Paulo Roberto Louzada

Taurine prevents the neurotoxicity of β-amyloid and glutamate receptor agonists: activation of GABA receptors and possible implications for Alzheimer’s disease and other neurological disorders

Alzheimers disease (AD) and several other neurological disorders have been linked to the overactivation of glutamatergic transmission and exci‐totoxicity as a common pathway of neuronal injury. The β‐amyloid peptide (Aβ) is centrally related to the pathogenesis of AD, and previous reports have demon¬strated that the blockade of glutamate receptors pre¬vents Aβ‐induced neuronal death. We show that tau¬rine, a β‐amino acid found at high concentrations in the brain, protects chick retinal neurons in culture against the neurotoxicity of Aβ and glutamate receptor ago¬nists. The protective effect of taurine is not mediated by interaction with glutamate receptors, as demon¬strated by binding studies using radiolabeled glutamate receptor ligands. The neuroprotective action of taurine is blocked by picrotoxin, an antagonist of GABAA receptors. GABA and the GABAA receptor agonists phenobarbital and melatonin also protect neurons against Aβ ‐induced neurotoxicity. These results suggest that activation of GABA receptors decreases neuronal vulnerability to excitotoxic damage and that pharmaco¬logical manipulation of the excitatory and inhibitory neurotransmitter tonus may protect neurons against a variety of insults. GABAergic transmission may repre¬sent a promising target for the treatment of AD and other neurological disorders in which excitotoxicity plays a relevant role.—Louzada, P. R., Lima, A. C. P., Mendonca‐Silva, D. L., Noël, F., de Mello, F. G., Ferreira, S. T. Taurine prevents the neurotoxicity of β‐amyloid and glutamate receptor agonists: activation of GABA receptors and possible implications for Alz¬heimers disease and other neurological disorders.

Inhibition of Alzheimer’s disease β-amyloid aggregation, neurotoxicity, and in vivo deposition by nitrophenols: implications for Alzheimer’s therapy

Alzheimers disease (AD) is a major public health problem, and there is currently no clinically accepted treatment to cure it or to stop its progression. Fibrillar aggregates of the β–amyloid peptide (Aβ) are major constituents of the senile plaques found in the brains of AD patients and have been related to AD neurotoxicity. Here it is shown that nitrophenols prevent aggregation and cause disaggregation of Aβ fibrils and that they strongly prevent the neurotoxicity of Aβ to rat hippocampal neurons in culture. Furthermore, by using an in vivo model system of cerebral amyloid deposition, it is shown that nitrophenols cause a marked reduction in the volume occupied by amyloid deposits in the hippocampi of rats. These results raise the possibility that nitrophenols or their derivatives may be useful lead compounds for the development of drugs to prevent the neurotoxicity and deposition of Aβ in AD.

Neuroprotection against Aβ and glutamate toxicity by melatonin: Are GABA receptors involved?

The β-amyloid peptide (Aβ) is centrally related to the pathogenesis of Alzheimers disease (AD). Previous studies have suggested that the neurotoxicity of Aβ may be related to the over activation of glutamatergic transmission and excitotoxicity, and that blockade of glutamate receptors prevents Aβ-induced cell death. Here, we show that melatonin, a pineal hormone, protects chick retinal neurons in culture against the neurotoxicity of Aβ and glutamate. Right-angle light scattering and thioflavin T fluorescence measurements, as well as light microscopy analysis, indicated that, under our experimental conditions, melatonin had no effect on the aggregation of Aβ. Interestingly, the neuroprotective action of melatonin against the toxicity of Aβ was significantly decreased in the presence of picrotoxin, an antagonist of GABAA-like receptors. By itself, picrotoxin had no effect. These results suggest that the neuroprotective effects of melatonin against Aβ neurotoxicity could be at least in part related to a decrease in the excitatory tonus, mediated by activation of GABA receptors and the resulting hyperpolarization of the neurons. Thus, selective pharmacological manipulation of neuronal excitatory/inhibitory tonus could be a potentially interesting new approach in the treatment of AD.

Dual role of glutamatergic neurotransmission on amyloid β1–42 aggregation and neurotoxicity in embryonic avian retina

The effects of glutamate receptor antagonists on the toxicity of the beta-amyloid peptide (Abeta(1-42)) in embryonic chick retina were investigated. When used alone or in combination, the N-methyl-D-asparate antagonist, MK-801, the (+/-)-alphaamino-3-hydroxyl-5-methylisoxazole-4-propionic acid/kainate antagonist, DNQX, and the metabotropic receptor antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid, blocked the neurotoxicity of Abeta(1-42). Aggregation of Abeta(1-42) was significantly increased in the presence of acidic glutamate solutions, but not in the presence of other neurotransmitters. These results point to a dual role of glutamatergic transmission in Alzheimers disease (AD): (i) Abeta neurotoxicity requires activation of glutamate receptors and its blockade prevents cell death; (ii) high concentrations of glutamate in the synaptic cleft indirectly enhance Abeta aggregation through acidification of the medium, resulting in increased amounts of neurotoxic amyloid fibrils. These results suggest that glutamatergic neurotransmission may represent a novel target for therapeutic approaches in AD.

Cerebellar cryptococcoma simulating metastatic neoplasm

. The authors described a 46 year-old male patient with left cerebellar hemispheric tumor-like lesion who had an initial diagnostic hy-pothesis of cerebellar metastatic lesion or even piogenic cerebel -lar abscess. After the surgical removal of the mass lesion, patho-logical examination revelead a cerebellar cryptococcoma. The au -thors emphasized that this was the first case of a solid cryptococ-cal mass lesion reported in Brazil

Bilateral extradural haematoma after acute ventricular over-drainage

Background: Ventricular over-drainage is a common complication of dysfunctional ventriculoperitoneal devices. Subdural haematomas are usually the most common lesions associated with that complication. Such lesions may arise after ventricular collapse and bridging veins disruption that follows over-drainage, thus contributing to distortion of brain parenchyma, increased intracranial hypertension and neurological decline. More rarely, extradural haematomas may also be observed after ventricular shunt hyperfunction and may result in rapid neurological decline unless a surgical procedure can be promptly performed. Case: This study reports the case of a 38-old-woman who presented supratentorial hydrocephalus and developed bilateral extradural haematomas after the placement of a ventricular shunt device. Both haematomas were surgically approached and the dysfunctional shunt device was replaced. Conclusion: Extradural haematomas may develop precociously after ventricular over-drainage. Surgical treatment is mandatory and must include not only the evacuation of haematoma, but also the replacement of dysfunctional shunt to prevent further recurrence. The pathophysiology of extradural haematomas consequent of ventricular over-drainage and the possible use of a programmable valve to prevent these lesions are briefly discussed.

Interhemispheric chronic subdural haematoma: Case report and brief review of the literature

Background: Chronic subdural haematoma usually arises from a traumatic acute haemorrhage in the subdural space, frequently causing mass effect and consequent neurological decline. This lesion is mainly found over the cortical convexity and its evolution and surgical approach has been extensively studied. Nevertheless, inter-hemispheric chronic subdural haematoma is considered a rare lesion. Aim and case report: This study reported a case of traumatic acute interhemispheric subdural haematoma, initially asymptomatic, and its evolution to a chronic symptomatic lesion, as well as the surgical approach employed. A brief review of the literature is presented with a discussion of the therapeutic options.

Bilateral cortical atrophy after severe brain trauma and extradural homatoma

We report the case of a severe head injured 43-year old male patient with a large extradural hematoma, Glasgow Coma Scale 3 and dilated fixed pupils. Patient was promptly submitted to surgical evacuation of the lesion, but remained in persistent vegetative state in the post-operative time. Head computed tomography scans performed before surgery, and at early and late post-operative periods comparatively revealed extreme bilateral cortical atrophy. Late consequences of severe head trauma drastically affect the prognosis of patients, being its prevention, and neuroprotection against secondary injury still a therapeutical challenge for neurosurgeons.

Free-floating adult human brain-derived slice cultures as a model to study the neuronal impact of Alzheimer's disease-associated Aβ oligomers

BACKGROUND Slice cultures have been prepared from several organs. With respect to the brain, advantages of slice cultures over dissociated cell cultures include maintenance of the cytoarchitecture and neuronal connectivity. Slice cultures from adult human brain have been reported and constitute a promising method to study neurological diseases. Despite this potential, few studies have characterized in detail cell survival and function along time in short-term, free-floating cultures. NEW METHOD We used tissue from adult human brain cortex from patients undergoing temporal lobectomy to prepare 200 μm-thick slices. Along the period in culture, we evaluated neuronal survival, histological modifications, and neurotransmitter release. The toxicity of Alzheimers-associated Aβ oligomers (AβOs) to cultured slices was also analyzed. RESULTS Neurons in human brain slices remain viable and neurochemically active for at least four days in vitro, which allowed detection of binding of AβOs. We further found that slices exposed to AβOs presented elevated levels of hyperphosphorylated Tau, a hallmark of Alzheimers disease. COMPARISON WITH EXISTING METHOD(S) Although slice cultures from adult human brain have been previously prepared, this is the first report to analyze cell viability and neuronal activity in short-term free-floating cultures as a function of days in vitro. CONCLUSIONS Once surgical tissue is available, the current protocol is easy to perform and produces functional slices from adult human brain. These slice cultures may represent a preferred model for translational studies of neurodegenerative disorders when long term culturing in not required, as in investigations on AβO neurotoxicity.