Translocator protein (TSPO) and neurosteroids: implications in psychiatric disorders.

The translocator protein (TSPO) is a five transmembrane domain protein localised primarily in the outer mitochondrial membrane of steroid-synthesizing tissues, including the brain. The TSPO mediates the rate-limiting step of steroidogenesis, consisting of the translocation of the substrate cholesterol from the outer to the inner mitochondrial membrane. In the recent years TSPO function has received attention in several psychiatric disorders since these diseases have been associated with unbalanced steroid levels. Accordingly, an alteration in the levels of TSPO has been found in various psychiatric disorders, including social phobia, post-traumatic stress disorder, adult separation anxiety and schizophrenia. The discovery that TSPO drug ligands are able to stimulate neurosteroid production in the brain, independently of peripheral endocrine sources, and restore neurosteroid-mediated neurotransmission, has made the TSPO an attractive drug target for treating a number of psychiatric disorders. In anxiety TSPO drug ligands have shown in vivo efficacy in pharmacologically induced anxiety models in both animals and humans. The focus of this review is to illustrate the currently available literature regarding the role of TSPO in psychiatric disorders.

Role of translocator protein (18 kDa) in adult separation anxiety and attachment style in patients with depression.

BACKGROUND AND OBJECTIVES: A role for the protein that mediates the rate-limiting step of steroidogenesis, the 18 kDa Translocator Protein (TSPO), has been suggested in the pathophysiology of Adult Separation Anxiety Disorder (ASAD). It has been shown that ASAD patients have 1) low TSPO expression levels and 2) a high frequency of the allele that substitutes Ala with Thr at position 147 of TSPO. The Thr147 ASAD-associated allele has been recently related with a low pregnenolone production. The aim of the present work was to evaluate the relationship between TSPO expression levels and Ala147Thr single nucleotide polymorphism (SNP), which are the two TSPO biological parameters that we have previously examined separately. A further aim was to confirm the genetic association of Ala147Thr SNP with ASAD in an extended case-control sample and to investigate whether this SNP was related to an anxious attachment style that is thought to be connected to ASAD. METHODS: TSPO expression levels were compared among patients with ASAD (n=26), without ASAD (n=26) and control samples (n=10) stratified into the two genotype groups: those with the Ala147 genotype (named "normal pregnenolone production") and those with the Thr147 genotype (named "reduced pregnenolone production"). The case-control genetic study included patients with (n=87) or without (n=101) ASAD and 236 controls. In the patient group, the association between the Ala147Thr SNP and an anxious attachment style was analysed by stepwise logistic regression analysis. RESULTS: The genotype with the lowest TSPO expression levels was the "normal pregnenolone production" genotype in the ASAD group. The genetic Ala147Thr SNP confirmed an excess of the Thr147 allele in ASAD patients. Stepwise logistic regression analysis did not show an association with an anxious attachment style. CONCLUSIONS: ASAD individuals who expressed normal TSPO levels exhibited the "reduced pregnenolone production" genotype. In contrast, the ASAD individuals with the "normal pregnenolone production" genotype expressed low TSPO levels. It is possible that low TSPO expression levels could compromise normal pregnenolone production. Such evidence may have therapeutic implications because it has been documented that drugs targeting TSPO increased pregnenolone production and have anxiolytic effects.

Evidence for complex binding profiles and species differences at the translocator protein (TSPO) (18 kDa).

The translocator protein (TSPO) (18 kDa) is an emerging drug target for the treatment of numerous pathologies including cancer and neurodegenerative disease. However, our limited knowledge of TSPO binding site(s) has hindered the development of TSPO ligands with potential therapeutic effects. We have synthesized a series of pyrrolobenzoxazepines (1-10) to better characterize the interaction of ligands with the TSPO across species, and to determine their functional profiles. All ligands 1-10 displaced the binding of [3H]PK 11195 to the TSPO at nanomolar concentrations, with discrepancies in binding affinity between rat and human TSPO. Interestingly, non-linear regression analysis revealed that some ligands bound to the protein with a Hill slope not equal to 1.0, suggesting possible additional TSPO binding sites with allosteric effects. However, this trend was not conserved between rat and human. When tested for their effects on pregnenolone production in rat C6 glioma cells, nitric oxide release in murine microglia, and cell proliferation in human MCF-7 breast cancer cells, the pyrrolobenzoxazepines (40 µM) displayed functional effects which did not correlate to the binding trend observed in competition assays. We propose that consideration of species differences and binding site cooperativity, plus optimization of currently accepted functional assays, will aid in the development of drugs targeting TSPO that can be used as therapeutics for human disease.

Inhibition of metalloproteinases derived from tumours: new insights in the treatment of human glioblastoma.

Glioblastoma multiforme is the most commonly diagnosed malignant primary brain tumour in adults. Invasive behaviour is the pathological hallmark of malignant gliomas; consequently, its inhibition has been suggested as a therapeutic strategy. Tumour cell-derived gelatinases (matrix metalloproteinase-2, matrix metalloproteinase-9) can be considered prime factors in glioma invasiveness: their expression correlates with the progression and the degree of malignancy. Thus, broad spectrum matrix metalloproteinase inhibitors (MMP inhibitors) have been included in clinical trials. In the present study, the invasiveness, viability and progression of the human glioma cell line U87MG were investigated following treatment with N-O-isopropyl sulfonamido-based hydroxamates (compounds 1 and 2) as MMP-2 inhibitors used at nanomolar concentration. A standard broad spectrum MMP-inhibitor belonging to the classical tertiary sulfonamido-based hydroxamates family (CGS_27023A) was used too. The compounds 1 and 2 resulted in potent inhibition of cell invasiveness (P<0.0001) without affecting viability. In some clinical trials, the combined therapy of temozolomide (an alkylating agent used in glioma treatment) plus marimastat (a broad spectrum MMP inhibitor) has provided evidence of the importance of MMPs to tumor progression and invasiveness. On this basis, the effect on U87MG cells of a combined treatment with temozolomide, plus each of the two MMP inhibitors at nanomolar concentration, was investigated. The obtained data demonstrated the inhibition of cell invasiveness and viability after treatment. These results can help in developing clinical combined therapy using MMP inhibitors that, at low doses, increase the anticancer efficacy of chemotherapeutic drugs, probably without causing the side effects typical of broad-spectrum MMP inhibitors.

Translocator protein ligands as promising therapeutic tools for anxiety disorders.

The Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, is an 18 kDa mitochondrial protein primarily involved in steroid biosynthesis in both peripheral and glial cells. It has been extensively reported that TSPO regulates the rate-limiting translocation of cholesterol from the outer to the inner mitochondrial membrane before its transformation by cytochrome P450(scc) into pregnenolone, which is further converted into an array of different steroids. In the brain, neurosteroids such as allopregnanolone and pregnenolone, acting as positive modulators of gamma-aminobutyric type A (GABA(A)) receptors, exert anxiolytic activity. Specific ligands targeting TSPO increase neurosteroid production and for this reason they have been suggested to play an important role in anxiety modulation. Unlike benzodiazepines (Bzs), which represent the most common anti-anxiety drugs administered around the world, selective TSPO ligands have shown anxiolytic effects in animal models without any of the side effects associated with Bzs. Therefore, specific TSPO ligands that are able to promote neurosteroidogenesis may represent the future of therapeutic treatment of anxiety disorders. Furthermore, TSPO expression levels are altered in several different psychiatric disorders in which anxiety is the main symptom. This article reviews the primary and patent literature over the last decade concerning the development of novel TSPO ligands that have resulted effective in various models of anxiety, taking into special consideration their structure-activity relationships.

The US National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III): prevalence of the metabolic syndrome in postmenopausal Latin American women.

BACKGROUND: Metabolic syndrome (METS) is a strong predictor of cardiovascular risk. Since the prevalence of METS increases after menopause, gynecological routine consultation offers an excellent screening opportunity. OBJECTIVES: To assess the prevalence of METS in Latin American postmenopausal women and factors modifying its risk; as well as to assess the role of simple routine care measurements in the diagnosis of the METS. METHODS: A total of 3965 postmenopausal women, aged 45-64 years, seeking health care at 12 gynecological centers in major Latin American cities were included in this cross-sectional study. The US National Cholesterol Education Programme Adult Treatment Panel III (NCEP ATP III) guidelines were applied to assess METS. This was present if three or more of the following conditions were present: waist circumference > or = 88 cm; blood pressure > or = 130/85 mmHg; fasting plasma triglycerides > or = 150 mg/dl; high density lipoprotein (HDL) cholesterol < 50 mg/dl; glucose > or = 110 mg/dl or subjects were receiving treatment for their condition. RESULTS: The prevalences of having at least two, three, four or five components were 62.5, 35.1, 13.5 and 3.2%, respectively. The prevalence increased from 28.1% in those aged 40-44 years to 42.9% in those aged 60-64 years. The risk of METS detection (multivariate analysis) increased with age (odds ratio (OR) 1.22, 95% confidence interval (CI) 1.03-1.43), time elapsed since menopause (OR 1.18, 95% CI 1.00-1.38), smoking cigarettes (OR 1.40, 95% CI 1.19-1.65), obesity (OR 13.01, 95% CI 10.93-15.49) and hypertension (OR 9.30, 95% CI 7.91-10.94). In contrast, hormone therapy reduces this risk (OR 0.59, 95% CI 0.51-0.70). CONCLUSION: There is a high prevalence of the metabolic syndrome in postmenopausal Latin American women seeking gynecologic health care. Age, years since menopause, obesity and hypertension are strong predictors of this condition.

Use of clozapine in 10 mentally retarded adults.

The cost, side effect profile, and required weekly blood draws associated with clozapine may dissuade some clinicians from prescribing this atypical neuroleptic to mentally retarded patients. All publications on clozapine use in mentally retarded patients are reviewed and the treatment of 10 such patients is described, bringing the total number of published cases to 84. Clozapine is efficacious and well tolerated in this population and should be considered for those patients with psychosis or bipolar illness who are intolerant of or unresponsive to other agents.

Psychosis and pregnancy: some new ethical and legal dilemmas for the physician.

Physicians who treat women of childbearing age may encounter the presentation of psychosis in a pregnant woman that presents special problems in diagnosis and treatment, particularly ethical and legal considerations that center on the rights of the mother as well as the continually evolving definition of fetal rights. This article represents a collaborative effort to address these considerations. Representative case material from the treatment of a psychotic pregnant patient is presented with a focus on the nature of the contractual relationship of the treating physician with the mother and fetus.