Neurorepair and Regeneration of the Brain: A Decade of Bioscaffolds and Engineered Microtissue.

Repairing the human brain remains a challenge, despite the advances in the knowledge of inflammatory response to injuries and the discovery of adult neurogenesis. After brain injury, the hostile microenvironment and the lack of structural support for neural cell repopulation, anchoring, and synapse formation reduce successful repair chances. In the past decade, we witnessed the rise of studies regarding bioscaffolds' use as support for neuro repair. A variety of natural and synthetic materials is available and have been used to replace damaged tissue. Bioscaffolds can assume different shapes and may or may not carry a diversity of content, such as stem cells, growth factors, exosomes, and si/miRNA that promote specific therapeutic effects and stimulate brain repair. The use of these external bioscaffolds and the creation of cell platforms provide the basis for tissue engineering. More recently, researchers were able to engineer brain organoids, neural networks, and even 3D printed neural tissue. The challenge in neural tissue engineering remains in the fabrication of scaffolds with precisely controlled topography and biochemical cues capable of directing and controlling neuronal cell fate. The purpose of this review is to highlight the existing research in the growing field of bioscaffolds' development and neural tissue engineering. Moreover, this review also draws attention to emerging possibilities and prospects in this field.

Neuroprotective effect of heparin Trisulfated disaccharide on ischemic stroke.

Cells undergoing hypoxia experience intense cytoplasmic calcium (Ca2+) overload. High concentrations of intracellular calcium ([Ca2+]i) can trigger cell death in the neural tissue, a hallmark of stroke. Neural Ca2+ homeostasis involves regulation by the Na+/Ca2+ exchanger (NCX). Previous data published by our group showed that a product of the enzymatic depolymerization of heparin by heparinase, the unsaturated trisulfated disaccharide (TD; ΔU, 2S-GlcNS, 6S), can accelerate Na+/Ca2+ exchange via NCX, in hepatocytes and aorta vascular smooth muscle cells. Thus, the objective of this work was to verify whether TD could act as a neuroprotective agent able to prevent neuronal cell death by reducing [Ca2+]i. Pretreatment of N2a cells with TD reduced [Ca2+]i rise induced by thapsigargin and increased cell viability under [Ca2+]I overload conditions and in hypoxia. Using a murine model of stroke, we observed that pretreatment with TD decreased cerebral infarct volume and cell death. However, when mice received KB-R7943, an NCX blocker, the neuroprotective effect of TD was abolished, strongly suggesting that this neuroprotection requires a functional NCX to happen. Thus, we propose TD-NCX as a new therapeutic axis for the prevention of neuronal death induced by [Ca2+]i overload.

Decreased viability and neurite length in neural cells treated with chitosan-dextran sulfate nanocomplexes.

CXCL12 is a chemokine known to regulate migration, proliferation, and differentiation of neural stem cells (NSCs) and to play a neuroprotective role in ischemic stroke. Chitosan-dextran sulfate nanocomplexes (Ch/DS NC) are known nanoparticulated systems used to efficiently deliver heparin-binding factors. Here we evaluate Ch/DS NC as carriers for CXCL12 in a mouse model of stroke. Free CXCL12 reduced the size of the ischemic brain lesion. However, when Ch/DS NC were administrated, the stroke volume increased. Neurotoxic screening revealed that Ch/DS NC reduced neuronal viability, decreased the extension of neurites and impaired NSC migration in vitro. To the best of our knowledge, neurotoxicity of Ch/DS NC has not been reported and further screenings will be needed in order to evaluate the biological safety of these nanocomposites. Our results add new data on nanoparticle neurotoxicity and may help us to better understand the complex interactions of the nanostructures with biological components.

Treatment of Recurrent Painful Ophthalmoplegic Neuropathy: A Case Where Pregabalin Was Successfully Employed.

Recurrent painful ophthalmoplegic neuropathy, previously known as ophthalmoplegic migraine, is a rare condition that affects children and young adults. Its cause and classification are still controversial and, consequently, there are no published treatment guidelines or consensus. Glucocorticoids seem to be beneficial for some patients, but there is no established treatment when failure of this therapy occurs. The aim of this study was to report a case where pregabalin was successfully used after failure of glucocorticoid therapy in a patient with recurrent painful ophthalmoplegic neuropathy.

Rotary jet-spun porous microfibers as scaffolds for stem cells delivery to central nervous system injury.

Stem cell transplantation is a promising strategy to treat brain injuries. However, cell-based therapies are limited because poor local cell engraftment. Here, we present a polylactic acid (PLA) scaffold to support mesenchymal stem cells (MSCs) delivery in stroke. We isolated bone marrow MSCs from adult C57/Bl6 mice, cultured them on PLA polymeric rough microfibrous (PRM) scaffolds obtained by rotary jet spinning, and transplanted over the brains of adult C57/Bl6 mice, carrying thermocoagulation-induced cortical stroke. No inflammatory response to PRM was found. MSCs transplantation significantly reduced the area of the lesion and PRM delivery increased MSCs retention at the injury site. In addition, PRM upregulated α6-integrin and CXCL12 production, which may be the cause for greater cell retention at the lesion site and may provide additional benefit to MSCs transplantation procedures. We conclude that PRM scaffolds offer a promising new system to deliver stem cells to injured areas of the brain.

Injection of SDF-1 loaded nanoparticles following traumatic brain injury stimulates neural stem cell recruitment.

Recruiting neural stem cell (NSC) at the lesion site is essential for central nervous system repair. This process could be triggered by the local delivery of the chemokine SDF-1. We compared two PLGA formulations for local brain SDF-1 delivery: SDF-1 loaded microspheres (MS) and SDF-1 loaded nanoparticles (NP). Both formulations were able to encapsulate more than 80% of SDF-1 but presented different release profiles, with 100% of SDF-1 released after 6days for the MS and with 25% of SDF-1 released after 2 weeks for NP. SDF-1 bioactivity was demonstrated by a chemotactic assay. When injected in mouse brain after traumatic brain injury, only SDF-1 nanoparticles induced NSC migration to the damage area. More neuroblasts (DCX+ cells) could be visualized around the lesions treated with NP SDF-1 compared to the other conditions. Rostral migratory stream destabilization with massive migration of DCX+ cell toward the perilesional area was observed 2 weeks after NP SDF-1 injection. Local injection of SDF-1-loaded nanoparticles induces recruitment of NSC and could be promising for brain injury lesion.

Cognitive impairment and antiphospholipid syndrome: is paradoxical embolism the rule?

OBJECTIVE: Although cognitive decline (CD) is described in antiphospholipid syndrome (APS), its physiopathology is unknown. Paradoxical embolization (PE) is related to CD in Alzheimer disease. The objective of this study was to determine whether PE plays a role in CD in APS patients through a significant right-to-left shunt (sRLS). METHODS: A total of 27 patients diagnosed with APS without a history of stroke were tested for the presence of an sRLS using a contrast-enhanced transcranial Doppler (cTCD) ultrasound. Cognitive decline was assessed using the mini mental state examination (MMSE), the Montreal cognitive assessment (MoCA), and a battery of neuropsychological tests. RESULTS: Of the 27 patients, 19 (70%) had a non-sRLS condition (≤ 10 high-intensity transient signs [HITS] on cTCD), and 8 (30%) had an sRLS. Patients with more than 10 years of scholarship performed significantly better on both the MMSE (P = 0.048) and MoCA (P = 0.03). Individuals of the non-sRLS group with more than 10 years of scholarship had better performances on the five-point test (FPT) when compared with the sRLS group (P = 0.01). CONCLUSIONS: Patients without sRLS and with more years of education exhibited a better performance in cognitive tests than sRLS patients.

Curitiba acute ischemic stroke protocol: a university hospital and EMS initiative in a large Brazilian city.

UNLABELLED: Few healthcare centers in Brazil perform thrombolytic therapy for acute ischemic stroke (AIS) patients. OBJECTIVE: The aim of this study was to describe an interinstitutional protocol for the rapid identification and thrombolytic treatment of AIS patients at a public health hospital in a large Brazilian city. METHOD: Emergency medical services (EMS) personnel evaluated 433 patients with possible stroke during a six-month period. After a standard checklist, patients with suspected AIS and symptoms onset of less than two hours were evaluated at our University Hospital (UH). RESULTS: Sixty-five (15%) patients met the checklist criteria and had a symptom onset of less than two hours, but only 50 (11%) patients were evaluated at the UH. Among them, 35 (70%) patients had ischemic stroke, 10 (20%) had hemorrhagic stroke, and 5 (10%) had other diagnoses. Of the 35 ischemic stroke patients, 15 (43%) underwent IV thrombolysis. CONCLUSION: The present study demonstrated that trained EMS workers could help to improve the rate of thrombolytic treatment in large Brazilian cities. Permanent training programs for EMS and hospital staff, with quality control and correct identification of AIS patients, should be implemented to increase appropriate thrombolytic therapy rates in Brazil.

Curitiba acute ischemic stroke protocol: a university hospital and EMS initiative in a large Brazilian city / Protocolo de AVCi agudo em Curitiba: uma iniciativa de um hospital universitário e do SAMU

Few healthcare centers in Brazil perform thrombolytic therapy for acute ischemic stroke (AIS) patients. OBJECTIVE: The aim of this study was to describe an interinstitutional protocol for the rapid identification and thrombolytic treatment of AIS patients at a public health hospital in a large Brazilian city. METHOD: Emergency medical services (EMS) personnel evaluated 433 patients with possible stroke during a six-month period. After a standard checklist, patients with suspected AIS and symptoms onset of less than two hours were evaluated at our University Hospital (UH). RESULTS: Sixty-five (15 percent) patients met the checklist criteria and had a symptom onset of less than two hours, but only 50 (11 percent) patients were evaluated at the UH. Among them, 35 (70 percent) patients had ischemic stroke, 10 (20 percent) had hemorrhagic stroke, and 5 (10 percent) had other diagnoses. Of the 35 ischemic stroke patients, 15 (43 percent) underwent IV thrombolysis. CONCLUSION: The present study demonstrated that trained EMS workers could help to improve the rate of thrombolytic treatment in large Brazilian cities. Permanent training programs for EMS and hospital staff, with quality control and correct identification of AIS patients, should be implemented to increase appropriate thrombolytic therapy rates in Brazil.

No Brasil, apenas alguns hospitais realizam terapia trombolítica para o acidente vascular cerebral isquêmico agudo (AVCiA). OBJETIVO: O objetivo deste estudo foi descrever um protocolo inter-institucional para a rápida identificação e para o tratamento trombolítico de pacientes com AVCiA em hospital público de Curitiba, PR. MÉTODO: O Serviço de Atendimento Médico de Urgência (SAMU) avaliou 433 pacientes com possível AVC durante um período de seis meses. Depois de um check list padrão, os pacientes com suspeita de AVCiA e início dos sintomas inferior a duas horas, foram avaliados no Hospital de Clínicas (HC). RESULTADOS: Sessenta e cinco (15 por cento) pacientes preencheram os critérios propostos, porém apenas 50 pacientes (11 por cento) foram avaliados no HC. Destes, 35 (70 por cento) eram AVC isquêmico (AVCi), 10 (20 por cento) eram hemorrágicos e 5 (10 por cento) tiveram outros diagnósticos. Dos 35 pacientes com AVCi, 15 (43 por cento) foram submetidos a trombólise IV. CONCLUSÃO: O presente estudo demonstrou que o treinamento do SAMU poderia auxiliar na otimização da terapia trombolítica em grandes cidades brasileiras. Programas permanentes de treinamento com controle de qualidade, caracterizados pela correta identificação de pacientes com AVCiA devem ser realizados nos hospitais em parceria com o SAMU para elevar as taxas de tratamento trombolítico no Brasil.

Neurological diagnoses in the emergency room: differences between younger and older patients.

UNLABELLED: Neurological diseases are prevalent in the emergency room (ER). The aim of this study was to compare the neurological diagnoses between younger and older patients evaluated in the ER of a tertiary care hospital. METHOD: Patients admitted to the ER who required neurological evaluation in the first 24 hours were separated into two groups based on age, ≤50 years old and >50 years old. RESULTS: Cerebrovascular disease (59.6% vs. 21.8%, p<0.01) was most frequent in the >50 years old group. Seizures (8.1% vs. 18.6%, p<0.01) and primary headache (3.7% vs. 11.4%, p<0.01) were most frequent in the ≤50 years old group. CONCLUSION: The current study demonstrated that these three neurological diagnoses represented the majority of the neurological evaluations in the ER. National guidelines for ER teams that treat these prevalent disorders must be included in clinical practice and training.

Neurological diagnoses in the emergency room: differences between younger and older patients / Diagnósticos neurológicos na sala de emergência: diferenças entre pacientes jovens e idosos

Neurological diseases are prevalent in the emergency room (ER). The aim of this study was to compare the neurological diagnoses between younger and older patients evaluated in the ER of a tertiary care hospital. METHOD: Patients admitted to the ER who required neurological evaluation in the first 24 hours were separated into two groups based on age, <;50 years old and >50 years old. RESULTS: Cerebrovascular disease (59.6 percent vs. 21.8 percent, p<0.01) was most frequent in the >50 years old group. Seizures (8.1 percent vs. 18.6 percent, p<0.01) and primary headache (3.7 percent vs. 11.4 percent, p<0.01) were most frequent in the <;50 years old group. CONCLUSION: The current study demonstrated that these three neurological diagnoses represented the majority of the neurological evaluations in the ER. National guidelines for ER teams that treat these prevalent disorders must be included in clinical practice and training.

Doenças neurológicas são prevalentes na sala de emergência (SE). O objetivo deste estudo é comparar a ocorrência de diagnósticos neurológicos entre pacientes jovens e idosos atendidos na SE de um hospital terciário. MÉTODO: Pacientes admitidos na SE que necessitaram avaliação neurológica nas primeiras 24 horas após a admissão foram separados em dois grupos baseados na idade, <;50 anos de idade e >50 anos de idade. RESULTADOS: Doença cerebrovascular foi o diagnóstico mais comum nos pacientes >50 anos (59,6 por cento vs. 21,8 por cento, p<0,01). Convulsões (8,1 por cento vs. 18,6 por cento, p<0,01) e cefaléias primárias (3,7 por cento vs. 114 por cento, p<0,01) foram mais frequentes no grupo <;50 anos. CONCLUSÃO: O presente estudo demonstrou que esses três diagnósticos neurológicos representam a maioria das avaliações neurológicas na SE. Diretrizes nacionais para os profissionais emergencistas que tratam estas doenças devem ser incluídos na prática clínica e no treinamento médico.