Stavroula Veletza

Neuropeptide and Sigma Receptors as Novel Therapeutic Targets for the Pharmacotherapy of Depression

Among the most prevalent of mental illnesses, depression is increasing in incidence in the Western world. It presents with a wide variety of symptoms that involve both the CNS and the periphery. Multiple pharmacological observations led to the development of the monoamine theory as a biological basis for depression, according to which diminished neurotransmission within the CNS, including that of the dopamine, noradrenaline (norepinephrine) and serotonin systems, is the leading cause of the disorder. Current conventional pharmacological antidepressant therapies, using selective monoamine reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors, aim to enhance monoaminergic neurotransmission. However, the use of these agents presents severe disadvantages, including a delay in the alleviation of depressive symptoms, significant adverse effects and high frequencies of non-responding patients.Neuroendocrinological data of recent decades reveal that depression and anxiety disorders may occur simultaneously due to hypothalamus-pituitary-adrenal (HPA) axis hyperactivity. As a result, the stress-diathesis model was developed, which attempts to associate genetic and environmental influences in the aetiology of depression. The amygdala and the hippocampus control the activity of the HPA axis in a counter-balancing way, and a plethora of regulatory neuropeptide signalling pathways are involved. Intervention at these molecular targets may lead to alternative antidepressant therapeutic solutions that are expected to overcome the limitations of existing antidepressants. This prospect is based on preclinical evidence from pharmacological and genetic modifications of the action of neuropeptides such as corticotropin-releasing factor, substance P, galanin, vasopressin and neuropeptide Y. The recent synthesis of orally potent non-peptide micromolecules that can selectively bind to various neuropeptide receptors permits the onset of clinical trials to evaluate their efficacy against depression.

Psychological vulnerability differences in students--carriers or not of the serotonin transporter promoter allele S: effect of adverse experiences.

To study the effect of the serotonin transporting gene L/S polymorphism on several psychological characteristics in a group of Greek University students.

Assessment of insertion/deletion polymorphism of the angiotensin-converting enzyme gene in abdominal aortic aneurysm and inguinal hernia

The aim of the paper is to determine whether the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is associated with abdominal aortic aneurysm (AAA) and inguinal hernia. A case-control study was conducted in 264 subjects: 65 patients with AAA, 91 patients with inguinal hernia, 19 patients with both AAA and hernia, and 89 controls were investigated for the ACE I/D polymorphism. Genotype analysis was performed using a polymerase chain reaction technique. Significant differences in the genotype between the patient groups and controls were identified (aneurysm versus control, P = 0.011; aneurysm plus hernia versus control, P = 0.022; hernia versus control, P = 0.001), whereas no differences were found within patient groups. Patients with AAA and/ or hernia had an increased prevalence of I/D heterozygosity, which persisted even after adjusting for differences in confounding clinical variables (aneurysm versus control, OR 0.3, 95% CI 0.2–0.8, P = 0.005; aneurysm plus hernia versus control, OR 0.3, 95% CI 0.1-0.9, P = 0.040; hernia versus control, OR 0.4, 95% CI 0.2–0.7, P = 0.004). In conclusion, an association between the heterozygote ACE I/D state and the presence of AAA and/or hernia was identified. The role of the ACE I/D polymorphism in aneurysm and hernia needs further investigation.

Apolipoprotein E and First-ever Ischaemic Stroke in Greek Hospitalized Patients

The association between apolipoprotein E (ApoE) polymorphism and stroke is still controversial. This study investigated the potential association between ApoE genotypes and stroke subtypes, and risk factors for ischaemic stroke in Greek patients hospitalized with their first-ever ischaemic stroke. One hundred patients (70 men and 30 women; mean age ± SD 60.7 ± 9.8 years) were included in the study. The control group comprised 96 age-and sex-matched healthy volunteers. Cerebral infarction was classified as atherothrombotic, cardio-embolic or lacunar small-vessel stroke. The three common ApoE alleles (E2, E3 and E4) were determined using the seminested polymerase chain reaction. No significant difference in the ApoE alleles was found between patients and controls. Similarly, there was no significant association between ApoE alleles and stroke subtypes, common risk factors for ischaemic stroke and neck vessel stenosis. Although the sample size was small, these results do not support a role for ApoE polymorphism in the pathogenesis of ischaemic stroke.

notch2 , notch4 gene polymorphisms in psoriasis vulgaris

BACKGROUND Evidence suggests that Notch gene aberrations may be involved in the clinical expression of psoriasis. There are reports of Notch2 receptor expression peculiarities in psoriatic skin and others, indicating that VEGF-induced Notch4 overexpression promotes endothelial cell morphology alterations and that increased dermis vessel permeability histogenetically precedes the development of psoriatic lesions. OBJECTIVE To investigate the correlation of polymorphisms in Notch2 and Notch4 genes with the appearance of psoriasis vulgaris. MATERIAL AND METHODS Up to 305 patients suffering from psoriasis vulgaris were included in the study, genotyped by either real time quantitative PCR or PCR-RFLP. RESULTS We observed: (a) Notch2: Statistically significant predominance of T/C genotype in male patients (p=0.037); (b) Notch4: Significantly higher frequency of the SNP1 T/T genotype (p=0.039) in psoriatic females; significant predominance of the SNP2 G/G and A/G (p=0.014) genotypes in female patients with late onset psoriasis (p=0.001). CONCLUSION This study supports the involvement of both Notch2 and Notch4 in the pathogenesis of psoriasis vulgaris. Pathogenetic participation of Notch2 seems more evident in male patients, possibly early onset, while that of Notch4 is more evident in late onset female patients.

The structure of the 5'-untranslated region of mammalian poly(A) polymerase-α mRNA suggests a mechanism of translational regulation

Poly(A)polymerase-α (PAPOLA) has been the most extensively investigated mammalian polyadenylating enzyme, mainly in regard to its multifaceted post-translational regulation. The possibility of translational regulation of this enzyme was addressed. The transcription start site was mapped and two uORFs, highly conserved among several species, were identified in the 211-bp long, GC-rich, 5′ UTR of the PAPOLA mRNA. Mutation of the 5′ proximal AUG resulted in increased translational efficiency of the adjacent coding sequence, whereas no significant effect was observed after mutation of the second AUG. These observations imply that translational regulation is among the conserved mechanisms regulating PAPOLA expression.

Assessment of Tachykinin Receptor 3′ Gene Polymorphism rs3733631 in Rosacea

Background. Rosacea is a chronic skin disease, possibly following the neurogenic skin inflammation model. Neurokinin B, involved in the pathogenesis of Parkinsons disease, frequently coexisting with subsequent onset of rosacea, is an endogenous ligand of the tachykinin receptor 3 (TACR3). Methods. 128 rosacea patients and 121 matched controls were genotyped for rs3733631 by PCR-RFLP and analyzed by chi-square test. Results. We observed statistically significant predominance of the C/G or G/G genotype (p = 0.006) and of the G allele (p = 0.004) in the papulopustular (PP) form of rosacea and statistically marginal significance of the C/G or G/G genotype in erythematotelangiectatic (ET) rosacea (p = 0.052). Significantly higher frequency of the C/G or G/G genotype and G allele in PP rosacea (p = 0.021 and p = 0.008, resp.) was ascertained within male patients. Conclusion. TACR3 rs3733631 G allele possibly predisposes the evolution of the initial phase of rosacea to the PP and not the ET form in male patients.

Effect of BDNF Val66Met and serotonin transporter 5-HTTLPR polymorphisms on psychopathological characteristics in a sample of university students.

Objective The aims of this study were to evaluate the impact of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on several psychological characteristics in a group of Greek University students and to explore putative interactions with the serotonin-transporter-linked polymorphic region (5-HTTLPR) and serious past adverse experiences. Methods A total of 224 students were genotyped and classified as (a) carriers or noncarriers of the Met allele of the BDNF Val66Met polymorphism and (b) carriers or noncarriers of the S or Lg alleles (S′) of the 5-HTTLPR polymorphism. Students were evaluated using a battery of standard psychological tests and answered questionnaires on serious past adverse experiences. Results The Val/Val BDNF genotype was associated with higher scores in several psychopathological dimensions. When the effect of the BDNF Met allele was examined in relation to 5-HTTLPR, it was restricted to S′ noncarriers. Among these students, BDNF Met allele carriers had lower scores compared with noncarriers. The effects of the Met allele on the S′ allele noncarriers in the anxiety and phobic anxiety dimensions were more pronounced among individuals who had reported no serious life adversities. Conclusion There may be a protective role of the BDNF Met allele in several psychopathological features and it is suggested that some of these effects are moderated by 5-HTTLPR.

Assessment of Leptin Gene Polymorphism rs2060713 in Psoriasis Vulgaris

Psoriasis is a lifelong disorder characterized by approximately 8-fold reduction of the duration of normal skin keratinocyte cell cycle and 2-fold increase of the number of dividing cells. Multiple genes, several environmental factors, and immune system alterations are involved in the pathogenesis of psoriasis. Hyperleptinemia is associated with psoriasis and leptin acts as an angiogenic factor. Angiogenetic processes precede the epidermal hyperplasia in psoriasis, indicating possible involvement of leptin in the pathogenesis of psoriasis. Leptin gene polymorphisms and their association with psoriasis have been given very little attention. We present a study of the rs2060713C/T genetic polymorphism in the pathogenesis of psoriasis vulgaris in 263 vulgaris patients and 252 unrelated matched healthy controls. No statistically significant differences were observed between patients and controls. A statistically nonsignificant trend was observed in males with the early onset type of psoriasis (11.1% C/T in patients versus 5.6% in controls) and in females with the late onset type of the disease (12.8% C/T in patients versus 3.3% in controls). Still, there is no hard evidence on correlation of psoriasis vulgaris with this polymorphism. Possible association with specific forms of the disease and either gender needs further investigation in larger studies.

Association of SCN1A gene polymorphism with antiepileptic drug responsiveness in the population of Thrace, Greece

Introduction The aim was to examine the influence of the SCN1A gene polymorphism IVS5-91 rs3812718 G>A on the response to antiepileptic drugs (AEDs) in monotherapy or polytherapy. Material and methods Two hundred epilepsy patients and 200 healthy subjects were genotyped for SCN1A IVS5-91 rs3812718 G>A polymorphism using TaqMan assay. Patients were divided into drug-responsive and drug-resistant patients. The drug-responsive group was further studied, comparing monotherapy in maximum and minimum doses and monotherapy-responsive and -resistant groups. Results There were no statistically significant differences in the allelic frequencies and genotype distributions between patients and controls (p = 0.178). The distribution of SCN1A IVS5-91 rs3812718 G>A genotypes was similar between drug-responsive and drug-resistant patients (p = 0.463). The differences in genotype distributions (A/A or A/G vs. G/G) between monotherapy-responsive and -resistant groups were statistically significant (p = 0.021). Within the monotherapy-responsive group, patients with the A/A or A/G genotype needed higher dose AEDs than patients with the G/G genotype (p = 0.032). The relative risk for generalized epilepsy due to A-containing genotypes was of marginal statistical significance when compared with the G/G genotype (p = 0.05). Conclusions Overall, our findings demonstrate an association of SCN1A IVS5-91 rs3812718 G>A polymorphism with AED responsiveness in monotherapy without evidence of an effect on drug-resistant epilepsy.