Moshe Gavish - Academia.edu (original) (raw)

Papers by Moshe Gavish

Pharmacological Reviews

Enigma of the Peripheral Benzodiazepine Receptor. ...

Psychopharmacology

This study examined the effect of the neuroactive steroid 3 alpha, 5 alpha-tetrahydrodeoxycortico... more This study examined the effect of the neuroactive steroid 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone (alpha-THDOC) as compared to the benzodiazepines diazepam and midazolam and the barbiturate phenobarbital on the number of rearing events and the number of steps ascended in the mouse staircase test. The benzodiazepines, phenobarbital and alpha-THDOC all reduced rearing activity at doses that did not affect climbing. The rearing-suppression effect of the benzodiazepines and alpha-THDOC, but not of phenobarbital, was blocked by the benzodiazepine antagonist flumazenil. It appears that, although such neuroactive steroids, like barbiturates, bind to distinct sites within the chloride ion channel of the gamma-aminobutyric acid type A (GABAA) receptor complex, alpha-THDOC behavioral activity is modulated by the benzodiazepine recognition site.

European Journal of Cancer Prevention, 2015

As redox iron and copper ions are found in lung pleural fluid and parenchyma, we aimed to examine... more As redox iron and copper ions are found in lung pleural fluid and parenchyma, we aimed to examine the effect of cigarette smoke (CS) alone and the combined effects of CS and redox metals, iron and copper ions, containing medium (saliva), on epithelial H1299 lung cancer cells. We also examined the expression levels of the anticarcinogenic and proapoptotic 18 kDa translocator protein (TSPO) and its closely associated protein voltage-dependent anion channel (VDAC). H1299 cells were subjected to western blot analysis using anti-TSPO and anti-VDAC antibodies. With the former, the 18 kDa band appeared as expected and a 72 kDa band also appeared. It may be assumed that in H1299 lung cancer cells, an additional form of TSPO protein appears as a four-unit tetrameric complex, which is affected by CS exposure. A significant decrease in the expression level of the 72 kDa protein occurred following only 60 min of CS exposure, whereas VDAC protein levels were increased following only 30 min of CS exposure. These results, together with our previous related studies, suggest a comprehensive two-arm novel paradigm for lung cancer induced by CS, and mediated by an altered TSPO protein, possibly resulting from both the 72 kDa TSPO degradation and redox metal ion-induced enhancement of free radical attack. We suggest that both of the most important proapoptotic and anticancer proteins, p53 and TSPO, are damaged by CS, paving the way for lung cancer initiation and progression.

Journal of cellular biochemistry, Jan 12, 2015

Lung cancer is prevalent in cigarette smokers. The mitochondrial membrane translocator protein (T... more Lung cancer is prevalent in cigarette smokers. The mitochondrial membrane translocator protein (TSPO), is thought to protect cells from free radical damage. We examined the effect of cigarette smoke (CS) (containing free radicals) alone and in the presence of saliva (containing redox active free iron), on survival of H1299 lung cancer cells and on their mitochondrial characteristics, and whether TSPO binding was influenced by CS and by saliva. We exposed H1299 cells to CS in the presence/absence of saliva and also characterized TSPO binding in the cells using [3H]PK 11195 as a radioligand. Cigarette smoke induced a significant drop in mitochondrial potential (ΔΨm), while addition of saliva did not lead to further loss of ΔΨm (42.5% versus 39.85%). Scatchard analysis of the saturation curve of [3H]PK 11195 binding (0.2-6 nM final concentration) yielded a straight-line plot (R= 0.9). Average Bmax value was 3274 ± 787 fmol/mg of protein, and average Kd value was 9.2 ± 1.3 nM. Benzodiaz...

The ability of a variety of detergents to solubilize peripheral benzodiazepine-binding sites from... more The ability of a variety of detergents to solubilize peripheral benzodiazepine-binding sites from rat kidney was tested. Of all the detergents tested, only digitonin was found to be suitable for solubilization. This detergent solubilized 21% of the binding activity; 47% was inactivated, and 32% remained in the pellet. Specific binding of (3H)Ro 5-4884 to membrane- bound and solubilized peripheral benzodiazepine-binding

Anti-cancer agents in medicinal chemistry, 2014

Many types of cancer, for example glioblastoma, show resistance against current anti-cancer treat... more Many types of cancer, for example glioblastoma, show resistance against current anti-cancer treatments. One reason is that they are not capable to effectively activate their intracellular cell death pathways. Novel treatments designed to overcome these deficiencies in cancer cells present promising concepts to eradicate chemotherapy-resistant cancer cells. One of these approaches includes the membrane seeking compound erucylphosphohomocholine (ErPC3) which is part of the latest generation of alkylphospholipid analogs developed over the last two-and-a-half decades. ErPC3 exerts potent antineoplastic effects in animal models and against established cancer cell lines including, for example, glioblastoma and different types of leukemia, while sparing their normal counterparts. Starting with a historical survey, we report here on the anticancer activity of ErPC3 and on ErPC3's established mechanisms of action. We cover the current knowledge on the induction of mitochondrial apoptosis...

British journal of cancer, Jan 30, 2010

Correct diagnosis of pleural effusion (PE) as either benign or malignant is crucial, although con... more Correct diagnosis of pleural effusion (PE) as either benign or malignant is crucial, although conventional cytological evaluation is of limited diagnostic accuracy, with relatively low sensitivity rates. We identified biological markers accurately detected in a simple PE examination. We analysed data from 19 patients diagnosed with lung cancer (nine adeno-Ca, five non-small-cell Ca (not specified), four squamous-cell Ca, one large-cell Ca) and 22 patients with benign inflammatory pathologies: secondary to trauma, pneumonia or TB. Pleural effusion concentrations of seven analysed biological markers were significantly lower in lung cancer patients than in benign inflammatory patients, especially in matrix metalloproteinase (MMP)-9, MMP-3 and CycD1 (lower by 65% (P<0.000003), 40% (P<0.0007) and 34% (P<0.0001), respectively), and in Ki67, ImAnOx, carbonyls and p27. High rates of sensitivity and specificity values were found for MMP-9, MMP-3 and CycD1: 80 and 100%; 87 and 73%; a...

Molecular medicine (Cambridge, Mass.), 2010

Juvenile idiopathic arthritis (JIA) is the most common autoimmune inflammatory disease in childre... more Juvenile idiopathic arthritis (JIA) is the most common autoimmune inflammatory disease in children; joint inflammation is the hallmark of the disease. Thirty-five children with JIA were studied, of whom 26 had active disease and 14 were receiving anti-TNF therapy (5 with Infliximab, 9 with Etanercept). Sixteen healthy controls also were studied. Saliva samples were obtained for analysis of anti-oxidant status, metalloproteinases (MMPs) and sialochemistry. The total antioxidant status was significantly higher in the saliva of all JIA patients, whether treated (P = 0.014) or not treated (P = 0.038) with anti-TNF agents. The increase in antioxidant status (TAS) in the saliva of the active patients was nearly two times higher than that of non-active patients (P = 0.01). MMP levels were significantly lower in JIA patients than in controls. MMP-9, MMP-3 and MMP-2 were lower in JIA patients without anti-TNF treatment by 36.7% (P = 0.01), 30.0% (P = 0.0001) and 10.7% (P = 0.0001), respectiv...

European Journal of Pharmacology: Environmental Toxicology and Pharmacology, 1995

In the present study we investigated the influence of acute lead poisoning upon the expression of... more In the present study we investigated the influence of acute lead poisoning upon the expression of benzodiazepine receptors. In addition, we examined if administration of PK 11195, an isoquinoline carboxamide derivative, to lead-poisoned rats could modulate the changes in receptor binding properties achieved by lead alone. Lead poisoning was ascertained by determination of urine delta-aminolevulinic acid levels and lead levels in rat livers. Scatchard analysis of saturation curves of [3H]PK 11195 binding to liver membranes of rats treated with lead alone or with both lead and PK 11195 showed and approximately two-fold decrease in receptor density in comparison with control groups. Peripheral benzodiazepine receptor density in kidneys and adrenals of poisoned rats was not changed by lead intoxication per se or by coadministration of PK 11195. Scatchard analysis of saturation curves of [3H]Ro 15-1788 binding in rat cerebral cortex tissue showed no difference in the receptor density between the various groups. The Kd values of all organs were in the nanomolar range (1-4 nM). We conclude that PK 11195 is not a protective agent of hepatic peripheral benzodiazepine receptors in lead intoxication. Moreover, it causes over-accumulation of lead in hepatocytes in an unknown mechanism of action.

Neurotoxicology, 1989

Mice who were exposed to phenobarbital prenatally (B mice) had at adulthood deficits in the hippo... more Mice who were exposed to phenobarbital prenatally (B mice) had at adulthood deficits in the hippocampal eight-arm maze, spontaneous alternations, and water maze behaviors. Morphological studies revealed neuronal losses in the hippocampus. The surviving neurons had reductions from control in the number of dendritic branches, area and spine density, but wider fission angle than control. Neurochemical studies on the hippocampus revealed the following alterations: (a) decrease in NE level and the number of the NE cell bodies (b) no change in the serotonergic system (c) an increase in muscarinic receptors Bmax in the hippocampus; (d) no changes in GABA and benzodiazepine receptors. However, neonatal phenobarbital exposure caused an increase in the Bmax of GABA and benzodiazepine receptors. Transplantation of fetal septal cholinergic neurons into the hippocampus of B mice reversed most of the deficits in eight-arm maze behavior, while transplantation of noradrenergic cells did not affect ...

Erucylphosphohomocholine (ErPC3), representative of a new class of antitumor agents, which target... more Erucylphosphohomocholine (ErPC3), representative of a new class of antitumor agents, which target biomembranes and induce cancer cell apoptosis, has been shown to be a promising preclinical anticancer agent. However, the precise mechanisms by which ErPC3 displays its antitumor activities are unknown. In previous studies we demonstrated that ErPC3 activates the mitochondrial apoptotic pathway via the 18 kDa Translocator Protein (TSPO), which in turn causes the MPTP to open leading to collapse of the mitochondrial membrane potential, the first stage of the mitochondrial apoptosis cascade. Cyclosporin A and oligomycin protected glioma cell lines against ErPC3-induced apoptosis.

Pharmacology, 1993

The present study was designed to investigate the effects of diazepam, a benzodiazepine (BZ) with... more The present study was designed to investigate the effects of diazepam, a benzodiazepine (BZ) with high affinity to central BZ receptors and moderate affinity to mitochondiral BZ receptors, and of Ro 5-4864 and PK 11195, ligands specific for mitochondrial BZ receptors, on cardiac function in the isolated working rat heart model. Five concentrations of these drugs (10–9–10–5 mol/l) were used,

It is known that the mitochondrial 18 kDa translocator protein (TSPO) is present in almost all pe... more It is known that the mitochondrial 18 kDa translocator protein (TSPO) is present in almost all peripheral tissues and also in glial cells in the brain. TSPO levels are typically enhanced in correlation with tumorigenesis of cancer cells including glioblastoma. Relevant for angiogenesis, TSPO is also present in almost all cells of the cardiovascular system. We studied the effect of TSPO knockdown by siRNA on various aspects of tumor growth of U118MG glioblastoma cells in two in-vivo models: a nude mouse model with intracerebral implants of U118MG glioblastoma cells and implantation of U118MG glioblastoma cells on the chorionallantoic membrane (CAM) of chicken embryos. In vitro, we further assayed the influence of TSPO on the invasive potential of U118MG cells. TSPO knockdown increased tumor growth in both in-vivo models compared with the scrambled siRNA control. Angiogenesis was also increased by TSPO knockdown as determined by a CAM assay. TSPO knockdown led to a decrease in adhesion to the proteins of the extracellular matrix, including fibronectin, collagen I, collagen IV, laminin I, and fibrinogen. TSPO knockdown also led to an enhancement in the migratory capability of U118MG cells, as determined in a modified Boyden chamber. Application of the TSPO ligand 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195) at a concentration of 25 µmol/l in the in-vitro models yielded results similar to those obtained on TSPO knockdown. We found no effects of PK 11195 on TSPO protein expression. Interestingly, at low nmol/l concentrations (around 1 nmol/l), PK 11195 enhanced adhesion to collagen I, suggesting a bimodal concentration effect of PK 11195. Intact TSPO appears to be able to counteract the invasive and angiogenic characteristics related to the aggressiveness of U118MG glioblastoma cells in vivo and in vitro.

Toxicologic Pathology, 2010

7,12-Dimethylbenz[a]anthracene (DMBA) presents a pollutant implicated in various toxicological ef... more 7,12-Dimethylbenz[a]anthracene (DMBA) presents a pollutant implicated in various toxicological effects. The aim of this experiment was to study the effects of DMBA administration on oxidative stress, histopathological signs, and 18 kDa translocator protein (TSPO) binding characteristics in rat liver. We also studied the effects of dose stoichiometry, dose frequency, and duration of protocol of DMBA administration. In this study, rats surviving eighteen weeks after DMBA exposure showed mild to moderate histopathological changes in the liver, mainly characterized by glossy appearance of hepatocytes, heterochromatic nuclei, and glycogen overload in the midzonal region of the hepatic lobe. These changes were accompanied by significant rises in oxidant levels, along with declines in nonenzymic antioxidants, indicating that DMBA induced oxidative stress in the liver. This finding correlated well with decreases in TSPO binding capacity in the liver of the rats in our study. Other studies have shown that TSPO can be affected by oxidative stress, as well as contribute to oxidative stress at mitochondrial levels. Further studies are needed to assay whether the decreases in TSPO density in the liver are part of the damaging effects caused by DMBA or a compensatory response to the oxidative stress induced by DMBA.

Psychopharmacology, 1996

ABSTRACT

Placenta, 1992

can modify placental metabolism, as evidenced by increased monooxigenases activity in cigarette s... more can modify placental metabolism, as evidenced by increased monooxigenases activity in cigarette smokers or those exposed to adverse environment at term. However, whether this occurs in the first trimester placenta is unknown. We have shown that maternal exposure to neuroleptics modifies placental hormone secretion in vitro (Hum Reprod, 1992).

Pharmacology Biochemistry and Behavior, 2002

Behavioral animal paradigms and experimental neuroendocrinological and neurochemical studies have... more Behavioral animal paradigms and experimental neuroendocrinological and neurochemical studies have shown that early environmental manipulations have profound effects on the late response to stress. The aim of the present study was to investigate the interactive effects of environmental manipulation (early handling) and experimentally induced behavioral differences on the peripheral benzodiazepine receptor (PBR) system, which is known to be involved in the response to stressors. Adult early-handled (EH) and nonhandled (NH; control) Wistar rats were placed in a two-way active avoidance/latent inhibition (LI) paradigm, and PBR densities in the adrenal glands, kidneys, and gonads were assessed. In line with previous studies, overall avoidance learning improved in the EH group, and LI was disrupted in the NH group (primarily in males). PBR densities were up-regulated in EH subjects, and more so in females than males. However, PBR densities did not correlate with any of the behavioral measures. These findings strengthen the hypothesis that differences in PBR densities between EH and NH rats are a reflection of trait rather than state, and they suggest that the PBR system is characterized by a highly stressor-specific response.

Pharmacogenetics and Genomics, 2008

The involvement of the 18-kDa translocator protein (TSPO), formerly known as the peripheral-type ... more The involvement of the 18-kDa translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, in apoptosis regulation of HT29 colorectal cancer cells was studied in-vitro. In-vivo TSPO involvement in tumor growth of HT29 cells xenografted into SCID mice was studied. Knockdown of TSPO expression in the human HT29 cell line was established by stable transfection with vectors containing the TSPO gene in the antisense direction. Successful TSPO knockdown was characterized by reduction of 20% in TSPO RNA levels, 50% in protein expression of the TSPO, and 50% in binding with the TSPO ligand, [3H]PK 11195. Subsequently, in-vitro cell viability and proliferation assays were applied. In addition, transient transfecton with short interfering RNA (siRNA) directed against human TSPO was studied in this way. Furthermore, we also grafted HT29 cells subcutaneously into the right thighs of SCID mice to examine the effects of the putative TSPO agonist, FGIN-1-27, on tumor growth in-vivo. In-vitro TSPO knockdown established by stable transfection of TSPO antisense gene resulted in HT29 clones displaying significantly lower levels of cell death as determined with trypan blue (50% less), lower apoptotic rates (28% less), and higher proliferation rates (48% more one week after seeding and 27% more two weeks after seeding). Transient transfection with anti-human TSPO siRNA resulted in similar viability and antiapoptotic effects. In-vivo, the proapoptotic TSPO ligand, FGIN-1-27 significantly reduced the growth rate of grafted tumors (40% less), in comparison with vehicle-treated mice. TSPO knockdown by genetic manipulation transforms the human HT29 cancer line to a more malignant type in-vitro. In-vivo pharmacological treatment with the putative TSPO agonist FGIN-1-27 reduces tumor growth of the HT29 cell line. These data suggest that TSPO involvement in apoptosis provides a target for anticancer treatment.