1,720,966 research outputs found
Le colture organotipiche come nuovo modello per lo studio degli eventi molecolari coinvolti nel danno regionale selettivo al cervello della bilirubina.
No full textL’ittero neonatale, caratterizzato da un moderato aumento della bilirubina sierica, è una condizione comune nel 60% dei neonati. Alcuni bambini possono sviluppare elevati livelli di bilirubina per un lungo periodo, favorendo l’aumento della concentrazione della frazione di bilirubina libera (Bf) non legata all’albumina e in grado di passare la barriera emato-encefalica. Il danno al cervello può essere limitato, come nell’encefalopatia da bilirubina, o progredire fino a livelli cronici e permanenti come nel kernittero. Il danno neurologico è variabile in base alla sede colpita e può interessare il comparto motorio (cervelletto), uditivo (collicoli inferiori) e cognitivo (ippocampo). Il livello di bilirubina totale e la durata dell’iperbilirubinemia sono parametri importanti per valutare la gravità della condizione patologica. In aggiunta, anche lo stadio di sviluppo del cervello dei bambini, specialmente nei prematuri, e una riportata ma ancor non spiegata differente sensibilità alla bilirubina di differenti regioni del cervello sono parametri che possono influenzare in modo rilevanti la severità e le manifestazioni cliniche della patologia.
Per studiare il ruolo dello sviluppo e della differente sensibilità regionale del cervello, le colture organotipiche di cervello di ratto (che mantengono l’eterogeneità cellulare del tessuto, nella sua struttura e connettività 3D, ma che possono essere coltivate in vitro) sono state sviluppate e ottimizzate per lo studio della tossicità da bilirubina. Colture d’ippocampo, cervelletto, collicoli inferiore e superiore e corteccia provenienti da animali di due differenti fasi dello sviluppo post-natale (2 e 8 giorni dopo la nascita) sono state trattate con differenti concentrazioni di Bf (70, 140, 300 nM) per 24 ore. La vitalità, apoptosi, attività mitocondriale sono stati valutati per studiare la differente sensibilità delle colture. Il ruolo dello stress ossidativo, infiammazione, astrogliosi ed eccitotossicità è stato valutato per studiare i meccanismi coinvolti nel danno da bilirubina.
I risultati ottenuti mostrano differenze nella sensibilità regionale e nello stadio di sviluppo. Corteccia, e meno collicoli inferiori e ippocampo sono state le regioni più sensibili nelle colture derivate da animali di 2 giorni a partire da una Bf di 140nM. Un incremento della sensibilità alla bilirubina è stato osservato nelle stesse regioni, con ippocampo il più danneggiato, in colture di animali di 8 giorni, dove anche la concentrazione di 70 nM, considerata moderata e non tossica, è stata in grado di causare danno. Diversamente da quanto ipotizzato, il cervelletto non ha mostrato un danno significativo da bilirubina, mentre i collicoli superiori hanno confermato la loro resistenza. Il danno in ippocampo sembra essere prevalentemente causato dal rilascio di glutammato e dall’infiammazione, come confermato dai trattamenti neuroprotettivi con MgCl2 e indometacina. Una reversione del danno a livelli similari al controllo è stata tuttavia raggiunta solo esponendo le colture ad un cocktail dei tre principi farmacologici. Al contrario, la curcumina è stata il farmaco più efficace nell’inibire il danno nei collicoli inferiori. La corteccia invece non ha mostrato un meccanismo preferenziale nel danno da bilirubina, con una reversione significativa quando trattata con ciascuno dei tre farmaci.
I dati ricavati da questo lavoro hanno dimostrato una differente sensibilità regionale e nello sviluppo del cervello alla bilirubina, ed ha inoltre dimostrato la multifattorialità dei meccanismi di danno. Il lavoro ha inoltre permesso di identificare farmaci efficaci nel prevenire il danno al SNC, suggerendo la possibilità di un nuovo approccio terapeutico basato sulla protezione diretta del cervello.Moderate unconjugated hyperbilirubinemia is a common condition in the first week of postnatal life. Some neonates may develop very high levels of unconjugated bilirubin (UCB), with an increase of the unbound free fraction (Bf), able to diffuse through the blood brain barrier. The clinical manifestations range from the less severe Bilirubin-Induced Neurological Damage (BIND) to a more severe chronic kernicterus. Neurological damage is characterized by variability in location and severity of symptoms, including: motor disorders and athetosis (basal ganglia and cerebellum), auditory dysfunction (inferior colliculus), memory and learning impairment (hippocampus). Amount and duration of hyperbilirubinemia are not the only parameters that influence the severity of the damages. The neurodevelopmental age at the time of insult exposition and a still unexplained selective regional brain sensitivity, seem to play an important role in influencing the damages.
To investigate the reason(s) of this variability we developed organotypic brain cultures (OBCs), which preserve the architecture, cellular complexity and connection of the in vivo nervous tissue in an in vitro system. These characteristics allow the identification of the most sensible brain regions and CNS developmental stages to acute bilirubin toxicity. These data were used to evaluate alternative therapeutical strategies. Cortex (Ctx), Cerebellum (Cll), Hippocampus (Hip), Superior and Inferior collicula (SC, IC) OBCs from 2 (P2) and 8 (P8) days old rats, were produced and challenged with 70, 140 and 300nM Bf for 24Hrs. Membrane leakage, mitochondrial activity, apoptosis, glutamate excitotoxicity, inflammation, astrogliosis, oxidative stress were monitored. Finally anti-inflammatory, anti-oxidant and drugs inhibiting the glutamate channels, were screened for their ability to reverse the damage.
We highlighted a differential developmental and regional sensitivity to bilirubin. Immediately after the birth (P2), Ctx displayed the maximal damage, followed by Hip and IC (starting from 140 nM Bf). In OBCs reproducing a more developed CNS (P8), sensitivity was increased. Surprisingly 70 nM Bf, usually considered safe, was able to induce damage in three regions (Hip, IC and Ctx). On the contrary, cerebellum was not damaged by bilirubin during treatment of 24 hours, while superior colliculus confirmed its resistance to bilirubin as expected by literature data. The Hip damage was mostly mediated by glutamate excitotoxicity and inflammation, with oxidative stress less relevant. In agreement, MgCl2 and indomethacin were more effective than curcumin, unable reverting damage to control levels. This objective was reached by exposing the OBC to a cocktail of the aforementioned molecules. IC showed a mechanism more related to inflammation and oxidative stress, efficiently reverted by curcumin and indomethacin. On the contrary, Ctx responded well to all therapeutic approach.
Our data documented the existence of a regional and developmental differential sensitivity to bilirubin insults. Data reported suggest a complex, but somehow region-specific mechanisms of toxicity, significantly reverted by the drugs we tested. This work opens the way to a new therapeutical approach aimed in protect directly the brain
Rivastigmine as a Symptomatic Treatment for Apathy in Parkinson's Dementia Complex: New Aspects for This Riddle
Full text linkSUMMARY
Over 90% of PDD patients show at least one neuro-psychiatric symptom (NPS); in the 60-70% two or more NPS are present. Their incidence is important in terms of prognosis and severity of pathology. However, among all NPS, apathy is often the most disturbing, associated with greater caregiver’s burden. Similarly to other NPS, apathy may be due to a dysfunction of the nigro-striatal pathway, even though, not all the PD patients become apathetic, indicating that apathy should not entirely be considered a dopamine-dependent syndrome, and in fact it might also be related to acetylcholine defects. Apathy has been treated in many ways, without sure benefits; among these, Rivastigmine may present benefic properties. We present a series of 48 patients, suffering from PDD, treated with Rivastigmine, and followed-up for one year; they have been devotedly studied for apathy, even though all the other NPS disorders have been registered. Rivastigmine did not have a prolonged benefic effect on apathy, in our work, on the contrary of what had been observed in Literature, probably due to the longer follow-up of our patients
Homocysteine in neurology: From endothelium to Neurodegeneration
No full textVitamin B12 and folate are supplied via two major pathways, the conversion of homocysteine to methionine and the conversion of methyl malonyl coenzyme A to succinyl coenzyme A. Therefore, the defect in both the vitamins results in an increase in both serum homocysteine and methylmalonic acid. Hence, homocysteine, vitamin B12, and folate are closely linked together in the so-called one-carbon cycle, making vitamin B12 the necessary co-enzyme for the methyl donation from 5-methyl-tetra-hydrofolate in tetra-hydro-folate, necessary for methionine synthetase. Folate is a cofactor in one-carbon metabolism, and it promotes the remethylation of homocysteine, which can cause DNA strand breakage, oxidative stress and apoptosis. Vitamin B12 and folate are involved in nucleic acid synthesis and in the methylation reactions, and their deficit causes the inhibition of S-adenosylmethionine mediated methylation reactions, and through the related toxic effects of homocysteine, a possible direct alteration of the vascular endothelium and inhibition of N-methyl-D-Aspartate receptors take place. We discussed the possible and still controversial role of homocysteine accumulation in cerebral pathologies, starting from vascular events to neurodegeneration and to endothelium damage mechanism
Subcortical vascular damages for post radiation brain radiotherapy
Full text linkIn the last decades radiotherapy induced brain injury has become an emerging issue for physicians. Brain RT-induced injury has been classified, according to its time of onset, into acute, early delayed, and late forms. The latter is not reversible. Etiopathogenesys of brain damage after RT has been at length discussed, vascular injury and white matter pathologic changes have been described. In our study we described the neurological cognitive and behavioural disruption produced by radiotherapy in primary brain neoplasia; moreover we demonstrated that the effect of radiation on the brain has a classic time dependent course, with a severity related to total radiation dose, individual fraction size, and the volume of brain irradiated. The patients, who suffered from the consequence of RT, did show slowness of executive functions, and profound alterations of frontal functions, such as attention focusing, mentation control, analogical judgement and insight, not differently from those obtained by the patients suffering from subcortical vascular dementia. The overall result of high dose- RT might be a severely demented, bedridden patient, who “has been cured” for his primary disease, the brain tumour, but it constrains us to make serious consideration before radiation therapy onset and in order to implement new strategies to avoid this damage
Neonatal hyperbilirubinemia
No full textUnconjugated hyperbilirubinemia is a common condition in the first week of postnatal life. Low levels of bilirubin exert antioxidant effects, but some neonates may develop very high levels of unconjugated bilirubin (UCB), with an increase of the unbound free fraction (Bf), able to diffuse through the blood brain barrier.
Amount and duration of hyperbilirubinemia and the neurodevelopmental age (preterm neonates) at the time of insult exposition is supposed to influence the location of selective brain damage, as well as the severity of consequences [1]. The clinical manifestations range from the less severe Bilirubin-Induced Neurological Damage (BIND) to a more severe chronic kernicterus, while the regional selectivity of damage may elicit to motor disorders and athetosis (basal ganglia and cerebellum), auditory dysfunction (inferior colliculus), memory and learning impairment (hippocampus) [2].
To avoid neurological consequences, the Clinical Practice Guideline of the American Academy of Pediatrics recommend total bilirubin determination (TSB) on every jaundice infant, both during hospital stay and post discharge follow-up. To this goal, Bilistik [3], a new minimally invasive method for measuring TSB, may improve substantially the triage of jaundice newborns with potential risk of brain damage and kernicterus to be addressed to phototherapy. Moreover, recent studies have raised concerns about the potential toxicity of intensive phototherapy in preterm neonates, and no information about its effectiveness in quickly reducing brain bilirubin concentration are yet available [4].
Early neuronal accumulation of bilirubin in damaged regions and its brain metabolism may have a role in the marked regional differences observed in kernicterus impairment. This hypothesis is supported by the role of brain cytochrome P-450 (Cyp), known to oxidize UCB. In the brain of Gunn rats, an early upregulation of Cyp mRNAs was observed in the unaffected brain regions, cortex and superior colliculus, in contrast to the delayed and slight upregulation observed in the affected regions, inferior colliculus and cerebellum [6], where UCB alters the cell cycle inducing apoptosis [7].
Clarification of pathophysiology of UCB neurotoxicity, that continues to be an important risk among newborns worldwide, may open new perspectives for therapeutic approaches, focused in protecting directly the brain, the final target of bilirubin toxicity. To this aim the development of new research models, appear of particular relevance. Among them the organotypic brain cultures, living slices of the CSN that can be cultured in vitro and challenged with bilirubin in controlled (concentration/timing) manner, strictly modelling different histopathological aspects of neurological conditions
Evaluation of region selective bilirubin-induced brain damage as a basis for a pharmacological treatment
No full textThe neurologic manifestations of neonatal hyperbilirubinemia in the central nervous system (CNS) exhibit high variations in the severity and appearance of motor, auditory and cognitive symptoms, which is suggestive of a still unexplained selective topography of bilirubin-induced damage. By applying the organotypic brain culture (OBC: preserving in vitro the cellular complexity, connection and architecture of the in vivo brain) technique to study hyperbilirubinemia, we mapped the regional target of bilirubin-induced damage, demonstrated a multifactorial toxic action of bilirubin, and used this information to evaluate the efficacy of drugs applicable to newborns to protect the brain. OBCs from 8-day-old rat pups showed a 2-13 fold higher sensitivity to bilirubin damage than 2-day-old preparations. The hippocampus, inferior colliculus and cerebral cortex were the only brain regions affected, presenting a mixed inflammatory-oxidative mechanism. Glutamate excitotoxicity was appreciable in only the hippocampus and inferior colliculus. Single drug treatment (indomethacin, curcumin, MgCl2) significantly improved cell viability in all regions, while the combined (cocktail) administration of the three drugs almost completely prevented damage in the most affected area (hippocampus). Our data may supports an innovative (complementary to phototherapy) approach for directly protecting the newborn brain from bilirubin neurotoxicity
Thiamine and alcohol for brain pathology: super-imposing or different causative factors for brain damage?
No full textBACKGROUND:
Drinking more than the recommended limits is a worldwide emerging problem, difficult to circumscribe, and alcohol-related brain damages are an under-recognized health problem. Alcohol-cognitive disruption can be considered as transient and recoverable if the alcohol consumption is limited and occasional; if not, it can progress to the so-called Alcohol-Related Dementia (ARD), or to the Wernicke encephalopathy, or it can even induce the Korsakoff syndrome, an irreversible and long-lasting medical condition. ARD still remains poorly diagnosed and addressed, despite having increased research interest being a frustrating condition, a relatively non-progressive, or even partially reversible condition in abstinent ex-drinkers. On the contrary, Wernicke encephalopathy, with its neurological symptoms (ocular coordination imbalance and gait ataxia), is a dramatic medical condition, potentially lethal which can lead towards Korsakoff dementia. The alcohol consumption is a strong reinforcing condition of the thiamine deficit, the main biochemical determinant factor that starts the cascade of the brain irreversible damaging events.
CONCLUSION:
Our review focuses on the possible common neural pathways of this three condition, on the biochemical basis of the damages, and tries to underline the strong need of better understanding the pathogenesis of the brain lesions, including epigenetics and the nutritional aspects of the problem
Hepatitis C-related cryoglobulinemic neuropathy: Potential role of oxcarbazepine for pain control
Full text linkBackground:
Peripheral neuropathy is one most common, limiting and invalidating neurological symptom in subjects with hepatitis C virus and mixed cryoglobulinemia. Notably, the medical therapy proposed to eradicate HCV, can frequently exacerbate the painful neuropathy. Therefore, neuropathy therapies are insufficient and inadequate, and comprise immunosuppressive drugs, such as steroid or cyclosporine, intravenous immunoglobulin or plasma exchange. These have shown variable success in case reports, with a presumably temporary effect, but with major side effects.
Methods:
We assessed the effects of oxcarbazepine treatment in 67 cases of cryoglobulinemia related neuropathy, who did not respond to either steroid or Gabapentin, or Pregabalin. Oxcarbazepine was chosen based on the promising preliminary results.
Results:
Patients treated with Oxcarbazepine showed a rapid, discrete and persistent relief of polyneuropathic signs, without consistent side effects, and with a limited interaction with concomitant drugs.
Conclusions: These data favor the use of oxcarbazepine
Vitamin D, homocysteine, and folate in subcortical vascular dementia and alzheimer dementia
Full text linkDementia is a worldwide health problem which affects millions of patients; Alzheimer's disease (AD) and subcortical vascular dementia (sVAD) are the two most frequent forms of its presentation. As no definite therapeutic options have been discovered, different risk factors for cognitive impairment have been searched for potential therapies. This report focuses on the possible evidence that vitamin D deficiency and hyper-homocysteinemia can be considered as two important factors for the development or the progression of neurodegenerative or vascular pathologies. To this end, we assessed: the difference in vascular risk factors and vitamin D-OH25 levels among groups of sVAD, AD, and healthy age-matched controls; the association of folate, B12, homocysteine, and vitamin D with sVAD/AD and whether a deficiency of vitamin D and an increment in homocysteine levels may be related to neurodegenerative or vessel damages. The commonly-considered vascular risk factors were collected in 543 patients and compared with those obtained from a healthy old volunteer population. ANOVA group comparison showed that vitamin D deficiency was present in demented cases, as well as low levels of folate and high levels of homocysteine, more pronounced in sVAD cases. The statistical models we employed, with regression models built, and adjustments for biochemical, demographic and neuropsychiatric scores, confirmed the association between the three measures (folate decrease, hyperhomocysteinemia and vitamin D decrease) and dementia, more pronounced in sVAD than in AD
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