About 80% of functional genes in the human genome are expressed in the brain and over 1,200 different genes have been associated with the pathogenesis of CNS disorders and dementia. Pharmacogenetic studies of psychotropic drug response have focused on determining the relationship between variations in specific candidate genes and the positive and adverse effects of drug treatment. Approximately, 18% of neuroleptics are substrates of CYP1A2 enzymes, 40% of CYP2D6, and 23% of CYP3A4; 24% of antidepressants are substrates of CYP1A2 enzymes, 5% of CYP2B6, 38% of CYP2C19, 85% of CYP2D6, and 38% of CYP3A4; 7% of benzodiazepines are substrates of CYP2C19 enzymes, 20% of CYP2D6, and 95% of CYP3A4. 10-20% of Western populations are defective in genes of the CYP superfamily; and the pharmacogenomic response of psychotropic drugs also depends on genetic variants associated with dementia. Prospective studies with anti-dementia drugs or with multifactorial strategies have revealed that the therapeutic response to conventional drugs in Alzheimer’s disease is genotype-specific. The disease-modifying effects (cognitive performance, biomarker modification) of therapeutic intervention are APOE-dependent, with APOE-4 carriers acting as the worst responders (APOE-3/3 > APOE-3/4 > APOE-4/4). APOE-CYP2D6 interactions also influence the therapeutic outcome in patients with dementia.
Dementia is a major problem of health in developed societies. Alzheimer's disease (AD), vascular dementia, and mixed dementia account for over 90% of the most prevalent forms of dementia. Both genetic and environmental factors are determinant for the phenotypic expression of dementia. AD is a complex disorder in which many different gene clusters may be involved. Most genes screened to date belong to different proteomic and metabolomic pathways potentially affecting AD pathogenesis. The ε4 variant of the APOE gene seems to be a major risk factor for both degenerative and vascular dementia. Metabolic factors, cerebrovascular disorders, and epigenetic phenomena also contribute to neurodegeneration. Five categories of genes are mainly involved in pharmacogenomics: genes associated with disease pathogenesis, genes associated with the mechanism of action of a particular drug, genes associated with phase I and phase II metabolic reactions, genes associated with transporters, and pleiotropic genes and/or genes associated with concomitant pathologies. The APOE and CYP2D6 genes have been extensively studied in AD. The therapeutic response to conventional drugs in patients with AD is genotype specific, with CYP2D6-PMs, CYP2D6-UMs, and APOE-4/4 carriers acting as the worst responders. APOE and CYP2D6 may cooperate, as pleiotropic genes, in the metabolism of drugs and hepatic function. The introduction of pharmacogenetic procedures into AD pharmacological treatment may help to optimize therapeutics.
CNS disorders are the third major problem of health in developed countries, with approximately 10% of direct costs associated with a pharmacological treatment of doubtful cost-effectiveness. There is an alarming abuse of psychotropic drugs worldwide and only 20-30% of patients with CNS disorders appropriately respond to conventional drugs. The pathogenesis of most CNS disorders is the result of the interplay of genetic and epigenetic factors with environmental factors leading to post-transcriptional changes and proteomic and metabolomic dysfunctions. It is estimated that genetics accounts for 20% to 95% of variability in drug disposition and pharmacodynamics, and about 25-60% of the Western population is defective in genes responsible for drug metabolism. In the European population only 25% of subjects are pure extensive metabolizers for the trigenic cluster integrated by the CYP2D6, CYP2C19 and CYP2C9 genes. About 50% of adverse drug events in CNS disorders might be attributed to pharmacogenomic factors. The rationale for practical pharmacogenomics and personalized therapeutics based on individual genomic profiles implies the management of different types of genes and their products including (i) genes associated with the mechanism of action of psychotropic drugs (neurotransmitters, receptors, transporters), (ii) genes encoding enzymes responsible for drug metabolism (phase I, phase II reactions), (iii) disease-specific genes associated with a particular pathogenic cascade, and (iv) pleiotropic genes with multilocative effects in metabolomic networks. The incorporation of genomic medicine procedures and pharmacogenomics into clinical practice, together with educational programs for the correct use of medication, must help to optimize therapeutics in CNS disorders.
Recent evidence indicates that different vascular risk factors are present in Alzheimer's disease (AD) and other prevalent dementia types probably contributing to deterioration of cerebrovascular function, thus enhancing neurodegeneration and premature neuronal death due to a reduction in brain perfusion. Brain blood flow shows a reduced velocity and increased pulsatility (PI) and resistance indices (RI) in different types of dementia and in diabetes and hypertension, as well. High levels of diastolic blood pressure correlate with diminished brain blood flow and elevated PI and RI, accompanied by cognitive deterioration. Nitric oxide (NO) levels are found increased in the sera and brain tissue of AD patients. Vascular risk factors (hyperglycemia, LDL-cholesterol, triglycerides, hypertension) and altered brain hemodynamic parameters correlate with APOE genotypes of which APOE-4/4 carriers represent the AD population with the highest cerebrovascular risk. In addition, the genomic profiles of patients with dementia integrating AD-related genes (APOE, PS1, PS2, cFOS) in a mini-tetragenic haplotype significantly differ from controls with an absolute genetic variation of about 50%-60%. Cerebrovascular dysfunction is a factor common to most types of dementia; however, genetic variation among different dementia types might be determinant for the activation of early vascular events inducing or accelerating neurodegeneration. In this regard, cerebrovascular dysfunction should be considered a potential therapeutic target in dementia.
Marine organisms and their metabolites represent a unique source of potential pharmaceutical substances. In this study, we examined marine-derived substances for their bioactive properties in a cell-based Chikungunya virus (CHIKV) replicon model and for in vitro anti-inflammatory activity. In the screening of a marine sample library, crude extracts from the Indian soft coral, Sinularia kavarattiensis, showed promising activity against the CHIKV replicon. Bioassay-guided chemical fractionation of S. kavarattiensis resulted in the isolation of six known norcembranoids (1–6) and one new compound, named kavaranolide (7). The structures were elucidated on the basis of NMR and MS spectroscopic data. Compounds 1–3 and 5–7 were evaluated for their replicon-inhibiting potential in the CHIKV model by using a luminescence-based detection technique and live cell imaging. Compounds 1 and 2 showed moderate inhibition of the CHIKV replicon, but imaging studies also revealed cytotoxic properties. Moreover, the effects of the isolated compounds on primary microglial cells, an experimental model for neuroinflammation, were evaluated. Compound 2 was shown to modulate the immune response in microglial cells and to possess potential anti-inflammatory properties by dose-dependently reducing the release of pro- and anti-inflammatory cytokines.
Alzheimer's disease (AD) and dementia with vascular component (DVC) are the most prevalent forms of dementia. Both clinical entities share many similarities, but they differ in major phenotypic and genotypic profiles as revealed by structural and functional genomics studies. Comparative phenotypic studies have identified significant differences in 25% of more than 100 parametric variables, including anthropometry, cardiovascular function, aortic atherosclerosis, brain atrophy, blood pressure, blood biochemistry, hematology, thyroid function, folate and vitamin B12 levels, brain hemodynamics and lymphocyte markers. The phenotypic profile of patients with DVC differs from that of AD patients in the following: anthropometric values (weight, height); cardiovascular function (ECG, heart rate); blood pressure; lipid metabolism (HDL-CHO, TGs); uric acid metabolism; peripheral calcium homeostasis; liver function (GOT, GPT, GGT); alkaline phosphatase; lactate dehydrogenase; red and white blood cells; regional brain atrophy (left temporal region, inter-hippocampal distance); and left anterior blood flow velocity. Functional genomics studies incorporating APOE-related changes in biological markers extended the difference between AD and DVC up to 57%. Brain perfusion studies show a severe brain hypoperfusion in dementia associated with enlarged age-dependent arterial perfusion times. Structural genomics studies with AD-related genes, including APP, MAPT, APOE, PS1, PS2, A2M, ACE, AGT, cFOS and PRNP genes, demonstrate different genetic profiles in AD and DVC, with an absolute genetic variation rate ranging from 30% to 80%, depending upon genes and genetic clusters. Single gene analysis identifies relative genetic variations ranging from 0% to 5%. The relative polymorphic variation in genetic clusters integrated by two, three or four genes associated with AD ranges from 1% to 3%. The main phenotypic differences between AD and DVC are genotype-dependent, especially in AD, probably indicating that different genomic factors are determinant for the expression of dementia symptoms which might be accelerated or induced by environmental and/or cerebrovascular factors.
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