Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 10, Issue 2, 2010

Genetic factors that increase susceptibility to oxidative stress, endothelial disfunction and, possibly, stroke include angiotensin-converting enzyme gene deletion polymorphism (ACE-DD) and the methylentetrahydropholate reductase (MTHFR) C677-TT polymorphism. The relationship of ACE-DD genotype to ischemic stroke and cardiovascular disease is controversial, but it has been independently linked to lacunar infarction, in the absence of carotid atheroma. Lea et al. (2005) reported that the ACE DD genotype acts in combination with the MTHFR T/T genotype to increase migraine susceptibility, with the greatest effect in those with aura. The “TT” polymorphism is also associated with an increased risk of migraine with aura, independent of other cardiovascular risk factors. The aim of our study was to evaluate the incidence of ACE and MTHFR genes polymorphisms in a consecutive series of migrainous patients and of patients affected by myocardial infarction. We studied a series of 103 migrainous patients (1), whose age was between 13 and 75 years (81 suffering from migraine without aura, MwA, 9 from migraine with aura, MWA, 13 from mixed forms MwA-MWA, according to ICHD-II 2004 criteria) and of 336 patients (2) suffering from ischaemic cardiopathy (myocardial infarction, MI). The analysis, based on Polymerase Chain Reaction (PCR) and on reverse-hybridization, showed as follows: MTHFR (C677T): 60 patients (58%) (1) and 186 (56%) (2) were heterozygous; 9 patients (9%) (1) and 54 (16%) (2) were mutated. The result of 1patient (2) was unknown. MTHFR (A1298C): 54 patients (52%) (1) and 146 (44%) (2) were heterozygous, 7 patients (7%) (1) and 33 (10%) (2) were mutated. The result of 1 patient (2) was unknown. ACE (evaluated on 101 patients (1) and 245 (2)): 45patients (43%) (1) and 133 (54%) (2) had an ID genotype; 42 (41%) (1) and 87 (36%) (2) had a DD genotype. The results of our study confirm the high incidence in the genetic polymorphisms ACE and MTHFR in migraineuse. These data are confirmed in the sample of patients affected by myocardial infarction. This gives evidence of a strong relationship between migraine and major vascular diseases and let us hypothesize an important role of ACE and MTHFR system in the pathogenetic model of migraine for its capability to interfere with the endothelial regulation tone. Once an effective role in the genesis of migraine and in the increased risk of migrainous patients to evolve into an ischemic pathology has been obviously assigned to this genetic mutation, future researches must aim through wider and more controlled casistics also to clarify the role that drugs acting on these systems may have on the resolution of these diseases.

In our study we have evaluated the theme of the platelet fatty acid composition in subjects with a clinical diagnosis of Major Depression (MD), in subjects with a clinical diagnosis of Ischemic Heart Disease (IHD) according to the coronary angiography and in control subjects. We have analyzed all the groups without taking in account therapies, gender and age. As far as we know, the platelet fatty acid composition has never been analyzed before, in MD. The results obtained with the Self Organizing Map (SOM) show the evidence of three fatty acids, Arachidonic Acid (AA), Linoleic Acid (LA), and Palmitic Acid (PA) in a peculiar position with respect to the biochemical characterization of MD and three fatty acids, Arachidonic Acid (AA), Linoleic Acid (LA) and Oleic Acid (OA) in a peculiar position with respect to the biochemical characterization of the IHD. Bio molecular considerations are made about the possibility of controlling positive changes in platelet viscosity, in both pathologies.

Undesired side-effects and toxicities of drugs, especially in the area of new-drug development, are negligibleless, unpredicable and often disastrous once being encountered. Increasing varieties of evidence suggest that the differences of chemical structures of drugs and human's genomic makeup and environmental causes totally decide the occurrences of side-effects and toxicities of drugs instead of chemical structures of a drug alone. The side-effects of central neural systems are relatively easy to be observed and conspicuous and sensitive to judgments with or by fixed grading systems. It could be an important area to systematically study the side-effects of drugs and underlying genetic mechanisms and relationships in between. This review discusses this issue through careful analyzing relevant clinical evidence and published data relating to genetic detection of suffered patients and gives further suggestions to improve.

The functions of the lower urinary tract (LUT) are dependent upon neural circuits located in the brain, spinal cord and peripheral ganglia, organized as on-off switching circuits to regulate storage and periodic elimination of urine. Damage or disease in any of the nervous pathways controlling the lower urinary tract can cause impairment of normal bladder function. Nociceptive information from different organs are delivered to the dorsal horn of the spinal cord where a network of descending pathways projecting from cerebral structures either suppress or potentiate the passage of the nociceptive messages to the brain. Some of the central structures involved in the micturition reflexes and pain modulation are common, e.g. nucleus raphe magnum, nucleus locus coeruleus alpha, periacqueductal grey, etc. Functionally, however, their effects may be similar or contrasting. The central micturition reflexes and descending control pathways of pain also utilize common transmitters and transmitter systems with similar or different effects on micturition and pain, suggesting a certain degree of overlapping between these systems. All these findings have provided a rich palette of novel mechanisms potentially available for the improved control of LUT and pain. The proliferation of potential analgesic drug targets for the therapeutic manipulation of descending control of pain is testimony of a more (in comparison with LUT) intensive research programme in this field. Nevertheless, with the exception of parenteral administration of μ-opioids and spinal application of α2-AR agonists, no other approach has been extensively validated in the clinic. Great effort should be invested in the characterization of central mechanisms controlling the micturition reflexes, although the possibility to find novel drugs for micturition disorders with central effect appears to be problematic.

The serotonergic system plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among 5-HT receptor subtypes, 5-HT1A receptors have long been implicated in the pathogenesis and treatment of anxiety and depressive disorders. 5-HT1A receptors function as both presynaptic (autoreceptor) and postsynaptic receptors in specific brain regions such as the limbic areas, septum and raphe nuclei. 5-HT1A receptors negatively regulate cAMP-dependent signal transduction and inhibit neuronal activity by opening G-protein-gated inwardly rectifying potassium channels. The therapeutic action of 5-HT1A agonists and their mechanism in alleviating anxiety and depressive disorders have been well documented. In addition, recent studies have revealed new insights into the therapeutic role of 5-HT1A receptors in treating various CNS disorders, including not only depressive disorders (e.g., delayed onset of action and refractory symptoms), but also schizophrenia (e.g., cognitive impairment and antipsychotic-induced extrapyramidal side effects) and Parkinson's disease (e.g., extrapyramidal motor symptoms and L-DOPA-induced dyskinesia). These lines of evidences encourage us to design new generation 5-HT1A ligands such as 5-HT1A agonists with greater potency, higher selectivity and improved pharmacokinetic properties, and 5-HT1A ligands which combine multiple pharmacological actions (e.g., inhibition of serotonin transporter, dopamine D2 receptors and other 5-HT receptor subtypes). Such new 5-HT1A ligands may overcome clinical efficacy limitations and/or improve adverse reactions in current CNS therapies.

Macroautophagy is an evolutionarily conserved lysosomal-dependent pathway of degradation of several cytoplasmic components, such as misfolded proteins or damaged organelles. This process of cellular self-digestion is involved in a number of physiological processes like survival, differentiation and development. The failure in the normal flow of the autophagic process has been associated with normal brain aging and with late-onset neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's diseases. A common characteristic between these disorders is the accumulation of protein deposits composed by aberrant protein aggregates. Also dysfunctional organelles, particularly mitochondria, have been implicated in the pathophysiology of several neurodegenerative diseases. Here we give an overview of the importance of autophagy in brain aging and in age-related neurodegeneration. Furthermore, we will discuss autophagy as a potential therapeutic target to mitigate the adverse effects of aging and age-related diseases on brain function.

Fukuyama type congenital muscular dystrophy (FCMD) is an autosomal recessive disease, exhibiting muscular dystrophy, and central nervous system (CNS) and ocular malformations. It is included in α-dystroglycanopathy, a group of muscular dystrophy showing reduced glycosylation of α-dystroglycan. α-Dystroglycan is one of the components of dystrophin-glycoprotein complex linking extracellular and intracellular proteins. The sugar chains of α-dystroglycan are receptors for extracellular matrix proteins such as laminin. Fukutin, a gene responsible for FCMD, is presumably related to the glycosylation of α-dystroglycan like other causative genes of α-dystroglycanopathy. The CNS lesion of FCMD is characterized by cobblestone lissencephaly, associated with decreased glycosylation of α-dystroglycan in the glia limitans where the basement membrane is formed. Astrocytes whose endfeet form the glia limitans seem to be greatly involved in the genesis of the CNS lesion. Fukutin is probably necessary for astrocytic function. Other components of the CNS may also need fukutin, such as migration and synaptic function in neurons. However, roles of fukutin in oligodendroglia, microglia, leptomeninges and capillaries are unknown at present. Fukutin is expressed in various somatic organs as well, and appears to work differently between epithelial cells and astrocytes. In the molecular level, since the dystrophin-glycoprotein complex is linked to cell signaling pathways involving c-src and c-jun, fukutin may be able to affect cell proliferation/ survival. Fukutin was localized in the nucleus on cancer cell lines. With the consideration that mutations of fukutin give rise to wide spectrum of the clinical phenotype, more unknown functions of fukutin besides the glycosylation of α-dystroglycan can be suggested. Trials for novel treatments including gene therapy are in progress in muscular dystrophies. Toward effective therapies with minimal side effects, precise evaluation of the pathomechanism of FCMD and the function of fukutin would be required.