Papel do receptor B2 de cininas na terapia da neurodegeneração dopaminérgica em modelo animal / Targeting Kinin-B2 receptors for the treatment of dopaminergic neurodegeneration in an animal mode

A Doença de Parkinson (DP) é um distúrbio neurodegenerativo, caracterizada em parte pela perda de neurônios dopaminérgicos da via nigroestriatal, originada na substância negra com projeções para o estriado, causando vários déficits motores. Atualmente, o tratamento mais utilizado é a administração de L-DOPA, um análogo da dopamina. Porém, essa droga apresenta eficácia limitada e induz diversos efeitos colaterais. A exploração dos efeitos neuroprotetores, proliferativos e neuroregenerativos da bradicinina (BK) em modelo animal de DP pode conduzir à substituição celular do tecido lesionado pela 6-hidroxidopamina (6-OHDA). De fato, a BK e seus receptores possuem um grande espectro de ações fisiológicas, estando classicamente envolvida no controle da homeostase cardiovascular e inflamação, além de exercer efeitos protetores em fisiopatologias do sistema nervoso, como em modelos de acidente vascular cerebral. Vários tipos celulares têm suas vias de sinalização associadas à ativação do receptor B2 de cininas (B2BKR). Trabalhos anteriores de nosso grupo mostraram que a BK está envolvida na diferenciação neural de células progenitoras neurais por um loop autócrino que resulta em ativação do B2BKR. Os resultados apresentados neste trabalho mostram a eficácia do tratamento com BK, um agonista de B2BKR, em animais submetidos à lesão da via nigro-estriatal induzida por 6-OHDA. Além disso, há uma recuperação comportamental e histológica desses animais quando tratados com Captopril®, um potencializador dos efeitos farmacológicos da BK, e com [Phe8Ψ(CH-NH)Arg9]-Bradicinina, agonista estável do receptor B2BKR. Assim, concluímos que a ativação de B2BKR pela BK desencadeiaum processo de neuroregeneração dopaminérgica de animais submetidos à lesão por 6-OHDA. Trabalhos recentes mostram que o receptor B2BKR desempenha um importante papel neuroprotetor em modelo animal da Doença de Alzheimer, o que corrobora nossos achados. Juntos, esses resultados contribuem para o estabelecimento da ação neuroprotetora e neurorregenerativa da BK no modelo de animal de neurodegeneração dopaminérgica, tornando-a uma excelente candidata para aplicação em terapias de reparo neuronal

Parkinson's disease (PD) is a neurodegenerative disorder partially characterized by the loss of dopaminergic neurons from the nigrostriatal pathway, originated in the substantia nigra with projections to the striatum, which causes several motor deficits. Currently, the most commonly used drug for PD treatment is levodopa. However, it has limited efficacy and induces several side effects. Elucidation of the neuroprotective, proliferative and neuroregenerative effects of bradykinin (BK) in animal models of PD can culminate in cellular replacement of the tissue damaged by 6-hydroxydopamine (6-OHDA). In fact, BK and its receptor have several physiological effects, being classically involved in the control of cardiovascular homeostasis and inflammation. Besides, BK exerts protective effects on nervous system pathophysiology, as observed in stroke models. Several cell types have their signaling pathways associated with the B2 kinin receptor (B2BKR) activation. Previous work from our group showed that BK is involved in differentiation of neural progenitor cells by an autocrine loop that results in activation of B2BKR. The results presented in this thesis show the efficacy of treatment with BK, through B2BKR activation, in animals submitted to nigrostriatal pathway injury induced by 6-OH dopamine. Furthermore, behavioral and histological recoveries of these animals were observed when treated with Captopril®, a potentiator of BK pharmacological effects, and with [Phe8Ψ (CH-NH) Arg9] -BK, a stable agonist of the B2BKR receptor. Thus, we conclude that BK activation of B2BKR triggers neuroregenerative processes in animals submitted to 6- OHDA injury. Recent studies showed that the B2BKR receptor plays an important neuroprotective role in an animal model of Alzheimer's disease, which corroboratesour findings. Together, these results contribute to the establishment of the neuroprotective and neuroregenerative actions of BK - an excellent candidate for neural repair therapies

Childhood disorders of neurodegeneration with brain iron accumulation (NBIA).

Neurodegeneration with brain iron accumulation (NBIA) comprises a heterogeneous group of progressive complex motor disorders characterized by the presence of high brain iron, particularly within the basal ganglia. A number of autosomal recessive NBIA syndromes can present in childhood, most commonly pantothenate kinase-associated neurodegeneration (PKAN; due to mutations in the PANK2 gene) and phospholipase A2 group 6-associated neurodegeneration (PLAN; associated with genetic defects in PLA2G6). Mutations in the genes that cause these two neuroaxonal dystrophies are thought to disrupt the normal cellular functions of phospholipid remodelling and fatty acid metabolism. A significant proportion of children with an NBIA phenotype have no genetic diagnosis and there are, no doubt, additional as yet undiscovered genes that account for a number of these cases. NBIA disorders can be diagnostically challenging as there is often phenotypic overlap between the different disease entities. This review aims to define the clinical, radiological, and genetic features of such disorders, providing the clinician with a stepwise approach to appropriate neurological and genetic investigation, as well as a clinical management strategy for these neurodegenerative syndromes.

Endothelial dysfunction and repair in Alzheimer-type neurodegeneration: neuronal and glial control.

Current theories state that Alzheimer's disease (AD) is a vascular disorder that initiates its pathology through cerebral microvascular abnormalities. Endothelial dysfunction caused by the injury or death of endothelial cells contributes to progression of AD. Also, functional relationships between neurons, glial cells, and vascular cells within so-called neurovascular unit are dramatically compromised in AD. Several recent studies have highlighted that endothelial cells might be the target for the toxic action of heavily aggregated proteins, glia-derived cytokines, and stimuli inducing oxidative and metabolic stress in AD brains. Here, we describe the properties of the brain endothelium that contribute to its specific functions in the central nervous system, and how endothelial-neuronal-glial cell interactions are compromised in the pathogenesis of AD. We also discuss the ways in which functioning of endothelial cells can be modulated in cerebral microvessels. Understanding of molecular mechanisms of endothelial injury and repair in AD would give us novel diagnostic biomarkers and pharmacological targets.

Staging disease severity in movement disorder tauopathies: brain atrophy separates progressive supranuclear palsy from corticobasal degeneration.

The movement disorders progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) both deposit tau in degenerating neurons and are considered to be tauopathies. The recently developed scheme for staging tissue degeneration in another tauopathy, frontotemporal dementia [Broe et al., Neurology 2003;60:1005-1011] was applied to pathologically confirmed PSP (n = 24) and CBD (n = 9) cases and correlated with clinical indices. In contrast to frontotemporal dementia, the majority of PSP cases had limited or no visible atrophy, while the pattern of atrophy in CBD cases conformed to the existing staging scheme (all but one case exhibiting substantial visible tissue atrophy). Despite similar clinical severity and disease duration between groups, there was a marked difference between the PSP and CBD cases in pathological disease stage (chi(2) = 8.86; P = 0.03). The degree of global atrophy in PSP appears to be distinct from other tauopathies, while CBD fits the same pattern as other pathological forms of frontotemporal dementia.

Agreement between the Sunnybrook, House-Brackmann, and Yanagihara facial nerve grading systems in Bell's palsy.

OBJECTIVE: To assess the agreement between the Sunnybrook facial nerve grading system and the House-Brackmann and Yanagihara systems. STUDY DESIGN: Prospective clinical facial nerve grading. SETTING: Tertiary referral center. PATIENTS: One-hundred assessments, 94 in patients with Bell's palsy and 6 with herpes zoster. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURES: Evaluation according to the weighted regional Sunnybrook system, the gross House-Brackmann system, and the unweighted regional Yanagihara system. Weighted kappa statistics was used to measure agreement between the grading systems. RESULTS: The average weighted kappa value between the Sunny-brook, House-Brackmann, and Yanagihara grading systems was 0.65; kappa values increased temporally (but not statistically significantly) up to day 180. The highest agreement value, 0.72, was found between the Sunnybrook and Yanagihara grading systems. The weighted kappa value between the Sunnybrook and House-Brackmann systems was 0.59. In Sunnybrook gradings less than 63, there was an overlap between House-Brackmann scores of III to VI. Reliable conversion tables between the gross House-Brackmann system and the regional Sunnybrook and Yanagihara systems could not be established. CONCLUSION: The Sunnybrook system scores at the same agreement level as the House-Brackmann and Yanagihara grading systems. There is an evaluative difference between the weighted regional Sunnybrook and the gross House-Brackmann systems. Substantial agreement was found between the regional Sunnybrook and Yanagihara scales. Sunnybrook grading is easy and quick. By adding objective measurements and additional secondary defects, the Sunnybrook system can be an alternative to the other predominating grading systems.

Evolution of Alzheimer's disease-related cytoskeletal changes in the basal nucleus of Meynert.

This study examines the evolution of Alzheimer's disease (AD)-related pathology in a subcortical predilection site, the basal nucleus of Meynert (bnM), which is a major source of cortical cholinergic innervation. Brains of 51 autopsy cases were studied using silver techniques and immunostaining for tau-associated neurofibrillary pathology and for amyloid beta protein (Abeta) deposits. All cases are classified according to a procedure permitting differentiation of six stages of AD-related neurofibrillary changes in the cerebral cortex. Initial cytoskeletal abnormalities in the bnM are already noted in stage I of cortical neurofibrillary changes. The gradual development of the neurofibrillary pathology in the bnM parallels the progression of the AD-related stages in the cerebral cortex. A variety of morphologically distinguishable cytoskeletal alterations are observed in large nerve cells which predominate in the bnM. Based on these cellular alterations, a sequence of cytoskeletal deterioration is proposed. Initially, the abnormal tau protein is distributed diffusely throughout the cell body and the neuronal processes. Subsequently, it aggregates to form a neurofibrillary tangle, which appears as a spherical somatic inclusion. The cell processes gradually become fragmented. Finally the parent cell dies, leaving behind an extraneuronal "ghost tangle". With regard to the cortical stages of AD-related neurofibrillary changes, the initial forms of cytoskeletal changes in the bnM predominate in the transentorhinal AD stages (I and II), while "ghost tangles" preferentially occur in the neocortical stages (V and VI). The considerable morphological diversity of cytoskeletal alterations is typical of stages III and IV. These results indicate that individual neurons of the bnM enter the sequence of cytoskeletal deterioration at different times.

'Axogenic' and 'somagenic' neurodegenerative diseases: definitions and therapeutic implications.

Neurodegenerative diseases are characterized by a relentless loss of specific groups of neuronal subtypes. Many of these diseases share similar molecular mechanisms and extracellular mediators of neuronal loss. We now suggest that neurodegeneration originating in the neuronal cell bodies (e.g. in Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis) should be distinguished from that originating in the axons (e.g. in glaucoma, certain peripheral neuropathies and spinal stenosis). We propose that the former group of diseases be defined as 'somagenic' and the latter as 'axogenic'. Although axogenic disorders may share common symptoms and mediators of toxicity with somagenic disorders, they have distinct temporal, subcellular and signal-transduction features. We further suggest that, by adopting this classification of disorders based on pathophysiological processes, we will come to recognize additional diseases (in particular, those defined as axogenic) as being neurodegenerative and therefore possibly amenable to neuroprotective therapy.

House-Brackmann and Yanagihara grading scores in relation to electroneurographic results in the time course of Bell's palsy.

The results of House Brackmann and Yanagihara grading were compared with electroneurographic (ENoG) data in 30 consecutive patients with Bell's palsy. The examinations were made on mean days 11, 36 and 99. Twenty-four patients had a favourable outcome (Yanagihara > or = 36 at three months). Based on our observations, 23 (96%) of these could have been predicted by ENoG, 18 (75%) by Yanagihara grading and 6 (25%) by House Brackmann grading. Initially, the relative House Brackmann scores showed a slightly milder palsy than the Yanagihara scores, but in the follow-up period the gradings were almost identical. The mild palsies, defined on the initial ENoG results, initially demonstrated relatively less nerve dysfunction on ENoG than the clinical grading; by the first follow-up, the ENoG and clinical grading had both returned to normal. The intermediate palsies had almost the same initial relative clinical and ENoG values, but at the first follow-up (mean day 36), the facial function had returned to normal despite abnormally reduced, but improved, ENoG values. In the severely affected patients, the follow-up studies showed an improved clinical function but ENoG values still demonstrated a high degree of degeneration (slightly improved at second follow-up). In this study, patients with a favourable outcome were best predicted with ENoG. Clinical identification of these patients was more accurate with Yanagihara than with House Brackmann. Furthermore, in all three groups a clinical improvement, due to the release of neurapraxia, was noted at the first follow-up. The slow ENoG improvement noted at follow-up was probably due to nerve regeneration by collateral sprouting. Based on the time course of our ENoG findings, it appears that patients with a high degree of degeneration at both the initial examination and first follow-up have a poorer prognosis.