomes of other drugs used for AD therapy are discussed within a scenario which deserves more attention and further investigations.

After injury to the central nervous system (CNS) of adult vertebrates, axonal regeneration is extremely limited because inhibitory proteins existing around the injury site prevent the regrowth of the lesioned axons. Previous studies have reported that several myelin-derived proteins (such as Nogo, MAG, OMgp) and developmental guidance proteins (such as RGM, semaphorin, ephrin) contribute to the inhibition of axonal regeneration after injury in the adult CNS. Although each neurite growth inhibitory protein induces neurite retraction and growth cone collapse through specific receptors, they commonly utilize the function of small GTPases, including Rho, Rac, Cdc42, and Ras, that regulate neurite outgrowth by controlling actin and microtubule cytoskeleton. The small GTPase Rho and its effector Rho-kinase play critical roles in the induction of neurite retraction and growth cone collapse in vitro and the inhibition of axonal regeneration in vivo. Therefore, the Rho inhibitor C3 transferase and Rho-kinase inhibitors are thought to be effective therapeutic candidates involved in the promotion of axonal regeneration after human CNS injuries such as spinal cord injury.

Ischaemic stroke is a leading cause of death and disability in the Western world and usually occurs as a consequence of progressing atherothrombosis resulting in embolism and associated local tissue damage due to loss of cell membrane integrity and altered signal transduction activity. Survival of neurones, particularly in peri-infarcted regions determines the extent of patient recovery. A significant proportion of neurones in these areas undergo programmed cell death by apoptosis, resulting in a worse prognosis. Angiogenesis is critical for the development of new microvessels and leads to re-formation of collateral circulation, reperfusion, enhanced neuronal survival and improved recovery. Recent evidence has suggested that both angiogenesis and neuronal survival may be affected following activation of cyclindependent kinase-5 (Cdk5). In this review, the functional roles of Cdk5 in stroke will be described, followed by an analysis and comparison of available pharmacological inhibitors with a view to their potential use in the future treatment of this disease.

The high-affinity glycine transporter 1 (GlyT1) is the primary endogenous regulator of glycine levels in the vicinity of the N-methyl-D-aspartate receptor (NMDAR). As a co-agonist, glycine can allosterically modulate NMDAR functions through its binding to the glycine binding site (glycine-B site). Under homeostatic conditions, GlyT1 mediated re-uptake is believed to maintain the synaptic glycine concentration below the saturation level of the glycine-B site. Given that glycine-B site occupation is obligatory for glutamatergic activation of the NMDAR, increased availability of glycine in the vicinity of NMDAR's glycine-B site has been suggested as an alternate strategy to enhance NMDAR functions. Because exogenously administered glycine shows poor blood-brain barrier penetration and must overcome potent regulatory brain mechanisms in order to efficiently enhance NMDAR function, one currently favored strategy is to target the glycine clearance mechanism through inhibition of GlyT1 mediated re-uptake. Numerous studies have demonstrated that pharmacological blockade or molecular down-regulation of GlyT1 leads to enhanced NMDAR functions and thus may provide novel therapeutic avenues in the treatment of neurological and psychiatric disorders in which NDMAR hypofunction has been implicated, including schizophrenia. Several modulatory agents targeted at the glycine-B site are currently undergoing pre-clinical and clinical development as potential antipsychotic drugs. Parallel research in animals with pharmacological inhibition of GlyT1 or GlyT1 knock-out mice has also generated promising results, reinforcing the hypothesis that disruption of glycine reuptake via GlyT1 may entail therapeutic value against primarily negative and cognitive symptoms of schizophrenia.

A large body of evidence shows that α7 nicotinic acetylcholine receptor (nAChR) is an important mechanism underlying attentional and cognitive deficits in schizophrenia. Several compounds acting as activators of α7 nAChRs have been identified and investigated for a potential therapeutic application. However, considering the complexity of neuropsychiatric disorders and the difficulty to meet an ideal product profile for drug discovery in the field, there is the need to define empirical product profiles from available data for the major α7 activators. Two classes of compounds are described, partial/full α7 agonists and α7 positive allosteric modulators (PAMs). Their critical pharmacological features are analysed by focussing on type of activity/selectivity at α7 nAChR, action in vivo in laboratory animal models, desired clinical activity, pharmacokinetics (PK)/dosing and safety/tolerability issues. Although the characterization of type of efficacy in vitro succeeded in the extrapolation to animal models and to patients, more efforts are needed to improve selectivity, PK/dosing and safety/tolerability features for α7 agonists. Such as limitations have not been seen for α7 PAMs, so that this class may offer a potential back-up strategy for α7 activators development. The empirical profiles proposed here might give pragmatical indications for the development and the optimization of α7 activators. Few issues need to be further optimized, i), in the clinic, mostly PK profiling, and, ii), at a preclinical level, downstream α7 receptors mechanisms involved in cognitive deficits. A successfully translation of α7 activators research for the treatment of schizophrenic patients will rely on a continuous clinical/preclinical cross-talk approach.

The CNS is both source and target of melatonin. It is released from the pineal to the circulation and, in elevated concentrations, into the third ventricle. Levels by 3 orders of magnitude higher than in the circulation have been found in the CNS. The mammalian circadian pacemaker, suprachiasmatic nucleus (SCN), controls the pineal, but is also major subject to feedback information on darkness, transduced by two G-protein coupled melatonin receptors, MT1 and MT2, which cause suppression of neuronal firing and circadian phase resetting. Two MT1 and MT2 agonists, ramelteon and agomelatine, display sleep-promoting properties. Agomelatine additionally inhibits 5-HT2C receptors, the basis of an antidepressant effect. Melatonin, ramelteon and agomelatine have been tested in clinical trials. Only ramelteon has received approval by the FDA, as a sleeping pill. Bioactive melatonin analogs, N-acetylserotonin, 5-methoxytryptamine, N,Ndimethyl- 5-methoxytryptamine, and 5-methoxytryptophol are produced in the CNS. Interplays between these compounds, including the serotoninergic system, are likely. N-Acetylserotonin is abundant in hippocampus, cerebellum, midbrain, pons and medulla. Neuroprotective actions of melatonin include antiamyloidogenic, antiexcitatory/antiexcitotoxic, antioxidant effects and modulation of mitochondrial metabolism, with consequences for radical formation and aging. The remarkable pleiotropy of melatonin includes other binding sites, such as calmodulin, calreticulin and a nuclear calreticulin homolog, members of the ROR/RZR family, quinone reductase 2 and specific mitochondrial sites. N1-acetyl-N2-formyl-5- methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK) are major melatonin metabolites in the CNS and also display biological activities. For instance, AMK inhibits neuronal NO synthase already at 10-11 M, and modulates mitochondrial metabolism. By interacting with NO, AMK forms 3-acetamidomethyl-6-methoxycinnolinone (AMMC).