Role of cardiac β1-adrenergic and A1-adenosine receptors in severe arrhythmias related to Parkinson's disease

Abstract Aims Although reduced life expectancy in Parkinson's Disease (PD) patients has been related to severe cardiac arrhythmias due to autonomic dysfunctions, its molecular mechanisms remain unclear. To investigate the role of cardiac β1-Adrenergic (β1AR) and A1-Adenosine (A1R) receptors in these dysfunctions, the pharmacological effects of stimulation of cardiac β1AR (isoproterenol, ISO), in the absence and presence of cardiac β1AR (atenolol, AT) or A1R (1,3-dipropyl-8-cyclopentyl xanthine, DPCPX) blockade, on the arrhythmias induced by Ischemia/Reperfusion (CIR) in an animal PD model were studied. Methods PD was produced by dopaminergic lesions (confirmed by immunohistochemistry analysis) caused by the injection of 6-hydroxydopamine (6-OHDA, 6 μg) in rat striatum. CIR was produced by a surgical interruption for 10 min followed by reestablishment of blood circulation in the descendent left coronary artery. On the incidence of CIR-Induced Ventricular Arrhythmias (VA), Atrioventricular Block (AVB), and Lethality (LET), evaluated by Electrocardiogram (ECG) analysis, the effects of intravenous treatment with ISO, AT and DPCPX (before CIR) were studied. Results VA, AVB and LET incidences were significantly higher in 6-OHDA (83%, 92%, 100%, respectively) than in control rats (58%, 67% and 67%, respectively). ISO treatment significantly reduced these incidences in 6-OHDA (33%, 33% and 42%, respectively) and control rats (25%, 25%, 33%, respectively), indicating that stimulation of cardiac β1AR induced cardioprotection. This response was prevented by pretreatment with AT and DPCPX, confirming the involvement of cardiac β1AR and A1R. Conclusion Pharmacological modulation of cardiac β1AR and A1R could be a potential therapeutic strategy to reduce severe arrhythmias and increase life expectancy in PD patients.

Discussion of the Brazilian neurologists about sudden unexpected death in epilepsy

SUMMARY OBJECTIVE: This study aimed to evaluate the concept of health professionals affiliated with the Brazilian League of Epilepsy on whether or not to inform patients about the risk factors related to the occurrence of sudden unexpected death in epilepsy. METHODS: A descriptive research of inquiry was conducted with direct survey on the Brazilian neurologist's view, regarding medical behavior in the health area to report or not about the risk of sudden unexpected death in epilepsy. Data collection consisted of a structured questionnaire available online. RESULTS: The study population consisted of a sample of 44 Brazilian League of Epilepsy members who answered the questionnaire, of which 25 (56.8%) were men and 19 (43.2%) were women. Among the analyzed questionnaires, 79.5% reported that they were aware of the risk factors for sudden unexpected death in epilepsy and 18.2% admitted not knowing the potential risk factors for sudden unexpected death in epilepsy. Notably, 59.1% of these professionals thought that an early discussion with the patient about sudden unexpected death in epilepsy must be considered. The majority (70%) felt that the neurologist should do this, and 22% believed that the subject should be discussed with psychologists. It was noted that 84.1% of respondents did not discuss or discussed only with some of their patients about the risk factors for sudden unexpected death in epilepsy. CONCLUSIONS: There is a need for encouraging early discussion of sudden unexpected death in epilepsy with epilepsy patients if the patient asks about the risks related to epilepsy and its treatment, when treatment adherence is low, in cases of intractable epilepsy with strong indication for surgical treatment, and when polytherapy is needed.

Ischemic stroke in 455 COVID-19 patients

ABSTRACT There is increasing evidence that COVID-19 can be associated with ischemic stroke (COVID-stroke). The frequency and pathogenesis of COVID-stroke, however, remains largely unknown. This narrative review aimed at summarizing and discussing current knowledge about frequency and pathogenesis of COVID-stroke in 455 patients collected from the literature. COVID-stroke occurs in all age groups and predominantly in males. The anterior circulation is more frequently affected than the posterior circulation. COVID-stroke is most frequently embolic. The severity of COVID-stroke ranges from NIHSS 3 to 32. Cardiovascular risk factors are highly prevalent in patients with COVID-stroke. COVID-stroke occurs simultaneously with the onset of pulmonary manifestations or up to 40 days later. Clinical manifestations of COVID-19 are most frequently mild or even absent. The majority of patients with COVID-stroke achieve complete or partial recovery, but in one-quarter of patients, the outcome is fatal. In conclusion, the frequency of ischemic stroke has not increased since the outbreak of the SARS-CoV-2 pandemic. COVID-stroke predominantly affects males and the anterior circulation. COVID-stroke is multifactorial but predominantly embolic and more frequently attributable to cardiovascular risk factors than to coagulopathy.

Peripheral neuropathy in COVID-19 is due to immune-mechanisms, pre-existing risk factors, anti-viral drugs, or bedding in the Intensive Care Unit / Neuropatia periférica na COVID-19 com mecanismos immunológicos, fatores de risco preexistentes, medicamentos antivirais e compressão dos nervos periféricos nos leitos da Unidade de Terapia Intensiva

ABSTRACT Background: This mini-review aims to summarize and discuss previous and recent advances in the clinical presentation, pathophysiology, diagnosis, treatment, and outcome of SARS-CoV-2-associated peripheral neuropathies. Methods: Literature review. Results: Altogether, 105 articles about SARS-CoV-2-associated neuropathy describing 261 patients were retrieved. Peripheral neuropathy in patients with COVID-19 is frequent and predominantly due to immune mechanisms or neurotoxic side effects of drugs used to treat the symptoms of COVID-19 and, to a lesser extent, due to the compression of peripheral nerves resulting from prolonged bedding in the Intensive Care Unit (ICU) and pre-existing risk factors such as diabetes. SARS-CoV-2 does not cause viral neuropathy. Neurotoxic drugs such as daptomycin, linezolid, lopinavir, ritonavir, hydro-chloroquine, cisatracurium, clindamycin, and glucocorticoids should be administered with caution and patients should be appropriately bedded in the ICU to prevent SARS-CoV-2-associated neuropathy. Patients with Guillain-Barré syndrome (GBS) benefit from immunoglobulins, plasma exchange, and steroids. Conclusions: Neuropathies of peripheral nerves in patients with COVID-19 are frequent and mostly result from immune mechanisms or neurotoxic side effects of drugs used to treat the symptoms of COVID-19 and, to a lesser extent, from the compression of peripheral nerves due to prolonged bedding on the ICU. SARS-CoV-2 does not cause infectious neuropathy.

RESUMO Introdução: A presente minirrevisão tem como objetivo resumir e discutir os avanços dos aspectos clínicos, fisiopatológicos, de diagnóstico, tratamento e evolução das neuropatias dos nervos periféricos associadas à COVID-19. Métodos: Revisão da literatura. Resultados: Foram avaliados 105 artigos sobre neuropatia associada à COVID-19. Nesses estudos, 261 pacientes apresentaram boa evolução. As neuropatias dos nervos periféricos em pacientes com COVID-19 são frequentes e se devem, principalmente, aos mecanismos immunológicos ou efeitos colaterais neurotóxicos dos medicamentos utilizados para o tratamento da COVID-19, a fatores de risco pré-existentes, como diabetes e, em menor parte, à compressão dos nervos periféricos nos leitos da UTI. A COVID-19 não causa neuropatia viral. Os medicamentos neurotóxicos, como daptomicina, linezolida, lopinavir, ritonavir, hidro-cloroquina, cisatracúrio, clindamicina e glicocorticoides devem ser administrados com cautela, e os pacientes deve ser adequadamente admitidos nos leitos da UTI para prevenir o desenvolvimento de neuropatia associada à COVID-19. Pacientes com síndrome de Guillain-Barré (GBS) se beneficiam de imunoglobulinas, plasmaférese e esteroides. Conclusões: As neuropatias dos nervos periféricos em pacientes com COVID-19 são raras e predominantemente devidas aos efeitos colaterais neurotóxicos das mecanismos immunológicos ou drogas utilizadas para o tratamento de COVID-19 e, em menor parte, devido à compressão dos nervos periféricos nos leitos da UTI. A COVID-19 não causa neuropatia infeciosa.

Cardioprotection stimulated by resveratrol and grape products prevents lethal cardiac arrhythmias in an animal model of ischemia and reperfusion

ABSTRACT Purpose To evaluate the preventive cardioprotective effects of resveratrol and grape products, such as grape juice and red wine, in animal model of cardiac ischemia and reperfusion. Methods Male Wistar rats orally pretreated for 21-days with resveratrol and grape products were anesthetized and placed on mechanical ventilation to surgically induce cardiac ischemia and reperfusion by obstruction (ischemia) followed by liberation (reperfusion) of blood circulation in left descending coronary artery. These rats were submitted to the electrocardiogram (ECG) analysis to evaluate the effects of pretreatment with resveratrol and grape products on the incidence of ventricular arrhythmias (VA), atrioventricular block (AVB) and lethality (LET) resulting from cardiac ischemia and reperfusion. Results It was observed that the incidence of AVB was significantly lower in rats pretreated with resveratrol (25%), grape juice (37.5%) or red wine (12.5%) than in rats treated with saline solution (80%) or ethanol (80%). Similarly, incidence of LET was also significantly lower in rats pretreated with resveratrol (25%), grape juice (25%) or red wine (0%) than in rats treated with saline solution (62.5%) or ethanol (75%). Conclusions These results indicate that the cardioprotective response stimulated by resveratrol and grape products prevents the lethal cardiac arrhythmias in animal model of ischemia and reperfusion, supporting the idea that this treatment can be beneficial for prevention of severe cardiac arrhythmias in patients with ischemic heart disease.

Cardioprotective effects of pharmacological blockade of the mitochondrial calcium uniporter on myocardial ischemia-reperfusion injury

Abstract Purpose To evaluate whether the attenuation of mitochondrial Ca2+ overload produced by pharmacological blockade of mitochondrial Ca2+ uniporter (MCU) protects the myocardium against injuries caused by cardiac ischemia and reperfusion (CIR). Methods CIR was induced in adult male Wistar rats (300-350 g) by occlusion of the left anterior descendent coronary artery (10 min), followed by reperfusion (120 min). Rats were treated with different doses of MCU blocker ruthenium red (RuR), administered 5 min before ischemia or reperfusion. Results In untreated rats, the incidences of ventricular arrhythmias (VA), atrioventricular block (AVB) and the lethality (LET) induced by CIR were 85%, 79% and 70%, respectively. In rats treated with RuR before ischemia, the incidences of VA, AVB and LET were significantly reduced to 62%, 25% and 25%, respectively. In rats treated with RuR after ischemia, the incidences of VA, AVB and LET were significantly reduced to 50%, 25% and 25%, respectively. Conclusion The significant reduction of the incidence of CIR-induced VA, AVB and LET produced by the treatment with RuR indicates that the attenuation of mitochondrial Ca2+ overload produced by pharmacological blockade of MCU can protect the myocardium against injuries caused by CIR.

Pharmacological modulation of b-adrenoceptors as a new cardioprotective strategy for therapy of myocardial dysfunction induced by ischemia and reperfusion

Abstract Purpose: To evaluate the cardioprotective response of the pharmacological modulation of β-adrenergic receptors (β-AR) in animal model of cardiac ischemia and reperfusion (CIR), in spontaneously hypertensive (SHR) and normotensive (NWR) rats. Methods: CIR was induced by the occlusion of left anterior descendent coronary artery (10 min) and reperfusion (75 min). The SHR was treated with β-AR antagonist atenolol (AT, 10 mg/kg, IV) 5 min before CIR, and NWR were treated with β-AR agonist isoproterenol (ISO, 0.5 mg/kg, IV) 5 min before CIR. Results: The treatment with AT increased the incidence of VA, AVB and LET in SHR, suggesting that spontaneous cardioprotection in hypertensive animals was abolished by blockade of β-AR. In contrast, the treatment with ISO significantly reduced the incidence of ventricular arrhythmia, atrioventricular blockade and lethality in NWR (30%, 20% and 20%, respectively), suggesting that the activation of β-AR stimulate cardioprotection in normotensive animals. Serum CK-MB were higher in SHR/CIR and NWR/CIR compared to respective SHAM group (not altered by treatment with AT or ISO). Conclusion: The pharmacological modulation of β-AR could be a new cardioprotective strategy for the therapy of myocardial dysfunctions induced by CIR related to cardiac surgery and cardiovascular diseases.

Omega-3 intake in people with epilepsy under regular hemodialysis program: here to stay / Suplementacao de omega 3 em pessoas com epilepsia submetidas a um programa regular de hemidialise: veio para ficar

Among the many risk factors suggested for sudden unexpected death in epilepsy (SUDEP), higher frequency of seizures is a very consistent issue. Furthermore, it has been established that hemodialysis-associated seizure is a complication of the dialysis procedure. Thus, since a possible relation between cardiovascular abnormalities and SUDEP among patients with chronic renal insufficiency in regular hemodialysis program should not be neglected, we propose in this paper that omega-3 fatty acids offer opportunities for prevention of sudden cardiac death or improved treatment in people with epilepsy under the regular hemodialysis program.

Dentre os fatores de risco sugeridos para a morte súbita inesperada em epilepsia (SUDEP), maior frequência de crises epilépticas é uma questão muito consistente. Além disso, tem sido estabelecido que as crises epilépticas associadas à hemodiálise são uma complicação do procedimento dialítico. Desse modo, como a existência de uma possível associação entre as alterações cardiovasculares e a SUDEP entre indivíduos com insuficiência renal crônica em tratamento dialítico não deve ser negligenciada, foi proposto neste artigo que o ômega 3 pode atuar na prevenção da morte súbita cardíaca ou melhorar o tratamento de pessoas com epilepsia inseridas em um programa regular de hemodiálise.

Surgical and postmortem pathology studies: contribution for the investigation of temporal lobe epilepsy / Patologia cirúrgica e post mortem: contribuição para a investigação da epilepsia do lobo temporal

Pathology studies in epilepsy patients bring useful information for comprehending the physiopathology of various forms of epilepsy, as well as aspects related to response to treatment and long-term prognosis. These studies are usually restricted to surgical specimens obtained from patients with refractory focal epilepsies. Therefore, most of them pertain to temporal lobe epilepsy (TLE) with mesial temporal sclerosis (MTS) and malformations of cortical development (MCD), thus providing information of a selected group of patients and restricted regions of the brain. Postmortem whole brain studies are rarely performed in epilepsy patients, however they may provide extensive information on brain pathology, allowing the analysis of areas beyond the putative epileptogenic zone. In this article, we reviewed pathology studies performed in epilepsy patients with emphasis on neuropathological findings in TLE with MTS and MCD. Furthermore, we reviewed data from postmortem studies and discussed the importance of performing these studies in epilepsy populations.

Estudos de patologia em pacientes com epilepsia trazem informações úteis para compreender a fisiopatologia de várias formas de epilepsia, bem como aspectos relacionados ao tratamento e ao prognóstico a longo prazo. Esses estudos são usualmente restritos a espécimes cirúrgicos obtidos de pacientes com epilepsias focais refratárias. Portanto, a maioria diz respeito à epilepsia do lobo temporal (ELT) com esclerose mesial temporal (EMT) e às malformações do desenvolvimento cortical (MDC). Desse modo, fornecem informações sobre um grupo selecionado de pacientes e sobre regiões restritas do cérebro. Raramente são realizados estudos post mortem do cérebro inteiro em pacientes com epilepsia; entretanto, eles podem prover informações relevantes sobre patologia cerebral, permitindo a análise de áreas além da zona epileptogênica putativa. Neste artigo, foram revisados estudos de patologia feitos em pacientes com epilepsia, com ênfase nos achados neuropatológicos em ELT com EMT e MDC. Foram revisados, ainda, dados de estudos post mortem e discutiu-se a importância da realização desses estudos em populações de pessoas com epilepsia.

Temporal lobe epilepsy with mesial temporal sclerosis: hippocampal neuronal loss as a predictor of surgical outcome / Epilepsia do lobo temporal com esclerose mesial temporal: o padrão da perda neuronal hipocampal como preditor do prognóstico cirúrgico

OBJECTIVE: To analyze retrospectively a series of patients with temporal lobe epilepsy (TLE) and mesial temporal sclerosis (MTS), and the association of patterns of hippocampal sclerosis with clinical data and surgical prognosis. METHOD: Sixty-six patients with medically refractory TLE with unilateral MTS after anterior temporal lobectomy were included. Quantitative neuropathological evaluation was performed on NeuN-stained hippocampal sections. Patient's clinical data and surgical outcome were reviewed. RESULTS: Occurrence of initial precipitating insult (IPI), as well as better postoperative seizure control (i.e. Engel class 1), were associated with classical and severe patterns of hippocampal sclerosis (MTS type 1a and 1b, respectively). CONCLUSION: Quantitative evaluation of hippocampal neuronal loss patterns predicts surgical outcome in patients with TLE-MTS.

OBJETIVO: Analisar retrospectivamente uma série de pacientes com epilepsia do lobo temporal (ELT) e esclerose mesial temporal (EMT), bem como correlacionar os padrões de esclerose hipocampal com os dados clínicos e o prognóstico cirúrgico. MÉTODOS: Foram incluídos neste estudo 66 pacientes com ELT refratária a tratamento medicamentoso e com EMT unilateral submetidos à lobectomia temporal anterior. A análise neuropatológica quantitativa foi realizada em seções hipocampais imunomarcadas com NeuN. Dados clínicos e resultados do acompanhamento pós-cirúrgico foram revisados. RESULTADOS: Ocorrência de evento precipitante inicial e melhor controle de crises após a cirurgia (i.e. classe 1 de Engel) foram associados aos padrões clássico (EMT tipo 1a) e severo (EMT tipo 1b) de esclerose hipocampal. CONCLUSÃO: A análise quantitativa do padrão de perda neuronal do hipocampo é capaz de predizer o prognóstico cirúrgico em pacientes com ELT-EMT.

Nestin down-regulation of cortical radial glia is delayed in rats submitted to recurrent status epilepticus during early postnatal life / Atraso no desaparecimento da nestina na glia radial cortical de ratos submetidos a recorrentes status epilepticus durante o desenvolvimento pós-natal precoce

OBJECTIVE: Nestin is temporarily expressed in several tissues during development and it is replaced by other protein types during cell differentiation process. This unique property allows distinguishing between undifferentiated and differentiated cells. This study was delineated to analyze the temporal pattern of nestin expression in cortical radial glial cells of rats during normal development and of rats submitted to recurrent status epilepticus (SE) in early postnatal life (P). METHOD: Experimental rats were submitted to pilocarpine-induced SE on P7-9. The cortical temporal profile of nestin was studied by immunohistochemistry at multiple time points (P9, P10, P12, P16, P30 and P90). RESULTS: We observed delayed nestin down-regulation in experimental rats of P9, P10, P12 and P16 groups. In addition, few radial glial cells were still present only in P21 experimental rats. CONCLUSION: Our results suggested that SE during early postnatal life alters normal maturation during a critical period of brain development.

OBJETIVO: A nestina, temporariamente expressa em diversos tecidos durante o desenvolvimento, é substituída no processo de diferenciação celular, o que permite a distinção entre células diferenciadas e indiferenciadas. O objetivo deste estudo foi verificar o padrão temporal da expressão da nestina nas células da glia radial cortical de ratos durante o desenvolvimento normal e nos ratos submetidos a sucessivos status epilepticus (SE) no periodo pós-natal precoce (P). MÉTODO: Os animais foram submetidos ao SE induzido pela pilocarpina em P7-9. O perfil temporal da nestina foi estudado por imuno-histoquímica em P9, P10, P12, P16, P30 e P90. RESULTADOS: Nos ratos experimentais, observamos atraso no desaparecimento da nestina nos grupos P9, P10, P12 e P16. Ainda, encontramos algumas glias radiais corticais apenas em P21 experimental. CONCLUSÃO: Nossos resultados sugerem que o SE durante o desenvolvimento pós-natal precoce altera o processo de maturação durante um periodo crítico do desenvolvimento encefálico.

Myocyte-specific enhancer binding factor 2C (MEF2C) expression in the dentate gyrus during development and after pilocarpine-induced status epilepticus: a preliminary report / Realce miócito específico ligado a expressão do fator 2C (MEF2C) no giro denteado durante o desenvolvimento e após uso de pilocarpina induzindo status epilepticus: estudo preliminar

OBJECTIVE: As axon outgrowth and dentate granule cell neurogenesis are hallmarks of hippocampal development and are also the two morphologic changes in the structure of the dentate gyrus after status epilepticus (SE), we hypothesized that molecules involved in normal development may also play a role during epileptogenesis. METHOD: Using in situ hybridization, we have characterized mRNA expression of myocyte-specific enhancer binding factor 2C (MEF2C) in the dentate gyrus during development (P0, P3, P7, P14 and P28) and at multiple time points following pilocarpine-induced SE (3, 7, 14, 28 days after SE). RESULTS: It was demonstrated that MEF2C is up-regulated during development (P0, P3, P7, P14 and P28) and in the adult rat dentate gyrus following SE (3, 7, 14, 28 days after SE). CONCLUSIONS: The molecules controlling cell-fate decisions in the developing dentate gyrus are also operative during epileptogenesis.

OBJETIVO: Como o crescimento axonal e a neurogênese do giro denteado são características intrínsecas do hipocampo durante o processo de desenvolvimento, e também são duas alterações morfológicas na estrutura do giro denteado após o status epilepticus (SE), nós hipotetizamos que as moléculas envolvidas no processo normal do desenvolvimento hipocampal também podem participar do processo de epileptogênese. MÉTODO: Utilizando hibridização in situ, caracterizamos a expressão do RNAm do fator de transcrição myocyte-specific enhancer binding factor 2C (MEF2C) no giro denteado durante o desenvolvimento (P0, P3, P7, P14 e P28) e em diferentes períodos após o SE (3, 7, 14, 28 dias após SE). RESULTADOS: Foi demonstrado um aumento da expressão de MEF2C no giro denteado durante o desenvolvimento e no giro denteado de animais adultos após o SE. CONCLUSÃO: As moléculas que controlam o destino celular durante o processo de desenvolvimento também estão operativas durante o processo de epileptogênese.

Lovastatin reduces neuronal cell death in hippocampal CA1 subfield after pilocarpine-induced status epilepticus: preliminary results

OBJETIVO: Capacidade da lovastatina em prevenir a perda de neurônios hipocampais após o status epilepticus (SE) induzido pela pilocarpina. MÉTODO: Ratos adultos Wistar foram divididos em 4 grupos: (A) ratos controles que não receberam pilocarpina nem lovastatina (n=5); (B) ratos controles que receberam somente lovastatina (n=5); (C) ratos que receberam somente pilocarpina (n=5); (D) ratos que receberam pilocarpina e lovastatina (n=5). Após a administração de pilocarpina (350mg/kg, i.p.), somente ratos que evoluíram para o status epilepticus foram incluídos em nosso estudo. A atividade epiléptica foi interrompida com uma injeção de diazepam (10 mg/kg, i.p.) após 4h do início do SE. Os ratos tratados com lovastatina receberam duas doses de 20mg/kg via esofágica, imediatamente e 24 h após a indução do SE. Sete dias após o SE induzido pela pilocarpina, todos os animais foram perfundidos e seus cérebros processados para análise histológica através do método de Nissl. RESULTADOS: A contagem celular da formação hipocampal mostrou uma significante perda celular nos animais que receberam pilocarpina e apresentaram SE (CA1= 26,8 ± 13,67; CA3= 38,1 ± 7,2; hilus= 43,8 ± 3,95) quando comparados com animais pertencentes ao grupo controle (Grupo A: CA1= 53,2 ± 9,63; CA3= 63,5 ± 13,35; hilus= 59,08 ± 10,24; Grupo B: CA1= 74,3 ± 8,16; CA3= 70,1 ± 3,83; hilus= 70,6 ± 5,10). O número de células neuronais na região CA1 do hipocampo de ratos que apresentaram SE e receberam lovastatina (44,4 ± 17,88) foi estatisticamente maior quando comparado com animais que somente apresentaram SE. CONCLUSÃO: A lovastatina exerce papel neuroprotetor na atenuação do dano cerebral após o SE.