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Biomedical subjects

Giovanni Grasso

Publications and source records attributed to Giovanni Grasso.

17 recordsLinked to original sources
PubMed2005

Brain and cancer: the protective role of erythropoietin.

Erythropoietin (Epo) is a pleiotropic agent, that is to say, it can act on several cell types in different ways. An independent system Epo/Epo receptor (EpoR) was detected in brain, leading to the hypothesis that this hormone could be involved in cerebral functions. Epo/EpoR expression changes during ontogenesis, thus indicating the importance of this system in neurodevelopment. Moreover, the hypoxia-induced production of Epo in the adult brain suggests that it could exert a neurotrophic and neuroprotective effect in case of brain injury. Epo could also influence neurotransmission, inducing neurotransmitters (NT) release. Epo therapy in anemic cancer patients is still a controversial issue, because of its possible action as a growth and an angiogenic factor. In our speculative hypothesis Epo could be involved in a "two steps process" that, after a neovascularization phase, leads to its down regulation. Moreover, Epo-activated signaling pathways could be modulated as possible targets to interfere in neoplastic cells cycle. In conclusion, treatment with rHuEpo could change therapeutical perspectives in different pathological conditions, such as central nervous system (CNS) diseases, but further studies are needed to clarify its physiopathological activities in different clinical fields.

Animals↗
PubMed2004

Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroreceptor.

The cytokine erythropoietin (Epo) is tissue-protective in preclinical models of ischemic, traumatic, toxic, and inflammatory injuries. We have recently characterized Epo derivatives that do not bind to the Epo receptor (EpoR) yet are tissue-protective. For example, carbamylated Epo (CEpo) does not stimulate erythropoiesis, yet it prevents tissue injury in a wide variety of in vivo and in vitro models. These observations suggest that another receptor is responsible for the tissue-protective actions of Epo. Notably, prior investigation suggests that EpoR physically interacts with the common beta receptor (betacR), the signal-transducing subunit shared by the granulocyte-macrophage colony stimulating factor, and the IL-3 and IL-5 receptors. However, because betacR knockout mice exhibit normal erythrocyte maturation, betacR is not required for erythropoiesis. We hypothesized that betacR in combination with the EpoR expressed by nonhematopoietic cells constitutes a tissue-protective receptor. In support of this hypothesis, membrane proteins prepared from rat brain, heart, liver, or kidney were greatly enriched in EpoR after passage over either Epo or CEpo columns but covalently bound in a complex with betacR. Further, antibodies against EpoR coimmunoprecipitated betacR from membranes prepared from neuronal-like P-19 cells that respond to Epo-induced tissue protection. Immunocytochemical studies of spinal cord neurons and cardiomyocytes protected by Epo demonstrated cellular colocalization of Epo betacR and EpoR. Finally, as predicted by the hypothesis, neither Epo nor CEpo was active in cardiomyocyte or spinal cord injury models performed in the betacR knockout mouse. These data support the concept that EpoR and betacR comprise a tissue-protective heteroreceptor.

Animals↗
PubMed2004

Derivatives of erythropoietin that are tissue protective but not erythropoietic.

Erythropoietin (EPO) is both hematopoietic and tissue protective, putatively through interaction with different receptors. We generated receptor subtype-selective ligands allowing the separation of EPO's bioactivities at the cellular level and in animals. Carbamylated EPO (CEPO) or certain EPO mutants did not bind to the classical EPO receptor (EPOR) and did not show any hematopoietic activity in human cell signaling assays or upon chronic dosing in different animal species. Nevertheless, CEPO and various nonhematopoietic mutants were cytoprotective in vitro and conferred neuroprotection against stroke, spinal cord compression, diabetic neuropathy, and experimental autoimmune encephalomyelitis at a potency and efficacy comparable to EPO.

Animals↗
PubMed2004

An overview of new pharmacological treatments for cerebrovascular dysfunction after experimental subarachnoid hemorrhage.

Cerebral vasospasm and the resulting cerebral ischemia occurring after subarachnoid hemorrhage (SAH) are still responsible for the considerable morbidity and mortality in patients affected by cerebral aneurysms. Mechanisms contributing to the development of vasospasm, abnormal reactivity of cerebral arteries and cerebral ischemia after SAH have been intensively investigated in recent years. It has been suggested that the pathogenesis of vasospasm is related to a number of pathological processes, including endothelial damage, smooth muscle cell contraction resulting from spasmogenic substances generated during lyses of subarachnoid blood clots, changes in vascular responsiveness and inflammatory or immunological reactions of the vascular wall. A great deal of experimental and clinical research has been conducted in an effort to find ways to prevent these complications. However, to date, the main therapeutic interventions remain elusive and are limited to the manipulation of systemic blood pressure, alteration of blood volume or viscosity, and control of arterial dioxide tension. Even though no single pharmacological agent or treatment protocol has been identified which could prevent or reverse these deadly complications, a number of promising drugs have been investigated. Among these is the hormone erythropoietin (EPO), the main regulator of erythropoiesis. It has recently been found that EPO produces a neuroprotective action during experimental SAH when its recombinant form (rHuEPO) is systemically administered. This topic review collects the relevant literature on the main investigative therapies for cerebrovascular dysfunction after aneurysmal SAH. In addition, it points out rHuEPO, which may hold promise in future clinical trials to prevent the occurrence of vasospasm and cerebral ischemia after SAH.

Animals↗
PubMed2004

Estrogen and mu-opioid receptor antagonists counteract the 17 beta-estradiol-induced licking increase and interferon-gamma reduction occurring during the formalin test in male rats.

Women have a higher incidence of chronic pain syndromes than men and are generally more sensitive to experimental pain. Numerous studies have shown that the female gonadal hormones, estrogens, can profoundly affect the nervous and immune systems, including mechanisms involved in pain and nociception. In the present study, we used antagonists of estrogen receptors (ER) or mu-opioid receptors (mu OR) to evaluate the effects of estrogens on formalin-induced behavioural and immune responses in male rats. After two days of priming with 17 beta-estradiol or saline (i.c.v.), animals were subjected to the formalin test; 15 min prior to formalin (50 microl, 5%) or sham injection in the hind paw, animals were treated with an ER antagonist (ICI 182,780, ICI) or a mu OR antagonist (beta-funaltrexamine, FNA) or saline. The spontaneous behaviours, pain-related behaviours and interferon-gamma (IFN-gamma) production by peripheral blood mononuclear cells were studied in all groups. We found that central administration of estradiol increased the amount of licking of the formalin-injected paw in the second phase of the formalin test. Whereas ICI and FNA had no effect on pain behaviour in saline-pre-treated animals, both antagonists reversed the estradiol-induced increase in licking. The immune system was differently affected by formalin and estradiol treatment. Indeed, formalin injection per se decreased IFN-gamma production; estradiol had no effect on sham-injected animals but strongly reduce the decrease of IFN-gamma production in formalin-injected animals. The results demonstrate that centrally acting estrogens affect ER- and mu OR-mediated pain processing and influence immune function.

Animals↗
PubMed2004

Erythropoietin as a tissue-protective cytokine in brain injury: what do we know and where do we go?

In the 10 years since neurotrophic activity was first reported for erythropoietin (EPO), a broad understanding of its multiple paracrine/autocrine functions has emerged. Recent studies firmly establish EPO as a multifunctional molecule, typical of the pliotrophic cytokine superfamily of which it is a member. The realization that EPO activates neuroprotection by multiple mechanisms has identified a generalized system of local tissue protection with EPO as a critical component. Here, the authors characterize the biology of the local tissue-protective system, review data that support this concept, and suggest why non-hematopoietic analogues of EPO may be better choices as therapeutics.

Animals↗
PubMed2004

A new computed-assisted technique for experimental sciatic nerve function analysis.

BACKGROUND: Peripheral nerve injury is a well-known experimental tool to evaluate the effect of various neurotrophic substances. Besides histological and electrophysiological techniques, nerve functional status has been assessed by means of the sciatic function index (SFI) and the static sciatic index (SSI). However, these techniques are still based on a complex and old-fashioned apparatus requiring a relatively long time of execution. This study aimed to assess a novel, rapid, computerized method for assessment of SSI in a rat model of sciatic nerve injury. MATERIAL/METHODS: Fourteen rats were used in this study. The left sciatic nerve was exposed and compressed for 2 minutes with an aneurysm clip. Functional evaluation was performed by analysing the footprints of standing rats, comparing the injured to the uninjured limb with the static sciatic index (SSI). For this purpose the rats were placed on a digital scanner and the resulting images were acquired on a personal computer. Analysis was carried out every day after surgery for 21 consecutive days. RESULTS: Two-minute compression of the sciatic nerve produced a major reduction in motor function as assessed by SSI. Improvement was observed by day 7. By day 20, SSI was completely restored. CONCLUSIONS: This technique is simple to use, quick, without expensive technical equipment. It provides good accuracy and precise quantification of the extent of functional loss and recovery after sciatic nerve injury.

Animals↗
PubMed2003

Asialoerythropoietin is a nonerythropoietic cytokine with broad neuroprotective activity in vivo.

Erythropoietin (EPO) is a tissue-protective cytokine preventing vascular spasm, apoptosis, and inflammatory responses. Although best known for its role in hematopoietic lineages, EPO also affects other tissues, including those of the nervous system. Enthusiasm for recombinant human erythropoietin (rhEPO) as a potential neuroprotective therapeutic must be tempered, however, by the knowledge it also enlarges circulating red cell mass and increases platelet aggregability. Here we examined whether erythropoietic and tissue-protective activities of rhEPO might be dissociated by a variation of the molecule. We demonstrate that asialoerythropoietin (asialoEPO), generated by total enzymatic desialylation of rhEPO, possesses a very short plasma half-life and is fully neuroprotective. In marked contrast with rhEPO, this molecule at doses and frequencies at which rhEPO exhibited erythropoiesis, did not increase the hematocrit of mice or rats. AsialoEPO appeared promptly within the cerebrospinal fluid after i.v. administration; intravenously administered radioiodine-labeled asialoEPO bound to neurons within the hippocampus and cortex in a pattern corresponding to the distribution of the EPO receptor. Most importantly, asialoEPO exhibits a broad spectrum of neuroprotective activities, as demonstrated in models of cerebral ischemia, spinal cord compression, and sciatic nerve crush. These data suggest that nonerythropoietic variants of rhEPO can cross the blood-brain barrier and provide neuroprotection.

Animals↗
PubMed2003

Prepro-endothelin-1 mRNA and its mature peptide in human appendix.

Because the precise immunopathological events occurring in appendicitis are not completely understood, possible local production of endothelin-1 (ET-1) in human appendix was investigated. We used immunohistochemistry and in situ hybridization to detect the presence, distribution, and phenotype of ET-1-positive cells and prepro-ET-1 (pp-ET-1) mRNA-expressing cells. ET-1-positive stromal cells and pp-ET-1 mRNA-expressing cells were detected with different distributions and relative frequencies in normal control appendix, histologically normal appendix, and inflamed appendix. Six of 20 histologically normal appendixes from patients with a clinical diagnosis of acute appendicitis had many ET-1-positive stromal cells and high pp-ET-1 mRNA expression, similar to inflamed appendix. Forty percent of the pp-ET-1 mRNA-expressing cells were neutrophils, and the other positive cells were mast cells and macrophages. We suggest that local production of ET-1 by neutrophils and other inflammatory cells could be a molecular sign of focal inflammation in histologically normal appendixes and that ET-1 could be implicated, with other cytokines, in the pathogenesis of appendicitis by inducing appendiceal ischemia through vasoconstriction.

Appendicitis↗
PubMed2003

Cerebellar hematoma in a patient with Marfan syndrome.

BACKGROUND: Marfan syndrome is a connective tissue disorder affecting many structures, including the skeleton, lungs, eyes, heart and blood vessels. It is an autosomal dominant inherited disorder due to a mutation of a gene encoding fibrillin-1, which affects connective tissue. Few case reports have associated Marfan syndrome with vascular malformations of the brain and spinal cord. In this regard, association with intracranial aneurysm has been vaguely proposed. CASE REPORT: We report here a patient with Marfan syndrome who was admitted because of a sudden loss of consciousness. The patient underwent computed tomography (CT) examination, which disclosed a right intracerebellar hematoma. Cerebral angiogram did not demonstrate aneurysm or arteriovenous malformation (AVM), or evidence of any other vascular lesions or neoplasms in the posterior fossa. Conservative treatment was undertaken. The clinical course was uneventful and after 6 weeks the patient was discharged free of symptoms. CONCLUSIONS: Although patients with Marfan syndrome are at high risk of vascular abnormalities, a clear association with cerebral aneurysm has not yet been established. Our experience and the contrasting reports available in the medical literature strongly warrant further studies in order to better clarify this controversial association.

Adult↗
PubMed2002

Beneficial effects of systemic administration of recombinant human erythropoietin in rabbits subjected to subarachnoid hemorrhage.

Cerebral vasospasm and ischemic damage are important causes of mortality and morbidity in patients affected by aneurysmal subarachnoid hemorrhage (SAH). Recently, i.p. administration of recombinant human erythropoietin (r-Hu-EPO) has been shown to exert a neuroprotective effect during experimental SAH. The present study was conducted to evaluate further the effect of r-Hu-EPO administration after SAH in rabbits on neurological outcome, degree of basilar artery spasm, and magnitude of neuronal ischemic damage. Experimental animals were divided into six groups: group 1 (n = 8), control; group 2 (n = 8), control plus placebo; group 3 (n = 8), control plus r-Hu-EPO; group 4 (n = 8), SAH; group 5 (n = 8), SAH plus placebo; group 6 (n = 8), SAH plus r-Hu-EPO. r-Hu-EPO, at a dose of 1,000 units/kg, and placebo were injected i.p. starting 5 min after inducing SAH and followed by clinical and pathological assessment 72 h later. Systemic administration of r-Hu-EPO produced significant increases in cerebrospinal fluid EPO concentrations (P < 0.001), and reduced vasoconstriction of the basilar artery (P < 0.05), ischemic neuronal damage (P < 0.001), and subsequent neurological deterioration (P < 0.05). These observations suggest that r-Hu-EPO may provide an effective treatment to reduce the post-SAH morbidity.

Animals↗
PubMed2002

Erythropoietin prevents cognition impairment induced by transient brain ischemia in gerbils.

Erythropoietin has recently been studied for its role in the central nervous system (CNS). It has been shown to exert neuroprotective effects in different models of brain injury. We studied whether neuroprotective effects assessed from the reduction of neuronal loss after transient brain ischemia are associated to the preservation of learning ability. Recombinant human erythropoietin (0.5-25 U) was injected in the lateral cerebral ventricle of gerbils that are subjected to temporary (3 min) bilateral carotid occlusion. Post-ischemic histological evaluation of CA1 area neuronal loss and passive avoidance test were performed. Treatment with recombinant human erythropoietin significantly reduced delayed neuronal death in the CA1 area of the hippocampus and prevented cognition impairment in the passive avoidance test. These data indicate that recombinant human erythropoietin neuroprotective effects in brain ischemia are associated with the preservation of learning function.

Animals↗
PubMed2002

Assessment of human brain water content by cerebral bioelectrical impedance analysis: a new technique and its application to cerebral pathological conditions.

OBJECTIVE: Total brain water content changes in several cerebral pathological conditions and the measurement of brain water content are important for the selection of appropriate therapeutic procedures. We present a quantitative, in vivo, bioelectrical impedance analysis (BIA) method and propose its use for the accurate assessment of brain water content among human subjects. METHODS: Cerebral BIA is based on the conduction of an applied current in the brain parenchyma. Application of an excitatory current of 800 microA at 50 kHz, via two electrodes placed on the eyelids with the eyes closed, and detection of the voltage drop with two electrodes placed in the suboccipital region allow brain resistance and reactance to be measured. By means of an equation that considers cranial circumference and resistance, it is possible to quantify the total brain water content, expressed as the bioelectrical volume. Cerebral BIA was performed with a series of healthy volunteers (n = 100), for determination of average brain water content values. The method was then applied to 50 patients with brain tumors (n = 20), intracranial hemorrhage (n = 16), or hydrocephalus (n = 14), for assessment of changes in global brain water contents. Data were compared with those obtained for healthy volunteers. RESULTS: Statistically significant differences (P < 0.001) were observed between the two groups. Mean brain water content values (expressed as bioelectrical volume values) were 38.2 +/- 3.9 cm2/Omega for healthy volunteers and 67.7 +/- 13.1 cm2/Omega for patients with cerebral pathological conditions. Statistically significant differences (P < 0.05) were also observed among patients with cerebral pathological conditions. CONCLUSION: The results of this study suggest that BIA, applied to the cerebral parenchyma, is a valid method for the prediction of brain water contents under both normal and pathological conditions. However, further studies are needed to establish whether it is sensitive and reliable enough for future clinical applications.

Adolescent↗
PubMed2002

Does administration of recombinant human erythropoietin attenuate the increase of S-100 protein observed in cerebrospinal fluid after experimental subarachnoid hemorrhage?

OBJECT: Results of recent studies indicate that erythropoietin (EPO) produces a neuroprotective effect on experimental subarachnoid hemorrhage (SAH). It has been reported that S-100 protein levels increase in cerebrospinal fluid (CSF) after SAH, providing a highly prognostic indication of unfavorable outcome. This study was conducted to validate further the findings of S-100 protein as an index of brain damage and to assess whether treatment with recombinant human EPO (rhEPO) would limit the increase of S-100 protein level in CSF following experimental SAH. METHODS: Thirty-two rabbits were each assigned to one of four groups: Group 1, control; Group 2, SAH; Group 3, SAH plus placebo; and Group 4, SAH plus rhEPO (each group consisted of eight rabbits). The rhEPO and placebo were administered to the rabbits after SAH had been induced, and S-100 protein levels in the CSF of these animals were measured at 24, 48, and 72 hours after the experimental procedure. In each group of animals levels of S-100 protein were compared with the mortality rate, neurological outcome, and neuronal ischemic damage. High S-100 protein levels were found in rabbits in Groups 2 and 3, which exhibited poor neurological status and harbored a high number of damaged cortical neurons. Favorable neurological outcome and significant reductions in total numbers of damaged neurons were observed in animals in Group 4 in which there were significantly lower S-100 protein concentrations compared with animals in Groups 2 and 3 (p < 0.001). CONCLUSIONS: The results of this study support the concept that determination of the S-100 protein level in CSF has prognostic value after SAH. The findings also confirm that rhEPO acts as a neuroprotective agent during experimental SAH.

Animals↗
PubMedDate not supplied

Recombinant human erythropoietin (rHuEPO): more than just the correction of uremic anemia.

Hematopoiesis is controlled by numerous interdependent humoral and endocrine factors. Erythropoietin (EPO), a hydrophobic sialoglycoproteic hormone, plays a crucial role in the regulation of hematopoiesis, and induces proliferation, maturation and differentiation of the erythroid cell line precursors. Thanks to recombinant DNA techniques, different recombinant hormones can now be produced at low cost and in large amounts. This has led to greater understanding of the pathophysiological factors regulating hematopoiesis. This in turn, hasprompted the search for new therapeutic approaches. EPO might also be used to treat patients with different types of anemia: uremics, newborns, patients with anemia from cancer or myeloproliferative disease, thalassemia, bone marrow transplants, chronic infectious diseases. Besides erythroid cells, EPO affects other blood cell lines, such as myeloid cells, lymphocytes and megakaryocytes. It can also enhance polymorphonuclear cell phagocytosis and reduce macrophage activation, thus modulating the inflammatory process. Hematopoietic and endothelial cells probably have the same origin, and the discovery of eyrthropoietin receptors also on mesangial, myocardial and smooth muscle cells has prompted research into the non-erythropoietic function of the hormone. EPO has an important, direct, hemodynamic and vasoactive effect, which does not depend only on an increase in hematocrit and viscosity. Moreover, EPO and its receptors have been found in the brain, suggesting a role in preventing neuronal death. Finally, the recently discovered interaction between EPO and vascular endothelial growth factor (VEGF), and the ability of EPO to stimulate endothelial cell mitosis and motility may be of importance in neovascularization and wound healing.

Anemia↗