Inhibition of the NMDA Currents by Probenecid in Amygdaloid Kindling Epilepsy Model.

Epilepsy is characterized by a sustained depolarization and repeated discharge of neurons, attributed to overstimulation of N-methyl-D-aspartate receptors (NMDAr). Herein, we propose that probenecid (PROB), an inhibitor of the activity of some ATP binding-cassette transporters (ABC-transporters) can modify NMDAr activity and expression in amygdaloid kindled model. Some studies have suggested that NMDAr expression could be regulated by inhibiting the activity of P-glycoprotein (MDR1) and drug resistance protein-1 (MRP1). Besides, PROB was found to interact with other proteins with proven activity in the kindling model, such as TRPV2 channels, OAT1, and Panx1. Administering PROB at two doses (100 and 300 mg/kg/d) for 5 d decreased after-discharge duration and Racine behavioral scores. It also reduced the expression of NR2B and the activity of total NOS and the expression of nNOS with respect to the kindling group. In a second protocol, voltage-clamp measurements of NMDA-evoked currents were performed in CA1 hippocampal cells dissociated from control and kindled rats. PROB produced a dose-dependent reduction in NMDA-evoked currents. In neurons from kindled rats, a residual NMDA-evoked current was registered with respect to control animals, while a reduction in NMDA-evoked currents was observed in the presence of 20 mM PROB. Finally, we evaluated the expression of MRP1 and MDR1 in order to establish a relationship between the reduction of kindling parameters, the inhibition of NMDA-type currents, and the expression of these transporters. Based on our results, we conclude that at the concentrations used, PROB inhibits currents evoked by NMDA in dissociated neurons of control and kindled rats. In the kindling model, at the tested doses, PROB decreases the after-discharge duration and Racine behavioral score in the kindling model. We propose a mechanism that could be dependent on the expression of ABC-type transporters.

[Subtle and subclinical neurological findings in patients with SARS-CoV-2]. / Hallazgos sutiles y subclínicos neurológicos en pacientes con SARS-CoV-2.

Background: There are severe neurological conditions in patients with COVID-19, such as: cerebrovascular disease, Guillain-Barré syndrome, encephalitis, acute hemorrhagic necrotizing encephalopathy and myelitis. Objective: We describe that the patient with SARS-CoV 2 with respiratory symptoms has subtle or subclinical neurological manifestations. Material and methods: Observational, cross-sectional, analytical study, which included patients aged 18-65 years with respiratory symptoms and a confirmed diagnosis of COVID-19. Intubated patients with chronic neurodegenerative diseases or pre-existing neurological compromise were excluded. Semiology of the headache and neurological examination were performed; Serum levels of glucose, protein, electrolytes, lactate, C-reactive protein, lactic dehydrogenase, and D-dimer were measured. Cerebrospinal fluid (CSF) analysis and electroencephalogram (EEG) were also performed in patients who accepted the risks. Results: A high prevalence of subtle neurological manifestations was found in patients with COVID-19 with only a respiratory clinical picture. Headache, anosmia, dysgeusia, and hypopalesthesia predominated in the early stages, with frequent abnormal findings in the CSF (>70%) and less frequently in the EEG (<20%). Conclusions: Headache, anosmia, dysgeusia and hypoesthesia were frequent at the beginning of the infection, together with abnormal findings in CSF and EEG, without other neurological symptoms or neurological disease.

Introducción: existen condiciones neurológicas severas en pacientes con COVID-19, como: enfermedad cerebrovascular, síndrome de Guillain-Barré, encefalitis, encefalopatía necrotizante hemorrágica aguda y mielitis. Objetivo: describimos que el paciente con SARS-CoV-2 con síntomas respiratorios tiene manifestaciones neurológicas sutiles o subclínicas. Material y métodos: estudio observacional, transversal, analítico, que incluyó pacientes de 18-65 años con síntomas respiratorios y diagnóstico de COVID-19 confirmado. Se excluyeron pacientes intubados, con enfermedades neurodegenerativas crónicas o compromiso neurológico preexistente. Se realizó semiología de la cefalea y exploración neurológica; Se midieron los niveles séricos de glucosa, proteínas, electrolitos, lactato, proteína C reactiva, deshidrogenasa láctica y dímero D. También se realizaron análisis de líquido cefalorraquídeo (LCR) y un electroencefalograma (EEG) en los pacientes que aceptaron los riesgos. Resultados: se encontró alta prevalencia de manifestaciones neurológicas sutiles en pacientes con COVID-19 con solo cuadro clínico respiratorio. Cefalea, anosmia, disgeusia e hipopalestesia predominaron en las primeras etapas, con hallazgos anormales frecuentes en el LCR (>70%) y con menos frecuencia en el EEG (<20%). Conclusiones: la cefalea, anosmia, disgeusia e hipoestesia fueron frecuentes al inicio de la infección, junto con hallazgos anormales en LCR y EEG, sin otros síntomas neurológicos ni enfermedad neurológica.

Gut dysbiosis and homocysteine: a couple for boosting neurotoxicity in Huntington disease.

Huntington's disease (HD), a neurodegenerative disorder caused by an expansion of the huntingtin triplet (Htt), is clinically characterized by cognitive and neuropsychiatric alterations. Although these alterations appear to be related to mutant Htt (mHtt)-induced neurotoxicity, several other factors are involved. The gut microbiota is a known modulator of brain-gut communication and when altered (dysbiosis), several complaints can be developed including gastrointestinal dysfunction which may have a negative impact on cognition, behavior, and other mental functions in HD through several mechanisms, including increased levels of lipopolysaccharide, proinflammatory cytokines and immune cell response, as well as alterations in Ca2+ signaling, resulting in both increased intestinal and blood-brain barrier (BBB) permeability. Recently, the presence of dysbiosis has been described in both transgenic mouse models and HD patients. A bidirectional influence between host brain tissues and the gut microbiota has been observed. On the one hand, the host diet influences the composition and function of microbiota; and on the other hand, microbiota products can affect BBB permeability, synaptogenesis, and the regulation of neurotransmitters and neurotrophic factors, which has a direct effect on host metabolism and brain function. This review summarizes the available evidence on the pathogenic synergism of dysbiosis and homocysteine, and their role in the transgression of BBB integrity and their potential neurotoxicity of HD.

Alterations in gene expression due to chronic lead exposure induce behavioral changes.

Lead (Pb) is a pollutant commonly found in the environment, despite the implementation of public health policies intended to remove it. Due to its chemical characteristics as a divalent ion, Pb interacts with cells, enzymes, and tissues, causing pathological, physical, and behavioral alterations. Recent biotechnological advances have helped us to understand the mechanisms underlying the damage caused by Pb in human populations and in experimental models, and new evidence on the epigenetic alterations caused by exposition to environmental Pb is available. It is known that Pb exposure impacts on behavior (causing aggressiveness, anxiety, and depression), leading to learning deficit and locomotor activity alterations, and its presence has been linked with the abnormal release of neurotransmitters and other biochemical changes involved in these disorders. Still, further reductionist studies are required to determine the effects of Pb exposure on DNA and protein expression and understand the processes underlying the diseases caused by Pb. This will also indicate possible therapeutic targets to offset the negative effects of the heavy metal. By elucidating the epigenetic changes involved, it would be possible to manipulate them and propose novel therapeutic approaches in this area. This review is aimed to provide an overview of studies that link Pb exposure to behavioral changes, as well as biochemical and epigenetic alterations at a neurotransmitter level, considering the importance of this metal in behavior abnormalities.

Dysregulated Brain Cholesterol Metabolism Is Linked to Neuroinflammation in Huntington's Disease.

Huntington's disease is an autosomal-dominant, neurodegenerative disorder caused by a CAG repeat expansion in exon-1 of the huntingtin gene. Alterations in cholesterol metabolism and distribution have been reported in Huntington's disease, including abnormal interactions between mutant huntingtin and sterol regulatory element-binding proteins, decreased levels of apolipoprotein E/cholesterol/low-density lipoprotein receptor complexes, and alterations in the synthesis of ATP-binding cassette transporter A1. Plasma levels of 24S-hydroxycholestrol, a key intermediary in cholesterol metabolism and a possible marker in neurodegenerative diseases, decreased proportionally to the degree of caudate nucleus atrophy. The interaction of mutant huntingtin with sterol regulatory element-binding proteins is of particular interest given that sterol regulatory element-binding proteins play a dual role: They take part in lipid and cholesterol metabolism, but also in the inflammatory response that induces immune cell migration as well as toxic effects, particularly in astrocytes. This work summarizes current evidence on the metabolic and immune implications of sterol regulatory element-binding protein dysregulation in Huntington's disease, highlighting the potential use of drugs that modulate these alterations. © 2020 International Parkinson and Movement Disorder Society.

Participation of the dentate-rubral pathway in the kindling model of epilepsy.

Lesions of the cerebellar dentate nucleus (DN) reduce the after-discharge duration induced by repetitive kindling stimulation and decrease seizures to a lower rank according to Racine's scale. The DN sends cholinergic and glutamatergic fibers to the red nucleus (RN), which is composed of glutamatergic and GABAergic cells. To test the participation of these neurotransmitters in seizures, we compared the levels of glutamate and gamma-aminobutyric acid (GABA) at the RN in a control condition, a kindled stage, and a kindled stage followed by DN lesions. We found that the kindled stage was associated with significant reductions in glutamate and GABA in the RN and that the lesions of the DN in kindled rats reversed the severity of seizures and restored the GABA levels. GAD65 , a GABA-synthesizing enzyme, was increased in kindled rats and decreased after DN lesions. GAD65 commonly appears localized at nerve terminals and synapses, and it is only activated when GABA neurotransmission occurs. Thus, it is possible that the increased expression of GAD65 found in kindled rats could be due to an exacerbated demand for GABA due to kindled seizures. It is known that GABA maintains the inhibitory tone that counterbalances neuronal excitation. The decreased expression of GAD65 found after the DN lesions indicated that the GABA-synthesizing enzyme was no longer required once it eliminated the excitatory glutamate input to the RN. We thus conclude that DN lesions and their consequent biochemical changes are capable of decreasing the generalized seizures induced by kindling stimulation. © 2016 Wiley Periodicals, Inc.

Exposure to ozone induces a systemic inflammatory response: possible source of the neurological alterations induced by this gas.

The World Health Organization identified urban outdoor air pollution as the eighth highest mortality risk factor in high-income countries. Exposure to ambient pollutants such as ozone (O3) increases the number of hospital admissions. O3 is a highly reactive gas that reacts with cells lining the airways, producing the formation of reactive oxygen species and inflammation. Beyond the respiratory system, O3 exposure also produces fatigue, lethargy, headaches, and significant decrease in rapid-eye-movement sleep related to an increase in slow-wave sleep. Interestingly, these sleep changes can be significantly mitigated by treatment with indomethacin, which suggests that an inflammatory mechanism may be responsible for these neurological symptoms. To characterize the inflammatory mechanisms by which O3 affects tissues outside the pulmonary system, we evaluated inflammatory factors in both lung and brain. Rats exposed to 1 part per million O3 for 1, 3 or 6 h, as well as rats exposed daily for 1 or 3 h over five consecutive days, showed increases in TNF-α and IL-6 levels within the lungs as well as increases in TNF-α, IL-6, NF-κB p50 and GFAP levels in the cerebral cortex. These results support the hypothesis that the neuroinflammatory response may be responsible for the central nervous system effects of O3 exposure.

The effects of ozone exposure and associated injury mechanisms on the central nervous system.

Ozone (O3) is a component of photochemical smog, which is a major air pollutant and demonstrates properties that are harmful to health because of the toxic properties that are inherent to its powerful oxidizing capabilities. Environmental O3 exposure is associated with many symptoms related to respiratory disorders, which include loss of lung function, exacerbation of asthma, airway damage, and lung inflammation. The effects of O3 are not restricted to the respiratory system or function - adverse effects within the central nervous system (CNS) such as decreased cognitive response, decrease in motor activity, headaches, disturbances in the sleep-wake cycle, neuronal dysfunctions, cell degeneration, and neurochemical alterations have also been described; furthermore, it has also been proposed that O3 could have epigenetic effects. O3 exposure induces the reactive chemical species in the lungs, but the short half-life of these chemical species has led some authors to attribute the injurious mechanisms observed within the lungs to inflammatory processes. However, the damage to the CNS induced by O3 exposure is not well understood. In this review, the basic mechanisms of inflammation and activation of the immune system by O3 exposure are described and the potential mechanisms of damage, which include neuroinflammation and oxidative stress, and the signs and symptoms of disturbances within the CNS caused by environmental O3 exposure are discussed.