Adenylate-cyclase-dependent pituitary adrenocorticotropin secretion is defective in the inflammatory-disease-susceptible Lewis rat.

Susceptibility to arthritis in the Lewis rat is associated with a defect of the hypothalamic-pituitary-adrenal axis. We examined the pituitary corticotropes of both intact and dexamethasone-treated male and female inflammatory-disease-susceptible Lewis and inflammatory-disease-resistant Fischer rats. We determined adrenocorticotropin levels in the media from primary cultures of anterior pituitary cells of both strains.

Neuroprotective effect of insulin-like growth factor I in immortalized hypothalamic cells.

The neuroprotective action of insulin-like growth factor I (IGF-I) was tested in immortalized hypothalamic GT1-7 cells exposed to reduced glutathione depleting agents, which cause oxidative stress and cell death. The extent of cell survival was assessed by either using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide cytotoxicity assay or counting at the fluorescence microscope GT1-7 cells prelabeled with fluorescent dyes selective for viable and dead cells. Treatments with buthionine sulfoximine (500 microns), diethylmaleate (1 mM), and ethacrynic acid (200 microns) caused diffuse GT1-7 cell death (40-60%).

May there exist specific MRI findings predictive of dementia in multiple sclerosis patients?

Cognitive deficits are present in a substantial number of Multiple Sclerosis (MS) patients, particularly in those with the chronic-progressive type of the disorder. We assessed cognitive decline and its relationship with T2-weighted images on magnetic resonance imaging (MRI). We submitted a group of 26 patients with progressive MS to both MRI and a battery of neuropsychological tests.

The inhibition of peroxide formation as a possible substrate for the neuroprotective action of dihydroergocryptine.

Dihydroergocryptine is an ergot alkaloid endowed with pharmacological actions mainly related to its dopaminomimetic activity. Free radical formation and subsequent lipid peroxidation had been postulated to participate broadly to the pathogenesis of tissue injury, including the brain injury induced by hypoxia, ischemia or trauma, as well as in the physiopathology of chronic neurodegenerative diseases, such as Parkinson's disease. Here we report that dihydroergocryptine protects cultured rat cerebellar granule cells against age-dependent and glutamate-induced neurotoxicity.

The phospholipid drug glyceryl-phosphoryl-O-serine modulates pituitary adrenocorticotropin and hypothalamic corticotropin releasing hormone in vitro secretion in the aging rat.

We have investigated the effects of the novel phospholipid drug glyceryl-phosphoryl-O-serine (GPS) on pituitary ACTH and hypothalamic corticotropin releasing hormone secretion in vitro in cultures from both 2- and 24 month-old Sprague-Dawley rats. Basal levels of ACTH in primary cultures of pituitary cells from 24 month-old rats were lower than (100 +/- 12 pg/10(5) cells) in 2 month-old rats (207 +/- 18 pg/10(5) cells). Basal medium corticotropin releasing hormone levels in hypothalamic cultures were higher in 24 month-old rats (45 +/- 7 pg/well/20 min.

Anti-inflammatory activity of amylin and CGRP in different experimental models of inflammation.

The anti-inflammatory activity of amylin was studied in different models of inflammation, and compared to that of CGRP. Both peptides were active against mouse ear oedema induced by croton oil and acetic acid-induced peritonitis in the rat. CGRP was more potent than amylin in both models.

Effect of pyrrolidone carboxylate (PCA) and pyridoxine on liver metabolism during chronic ethanol intake in rats.

Rats subjected to chronic ethanol intake for a period of 28 days showed significant elevation in blood ethanol levels, a marked decrease in hepatic reduced glutathione (GSH) content and a decrease in liver tryptophan pyrrolase (TPO) activity. A daily intraperitoneal injection of a combined solution of pyrrolidone carboxylate (PCA) and vitamin B6 (pyridoxine hydrochloride) (0.3 mmoles/kg) into ethanol-treated rats resulted in the blood ethanol levels becoming significantly reduced, while the hepatic GSH content and TPO activity were markedly elevated.

A role for nitric oxide in the anti-ulcer activity of calcitonin gene-related peptide.

The anti-ulcer activity of calcitonin gene-related peptide (CGRP) was inhibited, in a dose-dependent manner, by pretreatment with NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase. Our results suggest that endogenous nitric oxide is involved in the anti-ulcer activity of CGRP.

Protective effect of the metabotropic glutamate receptor agonist, DCG-IV, against excitotoxic neuronal death.

(2S,1'R,2'R,3'R)-2-(2,3-Dicarboxycyclopropyl)glycine (DCG-IV), a potent agonist of subtypes 2 and 3 of metabotropic glutamate receptors (mGluR2 or 3), protected cultured cortical neurons against excitotoxicity induced either by a brief exposure to N-methyl-D-aspartate (NMDA) or a prolonged exposure to kainate. As a neuroprotective agent, DCG-IV was much more potent than the mixed agonists 1S,3R-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) or (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I), suggesting a neuroprotective role for mGluR2 or 3 against excitotoxic neuronal death.

Modulating effects of the synthetic thymic dipeptide pidotimod on the immune system in the aging rat.

We have investigated the in vivo and in vitro effect of pidotimod, a synthetic thymic-derived drug, on the immune response in young (2 month-old), and aging (24 month-old) Sprague-Dawley rats. We studied the effect of different doses of pidotimod on the responsiveness of both cultured peripheral blood lymphocytes and splenocytes to mitogenic stimuli, as well as on interleukin-2 production by peripheral blood lymphocytes after stimulation with interleukin-1 and phytohemagglutinin. Treatment with pidotimod in vivo as well as in vitro resulted in an increase of tritiated thymidine incorporation in both mitogen-stimulated lymphocytes and splenocytes from 24 month-old rats.

Involvement of nitric oxide in the regulation of gonadotropin-releasing hormone release from the GT1-1 neuronal cell line.

A role for nitric oxide (NO) in the regulation of hypothalamic neurohormone secretion has been suggested. The aim of the present study was to establish a direct involvement of this novel intracellular regulatory molecule in the control of GnRH release. For this purpose, the GT1-1 GnRH-secreting continuous cell line was treated with various agents that can modify the endogenous NO synthase activity or, alternatively, with substances that can liberate NO, mimicking an increased concentration of this molecule in the cell.

Chronic L-alpha-glyceryl-phosphoryl-choline increases inositol phosphate formation in brain slices and neuronal cultures.

Repeated, but not single injections of L-alpha-glyceryl-phosphorylcholine (alpha GPC) significantly increased basal [3H]inositol monophosphate (InsP) formation in hippocampal, cortical, and striatal slices of male rats. The effect was dose-dependent and was accompanied by an increased incorporation of [3H]inositol into the phospholipid fraction. Incubation of brain slices with different neurotransmitter antagonists, such as atropine, prazosin, or L-2-amino-4-phosphonobutanoate (L-AP4) did not modify the increase in [3H]InsP formation produced by alpha GPC, suggesting that the effect is not mediated by an increased availability of a specific neurotransmitter.

Effects of CGRP in different models of mouse ear inflammation.

The anti-inflammatory activity of calcitonin gene-related peptide (CGRP) has been studied in cutaneous inflammation induced by croton oil (CO), arachidonic acid (AA), tetradecanoylphorbol acetate (TPA) or cantharidin (CA). Our results show that mouse ear inflammation induced by CO, AA or TPA is decreased by topical administration of CGRP, whereas that induced by CA is not affected. The dose-response and temporal analysis of CGRP effect show that the maximal activity is present at the dose of 30 pmol/ear and when administered 30 min after the irritating agent.

Changes in cerebrospinal fluid levels of malondialdehyde and glutathione reductase activity in multiple sclerosis.

The chemical composition of human cerebrospinal fluid (CSF) is considered to reflect brain metabolism. In this study we measured malondialdehyde (MDA) levels and the activity of enzymes involved in antioxidative processes, glutathione reductase and glutathione peroxidase, in human cerebrospinal fluid of multiple-sclerosis (MS) patients and normal healthy volunteers. Our results indicated that the cerebrospinal fluid in MS showed significantly higher endogenous levels of MDA than the control, as well as a much greater resistance to in-vitro stimulation test.

Protection by dihydroergocryptine of glutamate-induced neurotoxicity.

Dihydroergocryptine is a hydrogenated ergot derivative with pharmacological actions mainly related to its dopaminomimetic activity. Here we report that dihydroergocryptine can protect cultured rat cerebellar granule cells against glutamate-induced neurotoxicity, assessing cell viability with the fluorescein diacetate-propidium iodide technique. Dihydroergocryptine antagonized both the neuronal death produced by acute exposure to a toxic glutamate concentration as well as the normal age-dependent degeneration in culture.

Characterization of metabotropic glutamate receptors negatively linked to adenylyl cyclase in brain slices.

We have characterized the pharmacological profile of activation of metabotropic glutamate receptors negatively linked to adenylyl cyclase (mGluR decreases cAMP) in brain slices. Among the putative mGluR agonists, (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD), were the most potent inhibitors of forskolin-stimulated cAMP formation in hippocampal slices, followed by ibotenate, L-2-amino-3-phosphonopropionate (AP3), quisqualate, L-glutamate and beta-N-methylamino-L-alanine (BMAA). Inhibition of forskolin-stimulated cAMP formation by DL-2-amino-4-phosphonobutanoate (AP4) was biphasic, suggesting that the drug interacts with more than one mGluR decreases cAMP subtype.

Protective effects of calcitonin gene-related peptide in different experimental models of gastric ulcers.

Intravenous administration of calcitonin gene-related peptide (CGRP) prevented in a dose-dependent manner reserpine-induced gastric mucosal damage, but failed to affect the lesions produced by ethanol administration. In pylorus-ligated rats, CGRP significantly reduced gastric volume, total acid and peptic activity output as well as ulcer formation. These protective effects of CGRP were not present when rats were pretreated with cysteamine.

Comparative effects of eel calcitonin, salmon calcitonin and [Asu1,7]eel calcitonin on hypophyseal and osteoblastic function.

Three different calcitonins: salmon calcitonin, eel calcitonin and the semi-synthetic analog [Asu1,7]eel calcitonin have been evaluated for their ability to affect phosphoinositide hydrolysis in primary cultures of anterior pituitary cells and in the osteoblast-like UMR-106 cells. In both cellular systems a repeated treatment with any form of calcitonin induced an inhibition of inositol phospholipid turnover. Eel calcitonin and its analog were always more potent than salmon calcitonin, but the efficacy of the three polypeptides was comparable.

Thymic factors influence on behavior in rodents.

We studied the effect of thymopentin, a synthetic thymic peptide, on spontaneous behavior and stress models in BALB/c mice in which a WEHI 164 clone 13 murine fibrosarcoma had been implanted, as well as in the intact Sprague-Dawley rat. In untreated animals with tumors, spontaneous behavior was significantly inhibited. Resistance to swimming in cold water was also decreased in untreated animals.

Inhibitory effects of propionyl-L-carnitine on plasma extravasation induced by irritants in rodents.

The effects of propionyl-L-carnitine (PLC) in various models of inflammation were studied in rats and mice. PLC (50-200 mg/kg i.p.

Effects of metadoxine on cellular free fatty acid levels in ethanol treated rats.

Free fatty acids (FFA) and fatty-acid ethyl esters (FAEE) were extracted from different organs of rat after ethanol administration. The results showed that ethanol treatment increased the concentration of saturated and mono-unsaturated FFA and FAEE while decreasing the poly-unsaturated fatty-acid content. Pretreatment of animals with Metadoxine one hour before ethanol administration inhibited the increased formation of saturated and mono-unsaturated FFA.

Thyrotropin releasing hormone (TRH) and its analog, RGH-2202, accelerate maturation of cerebellar neurons in vitro.

We have studied the "trophic" action of thyrotropin releasing hormone (TRH) in cultured cerebellar granule cells, a pure and homogeneous population of glutamatergic neurons. As an index of neuronal maturation, we have measured the uptake of D-[3H]aspartate (a non-metabolizable analog of glutamate) at different days of maturation in vitro (DIV). In control cultures, D-[3H]Aspartate increased linearly during maturation reaching plateau values between 7 and 9 DIV; daily addition of TRH tartrate (TRH-t) or RGH-2202 (a TRH analog) accelerated in a concentration-dependent manner the maturation profile of D-[3H]aspartate uptake.

Psychoneuroendocrinoimmunology: the basis for a novel therapeutic approach in aging.

Along with the nervous and the endocrine systems, the immune system is one of the three major integrative systems in higher organisms. Growing evidence demonstrates an intimate relationship between the immune system and the endocrine and nervous systems: The psychoneuroendocrine system can influence the immune response and thereby the capacity of the organism to cope with illness, and the immune system can have an impact on neuroendocrine function. Such cross-talk among systems is dependent upon feedback loops working to maintain homeostatic equilibrium.

Effects of CDP-choline administration on receptor-stimulated inositol phospholipid hydrolysis in brain slices and neuronal cultures.

Repeated addition of CDP-choline (100 microM, once a day since the 2nd day of maturation in culture) to corticostriatal neurons led to an increased basal hydrolysis of inositol phospholipids, as revealed by an enhanced formation of [3H]inositolmonophosphate ([3H]InsP) in the presence of 10 mM Li+. This increase was prevented by the muscarinic receptor antagonist, atropine, or by tetrodotoxin, but not by other receptor antagonists, such as L-2-amino-4-phosphonobutanoate (L-AP4), prazosin or ketanserin. The increase in inositol phospholipid hydrolysis induced by repeated addition of CDP-choline was obliterated when cultures were incubated in the presence of the muscarinic receptor agonist, carbamylcholine.