Anxiolytic properties of a 2-phenylindolglyoxylamide TSPO ligand: Stimulation of in vitro neurosteroid production affecting GABAA receptor activity.

A number of neurosteroids have been demonstrated to exert anxiolytic properties by means of a positive modulation of inhibitory GABAergic neurotransmission. The observation that neurosteroid synthesis can be pharmacologically regulated by ligands to the mitochondrial translocator protein (TSPO) has prompted the search for new, more selective TSPO ligands able to stimulate steroidogenesis with great efficacy. In the present study, the potential anxiolytic activity of a selective TSPO ligand, N,N-di-n-propyl-2-(4-methylphenyl)indol-3-ylglyoxylamide (MPIGA), was tested by means of the elevated plus maze paradigm. Moreover, the in vitro effects on synaptoneurosomal GABA(A) receptor (GABA(A)R) activity exerted by the conditioned salt medium from MPIGA-treated ADF human glial cells were investigated. MPIGA (30mg/kg) was found to affect rats' performance in the elevated plus maze test significantly, leading to an increase in both entries and time spent in the open arms. This same dose of MPIGA had no effect on rats' spontaneous exploratory activity. The conditioned salt medium from MPIGA-treated ADF cells potentiated the (36)Cl(-) uptake into cerebral cortical synaptoneurosomes. The exposure of ADF cells to MPIGA stimulated the production of pregnelonone derivatives including allopregnanolone, one of the major positive GABA(A)R allosteric modulator. In conclusion, the TSPO ligand MPIGA is a promising anxiolytic drug. The mechanism of action by which MPIGA exerts its anxiolytic activity was identified in the stimulation of endogenous neurosteroid production, which in turn determined a positive modulation of GABA(A)R activity, thus opening the way to the potential use of this TSPO ligand in anxiety and depressive disorders.

High values of alpha (CXCL10) and beta (CCL2) circulating chemokines in patients with psoriatic arthritis, in presence or absence of autoimmune thyroiditis.

The possible role of circulating alpha and beta chemokines in psoriatic arthritis is not extensively studied. The aim of the study is to evaluate serum levels of CXCL10, CXCL9 (alpha) and CCL2 (beta) chemokines in a large series of psoriatic arthritis patients, with or without autoimmune thyroid (AT) disorders, and to relate chemokines levels to the clinical phenotype of these patients. Serum levels of CXCL10 and CCL2 were measured in 37 patients with psoriatic arthritis without AT (PsA) and 28 with AT (PsA+AT), and in gender- and age-matched (1:1) controls without (control 1) or with AT (control 2). Serum CXCL10 levels were significantly higher in control 2 than in control 1 (p < 0.001) and in PsA than control 1 or 2 (p < 0.0001). PsA+AT patients have CXCL10 higher than controls 1 and 2 (p < 0.0001, for both) and than PsA (p < 0.001). By defining a high CXCL10 level as a value at least 2 SD above the mean value of the control group (>192 pg/ml), 5% of control 1, 19% of control 2, 42% of PsA and 63% of PsA+AT, had high CXCL10 (p < 0.0001; chi(2)). Serum CCL2 levels were similar in controls 1 and 2. PsA or PsA+AT patients have serum CCL2 levels significantly (p < 0.01, for both) higher than controls 1 and 2. Serum CXCL9 was not significantly different in the study groups. In conclusion, our study demonstrates higher serum levels of CXCL10 and CCL2 chemokines in patients with PsA than in controls. Serum CXCL10 (alpha chemokine) levels in psoriatic arthritis patients are significantly higher in presence of AT.

High prevalence of thyroid autoimmunity and hypothyroidism in patients with psoriatic arthritis.

OBJECTIVE: To evaluate the prevalence of thyroid disorders in a group of patients with psoriatic arthritis (PsA). METHODS: A complete thyroid investigation was carried out in 80 patients with PsA, in gender- and age-matched subjects (1:5) drawn from the general population (controls), and in 112 patients with rheumatoid arthrtitis (RA) with similar iodine intake. RESULTS: Anti-thyroid peroxidase antibodies (AbTPO), a hypoechoic thyroid, and subclinical hypothyroidism were significantly more frequent in women with PsA than in control women, and their frequency was similar to that in patients with RA (positive AbTPO titer 28%, 12%, and 31%; hypoechoic thyroid 31%, 16%, and 36%; subclinical hypothyroidism 25%, 8%, and 12%, respectively). Among men, positive AbTPO titers and a hypoechoic thyroid were found more frequently in the patients with PsA and RA than in controls (positive AbTPO titer 14%, 5%, and 2%; hypoechoic thyroid 16%, 10%, and 3%, respectively). All patients with PsA with subclinical hypothyroidism had polyarticular involvement (p

The age-related accumulation of dolichol in rat liver may correlate with expectation of life.

In order to test the hypothesis that the ageing-related alteration in membrane lipids might reflect the biological age of rodents, the levels of liver dolichol were assayed by the HPLC procedure in male ad-libitum fed (AL) Sprague-Dawley rats aged 2, 6, 12 and 24 months, and in 24-month-old rats on anti-aging food-restrictions (FR) differing in duration and in their effects on longevity. Results showed that the effects on liver dolichol of FR initiated at 2, 6 and 12 months of age, or initiated at 2 and interrupted at 18 months of age were significantly different, and reflected the differences in the effects of FR on expectation of life (the longer the expected residual lifespan the lower the content in liver dolichol). The conclusion is that assay of the quantity of dolichol in the liver tissue may be used as a marker of the biological age of the animal and therefore as an important biomarker of ageing.

Effect of increasing age on tissue dolichol levels in ad libitum fed and food-restricted rats.

In order to test the hypothesis that the ageing-related alteration in membrane lipids might reflect the biological age of rodents, we studied the effects of age in ad libitum fed (AL) and food-restricted (FR) male Sprague-Dawley rats on the levels of dolichol in different organs involved [liver (L) and kidney (K)] or not involved [brain (B), sciatic nerve (SN), heart (H), soleus (S) and extensor digitorum longus (EDL) muscles] in dolichol excretion. At the given age, tissue dolichol was extracted and assayed by HPLC procedure. Results show that the levels of dolichol were significantly different in different tissues and increased dramatically with increasing age. The anti-ageing FR regimen had significant preventive effects on dolichol accumulation in the excretory organs. The effect of FR on the liver was much bigger than that of kidney. The effect of FR retarding dolichol accumulation in the liver co-varied with the effects of FR on longevity. In conclusion, these data show that the quantity of dolichol in the hepatic tissue might be used as a marker of the biological age of the animal.

The fate of dolichol in rat cells and tissues.

Dolichol (D) levels increase dramatically in older tissue. A better understanding of the fate of cell D and exchange between tissues could be essential for understanding the mechanism of the abnormal accumulation. The fate of red blood cell D was investigated by the use of phenylhydrazine-induced hyperhaemolysis. The effect of atrophy on D tissue levels was studied in the perineal muscles of castrated rats. Influence of D transportation between tissues on the levels of D was studied by the use of age-mismatched heterotopic transplantation of D-rich-hearts from older (22 months old) donor rats in younger (3 months old) D-poor syngenic recipients. Increased red blood cell destruction by splenic macrophages did not cause accumulation but rather a significant depletion of the D content of the spleen. The shrinkage of tissues by endocrine or disuse atrophy did not affect the D content of muscle, where D concentration increased. No significant net redistribution of D was observed from the transplanted older heart to liver and tissues of younger recipients. In conclusion, phagocytosis appears to be the only process resulting in the disposal of tissue D.

The effect of carbon tetrachloride and ultraviolet radiation on dolichol levels in liver cells isolated from 3- and 24-month-old male Sprague-Dawley rats.

Dolichol (D) is a long-chain polyprenoid broadly distributed in the cell membranes, possibly endowed with a free-radical scavenging activity, whose concentration in tissues increases with increasing age. No enzyme pathway for D degradation has been discovered. In order to test the hypothesis that D might undergo a non-enzymatic free-radical mediated decomposition the effects of a xenobiotic agent (carbon tetrachloride, CCl(4)) and ultraviolet-B (UV-B) radiation on D levels were studied in liver cells isolated from male ad libitum fed Sprague-Dawley rats aged 3 or 24 months. Liver cells (90 mg/ml) were incubated in sealed flasks (6 ml cell suspension each) for 0, 5, 10 and 20 min after the addition of 25, 50 or 200 microl CCl(4) in the central well. 50 ml of a 6 mg/ml liver cell suspension were poured in a 120 cm(2) Petri dish and the sediment liver cell monolayer was exposed to UVB radiation for 0, 5, 10, 20 and 40 min. At the given time, cells were taken and D was extracted and assayed by the HPLC procedure. D levels were remarkably higher in older than in younger cells as expected ( P < 0.001). Treatment with CCl(4) and UVB caused a highly significant decrease in D ( P < 0.001) whose percentage was larger in younger than in older cells. The conclusions are that free-radicals generated either by chemical or by physical agents cause a very rapid depletion of D in liver cells, and that the effect of the free radical attack on D decomposition may be lower percentage wise in older than in younger cells, which might account at least in part for the accumulation of D in older tissues.

Dolichol: a solar filter with UV-absorbing properties which can be photoenhanced.

Dolichol, the polyisoprenoid lipid found in all eukaryotic cells and suggested to represent a biomarker of aging, is inserted into cell membranes, also in tissues exposed to light such as the skin. A general question about its physiological role is whether dolichol may play the role of a natural barrier for the noxious components of solar radiation. In order to clarify this point, we established that dolichol is a component of human sebum and we performed an " in vitro " study of the effects of UV radiation on the spectral properties of dolichol in isopropanol. Our data clearly show that, following UV irradiation, the optical absorption spectrum of dolichol undergoes remarkable modifications below 400 nm: a significant, strongly dose-dependent, increase of the optical density around 320 nm and a minor, very slightly dose-dependent, raise of the absorbance at 250 nm. On the contrary, UV irradiation causes only minor changes in HPLC profiles and the formation of photooxidative products can be considered negligible in our experimental conditions. These results suggest that dolichol can be considered an innate, unusually efficient and promising UV screen for skin protection.

Dolichol levels in younger and older rat hearts heterotopically transplanted in younger recipients.

Dolichol (D) levels increase dramatically in older tissue. An understanding of the exchangeability of D between tissues may be essential in order to understand the mechanism of the abnormal accumulation associated with aging. The question was investigated by the use of organ transplantation. D-poor hearts donated by 3-mon-old and D-rich by 22-mon-old male Lewis rats were transplanted heterotopically in 3-mon-old syngenic recipients, whose peripheral tissues and liver were poor in D. Native and transplanted hearts were taken 7 and 21 d after surgery. Native hearts of 3-mon- and 22-mon-old male Lewis rats served as control. D concentration and quantity were higher in older than in younger native hearts as expected. In the transplanted hearts, the quantity of D was unchanged, irrespective of the age of the donor and of the time of transplantation, whereas D concentration increased because of the remarkable disuse atrophy. No changes in D were observed in recipients' tissues. It is concluded that dolichol is not redistributed via circulation from the transplanted heart to the tissues and liver of the younger recipient.