Erythropoietin: a new paradigm for neuroprotection.
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Brain Injuries↗
Biomedical subjects
Giovanni Grasso
Publications and source records attributed to Giovanni Grasso.
Amelioration of spinal cord compressive injury by pharmacological preconditioning with erythropoietin and a nonerythropoietic erythropoietin derivative.
OBJECT: Spinal cord injury (SCI) is a devastating clinical syndrome for which no truly efficacious therapy has yet been identified. In preclinical studies, erythropoietin (EPO) and its nonerythropoietic derivatives asialoEPO and carbamylated EPO have markedly improved functional outcome when administered after compressive SCI. However, an optimum treatment paradigm is currently unknown. Because the uninjured spinal cord expresses a high density of EPO receptor (EPOR) in the basal state, signaling through these existing receptors in advance of injury (pharmacological preconditioning) might confer neuroprotection and therefore be potentially useful in situations of anticipated damage. METHODS: The authors compared asialoEPO, a molecule that binds to the EPOR with high affinity but with a brief serum half-life (t1/2 < 2 minutes), to EPO to determine whether a single dose (10 microg/kg of body weight) administered by intravenous injection 24 hours before 1 minute of spinal cord compression provides benefit as determined by a 6-week assessment of neurological outcome and by histopathological analysis. Rats pretreated with asialoEPO or EPO and then subjected to a compressive injury exhibited improved motor function over 42 days, compared with animals treated with saline solution. However, pretreatment efficacy was substantially poorer than efficacy of treatment initiated at the time of injury. Serum samples drawn immediately before compression confirmed that no detectable asialoEPO remained within the systemic circulation. Western blot and immunohistochemical analyses performed using uninjured spinal cord 24 hours after a dose of asialoEPO exhibited a marked increase in glial fibrillary acidic protein, suggesting a glial response to EPO administration. CONCLUSIONS: These results demonstrate that EPO and its analog do not need to be present at the time of injury to provide tissue protection and that tissue protection is markedly effective when either agent is administered immediately after injury. Furthermore, the findings suggest that asialoEPO is a useful reagent with which to study the dynamics of EPO-mediated neuroprotection. In addition, the findings support the concept of using a nonerythropoietic EPO derivative to provide tissue protection without activating the undesirable effects of EPO.
Analysis of Variance↗
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↗
Brain dysfunction in uremia: a question of cortical hyperexcitability?
OBJECTIVE: To investigate whether patients with end-stage renal disease (ESRD) in different stages of the disease and undergoing different treatments display alterations in cortical excitability. METHOD: A total of 36 patients with ESRD were evaluated at different stages of the disease and under different treatment by using standard transcranial magnetic stimulation (TMS) parameters. Moreover patients under haemodialysis underwent a double-blind crossover study (mannitol vs placebo) in order to better elucidate the pathophysiology of the acute effects of haemodialysis on cortical excitability. RESULTS: Patients with ESRD in conservative therapy showed a significant reduction of short-interval intra-cortical inhibition (SICI). This alteration could be reversed by haemodialysis, peritoneal dialysis and by renal transplantation. After haemodialysis there was a significant increase of intra-cortical facilitation (ICF) inversely correlated with the drop in plasma osmolarity induced by the dialytic procedure. Mannitol infusion prevented the drop in plasma osmolarity and the haemodialysis-related changes in ICF. CONCLUSIONS: ESRD patients showed alterations in cortical excitability that can be reversed by replacement therapies. We propose that the drop in plasma osmolarity is a key to the mechanism underlying post-haemodialysis cortical hyperexcitability. SIGNIFICANCE: The results of this study give further insight to the pathophysiology of brain abnormalities in patients with chronic renal failure.
Brain Diseases, Metabolic↗
Landmarks for vertebral artery repositioning in bulbar compression syndrome: anatomic and microsurgical nuances.
OBJECTIVE: The purpose of this study was to better elucidate the anatomic relationship between the vertebral artery (VA) along with its perforating vessels and the brainstem to develop anatomic guidelines that would be helpful when decompressing medulla oblongata compressed by the VA. METHODS: Microanatomy dissection was performed in six formalin-fixed cadaveric heads. The VA, posteroinferior cerebellar artery (PICA), anteroinferior cerebellar artery (AICA), and lower brainstem perforators were examined under magnification using a surgical microscope. The outer diameters of the VA, PICA, and AICA were measured. The distance between the VA, lying within the lateral cerebellomedullary cistern, and the medulla oblongata was quantified. The lower brainstem perforating vessels were examined in relation to their course, outer diameter, and length. RESULTS: In four of six brains, the left VA was dominant, presenting an outer diameter at least 0.8 mm larger than the contralateral VA. The average distance between the VA and the medulla oblongata was 3 mm. The perforating branches presented a mean outer diameter of 0.7 mm. In particular, perforators arising from the VA and PICA (Groups 1 and 2) presented an average outer diameter of 0.2 mm and an average length of 7 mm. Perforating vessels arising from the AICA and vertebrobasilar junction (Groups 3 and 4) presented an average outer diameter of 0.4 mm and an average length of 12 mm. CONCLUSION: This work provides new information that may be useful to minimize the risk of injury of perforators when operating on medulla oblongata compression by the VA.
Brain Stem↗
Erythropoietin and erythropoietin receptor expression after experimental spinal cord injury encourages therapy by exogenous erythropoietin.
OBJECTIVE: Erythropoietin (EPO) is a pleiotropic cytokine originally identified for its role in erythropoiesis. Recent studies have demonstrated that EPO and its receptor (EPO-R) are expressed in the central nervous system, where EPO exerts neuroprotective functions. Because the expression of the EPO and EPO-R network is poorly investigated in the central nervous system, the aim of the present study was to investigate whether the resident EPO and EPO-R network is activated in the injured nervous system. METHODS: A well-standardized model of compressive spinal cord injury in rats was used. EPO and EPO-R expression was determined by immunohistochemical analysis at 8 hours and at 2, 8, and 14 days in the spinal cord of injured and noninjured rats. RESULTS: In noninjured spinal cord, weak immunohistochemical expression of EPO and EPO-R was observed in neuronal and glial cells as well as in endothelial and ependymal cells. In injured rats, a marked increase of expression of EPO and EPO-R was observed in neurons, vascular endothelium, and glial cells at 8 hours after injury, peaking at 8 days, after which it gradually decreased. Two weeks after injury, EPO immunoreactivity was scarcely detected in neurons, whereas glial cells and vascular endothelium expressed strong EPO-R immunoreactivity. CONCLUSION: These observations suggest that the local EPO and EPO-R system is markedly engaged in the early stages after nervous tissue injury. The reduction in EPO immunoexpression and the increase in EPO-R staining strongly support the possible usefulness of a therapeutic approach based on exogenous EPO administration.
Aneurysm↗
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↗
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↗
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↗
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↗
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↗
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↗
Editorial comment--Age-dependent brain AVM characteristics: what is the evidence?
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Age Distribution↗
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↗
Erythropoiesis and neuroprotection: two sides of the same coin?
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Brain Ischemia↗
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↗
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↗
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↗