Biomedical subjects

S Genedani

Publications and source records attributed to S Genedani.

At least 19 recordsLinked to original sources

PubMed2006

Intramembrane receptor-receptor interactions: a novel principle in molecular medicine.

In 1980/81 Agnati and Fuxe introduced the concept of intramembrane receptor-receptor interactions and presented the first experimental observations for their existence in crude membrane preparations. The second step was their introduction of the receptor mosaic hypothesis of the engram in 1982. The third step was their proposal that the existence of intramembrane receptor-receptor interactions made possible the integration of synaptic (WT) and extrasynaptic (VT) signals. With the discovery of the intramembrane receptor-receptor interactions with the likely formation of receptor aggregates of multiple receptors, so called receptor mosaics, the entire decoding process becomes a branched process already at the receptor level in the surface membrane. Recent developments indicate the relevance of cooperativity in intramembrane receptor-receptor interactions namely the presence of regulated cooperativity via receptor-receptor interactions in receptor mosaics (RM) built up of the same type of receptor (homo-oligomers) or of subtypes of the same receptor (RM type1). The receptor-receptor interactions will to a large extent determine the various conformational states of the receptors and their operation will be dependent on the receptor composition (stoichiometry), the spatial organization (topography) and order of receptor activation in the RM. The biochemical and functional integrative implications of the receptor-receptor interactions are outlined and long-lived heteromeric receptor complexes with frozen RM in various nerve cell systems may play an essential role in learning, memory and retrieval processes. Intramembrane receptor-receptor interactions in the brain have given rise to novel strategies for treatment of Parkinson's disease (A2A and mGluR5 receptor antagonists), schizophrenia (A2A and mGluR5 agonists) and depression (galanin receptor antagonists). The A2A/D2, A2A/D3 and A2A/mGluR5 heteromers and heteromeric complexes with their possible participation in different types of RM are described in detail, especially in the cortico-striatal glutamate synapse and its extrasynaptic components, together with a postulated existence of A2A/D4 heteromers. Finally, the impact of intramembrane receptor-receptor interactions in molecular medicine is discussed outside the brain with focus on the endocrine, the cardiovascular and the immune systems.

Animals↗

PubMed2006

Abeta peptides as one of the crucial volume transmission signals in the trophic units and their interactions with homocysteine. Physiological implications and relevance for Alzheimer's disease.

Amyloid peptides (Abeta) can operate as volume transmission (VT) signals since they are continuously released from cells of the central nervous system and diffuse in the extra-cellular space of the brain. They have both regulatory and trophic functions on cellular networks. In agreement with Abeta regulatory actions on glial-neuronal networks, the present paper reports new findings demonstrating that intrastriatal injections of Abeta peptides reduce striatal tyrosine hydroxylase, increase striatal GFAP immunoreactivities and lower pain threshold in experimental rats. Furthermore, it has been demonstrated that exogenous homocysteine (Hcy) binds Abeta(1-40) favouring its beta-sheet conformation both in vitro and in vivo and hence the formation of beta-fibrils and development of neurotoxicity. Thus, the hypothesis is discussed that Abeta peptides represent crucial VT-signals in the brain and their action is altered by dysmetabolic signals such as high Hcy extra-cellular levels, known to be an important risk factor for Alzheimer's disease.

Alzheimer Disease↗

PubMed2006

The nigrostriatal DA pathway and Parkinson's disease.

The discovery of the nigrostriatal DA system in the rat was made possible by the highly specific and sensitive histochemical fluorescence method of Falck and Hillarp in combinations with electrolytic lesions in the substantia nigra and removal of major parts of the neostriatum. Recent work on DA neuron evolution shows that in the Bottlenose Dolphin the normal DA cell groups of the substantia nigra are very cell sparse, while there is a substantial expansion of the A9 medial and A10 lateral subdivisions forming an impressive "ventral wing" in the posterior substantia nigra. The nigrostriatal DA pathway mainly operates via Volume Transmission. Thus, DA diffuses along concentration gradients in the ECF to reach target cells with high affinity DA receptors. A novel feature of the DA receptor subtypes is their physical interaction in the plasma membrane of striatal neurons forming receptor mosaics (RM) with the existence of two types of RM. The "functional decoding unit" for DA is not the single receptor, but rather the RM that may affect not only the integration of signals in the DA neurons but also their trophic conditions. In 1991 A2A receptor antagonists were indicated to represent novel antiparkinsonian drugs based on the existence of A2A/D2 receptor-receptor interactions and here P2X receptor antagonists are postulated to be neuroprotective drugs in treatment of Parkinson's Disease.

Animals↗

PubMed2006

On the existence of a global molecular network enmeshing the whole central nervous system: physiological and pathological implications.

Proteins are endowed with the "Lego property", i.e., the capability of steric fitting with other proteins to form high molecular weight complexes with emergent functions. These interactions may occur both as horizontal molecular networks at the plasma membrane level and as vertical molecular networks, i.e., towards the extra- and/or intracellular side of the cell. The present paper broadens this view by proposing the existence of three dimensional molecular networks, mainly made by proteins and carbohydrates, which might interact with each other at boundaries of compartments such as plasma membranes to form a "global molecular network" (GMN) that pervades the intra- as well as the extra-cellular environment of the entire central nervous system. The GMN is a potentially plastic structure regulated through several means. For example, its extra-cellular part is under the remodeling action of the matrix metalloproteinases. The proposal of a GMN has physiological and pathological implications. In primis, classical synaptic transmission, gap junctions and volume transmission signals by modulating GMN could importantly contribute to the "binding phenomenon", i.e. the phase synchronization of firing rates in far-located neuronal cortical groups. Secondly, alterations in protein conformation could alter the GMN organization and hence the neuronal network morphology and function. This could lead to the formation of abnormal protein aggregates such as amyloid plaques and neurofibrillary tangles, which, in turn, might affect the GMN function and/or the reciprocal interactions between its parts especially at the boundaries between compartments.

Animals↗

PubMed2004

Energy gradients for the homeostatic control of brain ECF composition and for VT signal migration: introduction of the tide hypothesis.

Animals↗

PubMed2004

Studies on homocysteine plasma levels in Alzheimer's patients. Relevance for neurodegeneration.

Homocysteine (HC) may work inter alia as a Volume Transmission signal since HC is present in the brain and cerebrospinal fluid and binds to NMDA receptors. Furthermore, in cell cultures increased HC formation increases its export. In the present study we have shown that after intravenous injection in intact animals HC penetrates the blood-brain barrier. Hence, it works as a blood-born humoral signal. Furthermore, we have studied HC plasma levels in a group of Alzheimer's (AD) patients and compared with a group of age-matched patients. It has been confirmed that a positive correlation exists between age and HC plasma levels in the control group, but not in the AD patients. These results may depend on the fact that in AD patients high HC plasma levels (possibly associated with high glycine levels and/or excessive glutamate release) have favored neurodegeneration and, once this pathological process has been triggered off, the plasma HC levels become independent of the "physiological" aging-induced increase of HC plasma levels.

Aged↗

PubMed2004

Studies on homocysteine and dehydroepiandrosterone sulphate plasma levels in Alzheimer's disease patients and in Parkinson's disease patients.

Homocysteine (HC) and dehydroepiandrosterone sulphate (DHEAS) plasma levels have been evaluated in groups of male and female patients with Parkinson's disease (PD) and in a group of female patients with Alzheimer's disease (AD) and compared with the corresponding plasma levels observed in a group of age-matched subjects. It has been confirmed that HC plasma levels are enhanced in both PD and AD patients. As far as the DHEAS plasma levels are concerned no changes have been observed in PD patients while a marked decrease has been observed in AD patients. These results support the view that while the pro-oxidant effects of HC and its agonist action at NMDA receptors can play a role in both neurodegenerative diseases, the role of DHEAS is more complex and may be an important factor only in certain neurodegenerative diseases. Thus, according to the present study DHEAS is likely to be involved in AD but not in PD.

Aged↗

PubMed2004

Energy gradients for VT-signal migration in the CNS: studies on melanocortin receptors, mitochondrial uncoupling proteins and food intake.

The present paper enlightens a new point of view on brain homeostasis and communication, namely how the brain takes advantage of different chemical-physical phenomena such as pressure waves, and temperature and concentration gradients to allow the homeostasis of the brain internal milieu as well as some forms of intercellular communications (volume transmission, VT) at an energy cost much lower than the classical synaptic transmission (the prototype of wiring transmission, WT). The possible melanocortin control of uncoupling protein 2 (UCP2) expression (hence of local brain temperature gradients) has been studied in relation to food intake in male Wistar rats. Osmotic minipumps were subcutaneously (sc) implanted in the midscapular region for intracerebroventricular (icv) infusion. The control rats received an icv infusion of 0.5 microl/h of artificial cerebrospinal fluid (ACSF), while experimental rats received either an icv infusion of 0.16 nmol/h of HS024 or of 0.16 nmol/h of adrenocorticotropin-(1-24) [ACTH-(1-24)]. The ACTH-treated group ate significantly less than the ACSF-treated group during the first three days of infusion, while, subsequently, food intake of the two groups was similar. On the other hand, the HS024-treated group ate significantly more (up to 153% of the control value) than ACSF- and ACTH-treated rats during the entire period. UCP2 mRNA analysis in arcuate nuclei of ACTH, HS024 and ACSF-treated animals showed a significant 75% decrease (p<0.05 vs saline) of the total specific mRNA level in the HS024-treated group vs ACSF-treated animals (control group), while no significant change was observed between ACTH- and ACSF-treated animals. Melanocortin antagonist HS024 via blockade of MCR4 increases food intake and via a reduction of UCP2 expression enhances the food consumption ratio. This result underlines the fact that UCP2 expression and food intake can be differentially regulated. In other words, via a peptidergic control the central nervous system (CNS) can modulate the energy stored from the amount of the food that the animal has eaten and also uncouple the thermal micro-gradients (dependent on UCP2 expression) and hence the VT-signal micro-migrations from the food intake. It should also be noticed that the control of the thermal gradients affects also the neuronal firing rate and hence the transmitter release (likely above all the release of peptides such as neuropeptide Y (NPY), melanin-concentrating hormone (MCH) and beta-endorphin, e.g., in the arcuate nucleus representing signals relevant to energy homeostasis). Thus, WT and VT are both modulated by peptidergic signals that affect thermal gradients.

Adrenocorticotropic Hormone↗

PubMed2002

Pharmacological manipulation of brain galaninergic system and sexual behavior in male mice.

RATIONALE: Available data suggest a complex role for the brain galaninergic system in male sexual behavior; however, the results so far obtained in animals with either galanin or galanin antagonists are conflicting. OBJECTIVE: To define the better influence of galanin on male sexual behavior by studying, in mice, (i) the effect of galanin and of the chimeric galanin peptide M40 on the copulatory performance, and (ii) galanin mRNA levels in hypothalamic arcuate and dorso-medial nuclei. METHODS: For the behavioral testing, only sexually sluggish male mice were used. Galanin mRNA levels were studied in both sexually potent and impotent mice by means of in situ hybridization. Standard behavioral parameters for sexual behavior were recorded or calculated. Synthetic galanin (0.05, 0.1 or 1 microg/mouse) and M40 (5 or 20 microg/mouse) were intracerebroventricularly (ICV) injected, 15 min before the copulatory test. Galanin mRNA levels were evaluated. RESULTS: In sexually sluggish male mice, both galanin (0.1 and 1 microg/mouse ICV) and M40 (20 microg/mouse ICV), significantly increased intromission frequency and ejaculation latency; M40 also improved copulatory efficacy. On the other hand, in the hypothalamic arcuate and dorso-medial nuclei, the levels of galanin mRNA were not significantly different in sexually potent and impotent male mice. CONCLUSIONS: These results show that in sexually sluggish male mice the ICV injection of either galanin or the chimeric analogue M40 greatly prolongs the duration of the copulation; without a reduction of the sexual drive or of the copulatory performance. On the other hand, the hybridization experiments seem to rule out an important physiological role of the brain galaninergic system in the regulation of male sexual behavior, at least in mice.

Animals↗

PubMed2001

Influence of SAMe on the modifications of brain polyamine levels in an animal model of depression.

The mechanism(s) of the antidepressant activity of S-adenosyl-L-methionine (SAMe) have not yet been elucidated. SAMe is essential for the synthesis of polyamines, which have a key role in protein synthesis, cell proliferation, and neuronal plasticity. On the other hand, accumulating data indicate that depression is associated with a reduction in regional brain volume and that antidepressants increase neurogenesis in defined brain regions and also influence neuronal plasticity. Here we show that in a validated rat model of depression (chronic unpredictable mild stress-induced anhedonia) there is a significant reduction of putrescine, spermidine and spermine in the hippocampus, and of only putrescine in the nucleus accumbens septi. SAMe, at a fully antidepressant dose (300 mg/kg i.m., daily for 7 days), completely restores the levels of putrescine in the nucleus accumbens, and restores in part the levels of both spermidine and spermine in the hippocampus. These results may suggest (i) a role for brain polyamines in depression and in reward processes, and (ii) that the antidepressant effect of SAMe may be due, at least in part, to a normalization of putrescine levels in the nucleus accumbens septi.

Animals↗

PubMed2001

Effectiveness of clozapine and olanzapine: a comparison in severe, psychotically ill patients.

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Adult↗

PubMed2000

Neuroprotective effect of gamma-hydroxybutyrate in transient global cerebral ischemia in the rat.

The effect of gamma-hydroxybutyrate on the histological and behavioral consequences of transient brain ischemia was studied in the four vessel occlusion rat model. In saline-treated animals, 30 min ischemia caused a massive loss of neurons in the hippocampal CA1 subfield (normal neurons: 14%, 5%, 23% and 30% on the 3rd, 10th, 15th and 65th day after ischemia, respectively). gamma-Hydroxybutyrate - 300 mg/kg intraperitoneally (i.p.) 30 min before or 10 min after arteries occlusion, followed by 100 mg/kg i.p. twice daily for the following 10 days - afforded a highly significant protection (normal neurons on the 3rd, 10th, 15th and 65th day after ischemia: 88% and 91%, 80% and 80%, 91% and 90%, 72% and 71% in rats receiving the first dose before or after arteries occlusion, respectively). The ischemia-induced sensory-motor impairment was significantly attenuated in rats receiving the first dose of gamma-hydroxybutyrate before arteries occlusion. Finally, the ischemia-induced impairment in spatial learning and memory, evaluated starting 27 days after the ischemic episode, was significantly attenuated by gamma-hydroxybutyrate, either injected first at 30 min before or 10 min after arteries occlusion. Lower doses of gamma-hydroxybutyrate had no significant effect. In conclusion, these results indicate that gamma-hydroxybutyrate provides significant protection against both histological and behavioral consequences of transient global cerebral ischemia in rats.

Animals↗

PubMed2000

Immunomodulation by recombinant human interleukin-8 and its signal transduction pathways in invertebrate hemocytes.

We report the presence of interleukin (IL)-8-immunoreactive molecules in hemocytes from the mollusc Mytilus galloprovincialis. Functional studies demonstrate that recombinant human (rh)IL-8 provokes conformational changes, induces chemotaxis, and increases bacterial phagocytic activity in hemocytes. rhIL-8 induces cell shape changes via protein kinase A and C pathways. These morphological changes are followed by reorganization of the actin microfilaments. The findings suggest that, as previously reported for other cytokines, IL-8 is well conserved and deeply involved in immune functions from invertebrates to mammals.

Animals↗

PubMed2000

[In vitro study of periodontal ligament cells].

BACKGROUND: The aim of this research is to outline a procedure able to promote specific cellular differentiation and proliferation with consequent periodontal regeneration. To achieve this goal, use was made of various compounds supposed to have the capacity of aiding periodontal regeneration. METHODS: The cells utilised for this study were obtained from explants of human periodontal ligaments. Their proliferation and differentiation capacity was examined in the presence of: coral granules (350, 500 mu), collagene type 1, growth factors (Platelet derived growth factor, PDGF and Transforming growth factor beta 1, TGF beta 1), both on their own and in different combination with one another. The differentiation activity was evaluated by ultrastructural morphological method (Transmission electron microscope-TEM) and by spectrophotometric investigation of the alkaline phosphatasis (ALP). RESULTS: The data show that the coral granules and among the growth factors used only TGF beta 1 stimulate the differentiation activity of the periodontal ligament cells valued on the basis of their capacity of producing ALP. These data are supported by the observation with TEM. CONCLUSIONS: From these results it is suggested that there may be therapeutic efficiency in the periodontal field of substances promoting cellular proliferation and differentiation.

Cell Culture Techniques↗

PubMed1999

Influence of antineoplastic drugs on morphine analgesia and on morphine tolerance.

The possible influence of cisplatin, methotrexate, adriamycin and vincristine on thermal pain threshold, morphine analgesia and development of morphine tolerance was investigated in mice. In the hot-plate test, the nociceptive threshold was not affected by acute or repeated administration of any of the antineoplastic drugs used. The analgesic activity of morphine was significantly reduced by pretreatment with cisplatin, intraperitoneally (i.p.) injected at the dose of 2 mg/kg. In contrast, methotrexate, subcutaneously (s.c.) injected at the dose of 1 and 5 mg/kg, adriamycin (1 and 3 mg/kg s.c.), vincristine (0.25 and 0.5 mg/kg i.p.) and a lower dose of cisplatin (1 mg/kg i.p.) had no effect. The development of tolerance to morphine analgesia was delayed by adriamycin but was not influenced by the other antineoplastic drugs used. These data show that, of the four antineoplastic agents used in this study, cisplatin may interfere in the mechanism of action of morphine, and that adriamycin may delay the development of opiate tolerance.

Analgesics, Opioid↗

PubMed1999

Influence of S-adenosyl-L-methionine on chronic mild stress-induced anhedonia in castrated rats.

1. S-adenosyl-L-methionine (SAMe) is the most important methyl donor in the brain and is essential for polyamine synthesis. Methyl group deficiency in the brain has been implicated in depression; on the other hand, polyamines enhance phosphorylation processes, and phosphorylation of functional proteins in neurons in involved in the therapeutic mechanisms of antidepressants. 2. The effect of SAMe in an animal model of 'depression', the chronic mild stress-induced anhedonia, was studied using long-term castrated male and female Lister hooded rats. 3. Chronic daily exposure to an unpredictable sequence of mild stressors produced, within 3 weeks, a significant reduction of the consumption of a sucrose solution. SAMe (100, 200 or 300 mg kg-1 daily i.m.) while having no influence on sucrose intake in non-stressed animals, dose-dependently reinstated sucrose consumption within the first week of treatment, both in male and in female stressed rats. Imipramine (10 mg kg-1 daily i.p.) produced a similar effect after a 3 week treatment. 4. Similarly, a palatable food reward-induced place preference conditioning was developed in SAMe (200 or 300 mg kg-1 daily i.m.)--and in imipramine (10 mg kg-1 daily i.p.)--treated chronically stressed animals (males and females), whilst it could not be obtained in vehicle-treated rats. 5. Moreover, the same doses of SAMe (but not of imipramine) restored the exploratory activity and curiosity for the environment (rearing), in the open-field test. 6. While imipramine caused a blockade of the growth throughout the treatment, SAMe produced only a transient growth arrest during the first week of treatment. 7. These results show that SAMe reverses an experimental condition of 'depression-like' behaviour in rats, the effect being more rapid and complete than that of imipramine, and without apparent side effects.

Animals↗

PubMed1999

ACTH and its role in immune-neuroendocrine functions. A comparative study.

Adrenocorticotropic hormone (ACTH) belongs to the melanocortine group of related peptides which share a common precursor, the pro-opiomelanocortin (POMC). Melanocortin expresses its functional effects by the stimulation of specific G-protein coupled receptors. To date, five receptor subtypes have been cloned. The POMC gene has been highly conserved during evolution, and ACTH has been found in different cells from invertebrates to vertebrates to vertebrates, including man. With regards the immune system, the presence of melanocortin receptors and the production of ACTH have been reported in invertebrate and vertebrate immuno-competent cells. Among its various physiological effects, ATCH has been shown to play a central role in immmune responses, such as chemotaxis and phagocytosis, in lower and higher forms of life. Moreover, ACTH is a key actor in stress response, and the complex cascade of events observed in vertebrates is reproduced and concentrated in intvertebrate immunocytes. On the basis of the present findings, ACTH should be considered an important immuno-regulator, forming part of the complex mosaic of relationships between the immune and neuroendocrine system which appears to have been substantially maintained over the course of evolution.

Adrenocorticotropic Hormone↗

PubMed1996

Blockade of the polyamine site of NMDA receptors produces antinociception and enhances the effect of morphine, in mice.

The possible effect of ifenprodil--a potent antagonist at the polyamine site of the NMDA receptor complex--on nociceptive threshold and morphine analgesia was investigated in mice. In the hot plate test, the intraperitoneal (i.p.) injection of ifenprodil significantly prolonged the reaction time of mice at the dose of 30 mg/kg, and increased the analgesic effect of morphine. In the phenylquinone writhing test, ifenprodil reduced the number of abdominal constrictions of mice starting from the dose of 2.5 mg/kg i.p., and increased the effect of morphine. The effect of ifenprodil on pain threshold was prevented by naloxone. Moreover, ifenprodil antagonized the pain threshold-reducing effect of alpha-melanocyte-stimulating hormone (0.05 microgram/mouse, intracerebroventricularly). These data show that blockade of the polyamine site of the NMDA receptor complex produces analgesia and increases the analgesic effect of morphine.

Analgesia↗