Mei-Li Díaz Hung

Bio: Mei-Li Díaz Hung is an academic researcher. The author has contributed to research in topics: Dopaminergic & Unfolded protein response. The author has an hindex of 2, co-authored 5 publications receiving 22 citations.

Follow-Up of Peripheral IL-1β and IL-6 and Relation with Apoptotic Death in Drug-Resistant Temporal Lobe Epilepsy Patients Submitted to Surgery

Abstract: Increasing amounts of evidence support the role of inflammation in epilepsy. This study was done to evaluate serum follow-up of IL-1β and IL-6 levels, as well as their concentration in the neocortex, and the relationship of central inflammation with NF-κB and annexin V in drug-resistant temporal lobe epileptic (DRTLE) patients submitted to surgical treatment. Peripheral and central levels of IL-1β and IL-6were measured by ELISA in 10 DRTLE patients. The sera from patients were taken before surgery, and 12 and 24 months after surgical treatment. The neocortical expression of NF-κB was evaluated by western blotting and annexin V co-localization with synaptophysin by immunohistochemistry. The neocortical tissues from five patients who died by non-neurological causes were used as control. Decreased serum levels of IL-1 and IL-6 were observed after surgery; at this time, 70% of patients were seizure-free. No values of IL-1 and IL-6 were detected in neocortical control tissue, whereas cytokine levels were evidenced in DRTLE. Increased NF-κB neocortex expression was found and the positive annexin V neurons were more obvious in the DRTLE tissue, correlating with IL-6 levels. The follow-up study confirmed that the inflammatory alterations disappeared one year after surgery, when the majority of patients were seizure-free, and the apoptotic death process correlated with inflammation.

Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging

Abstract: Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age‐related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Mecanismos fisiopatológicos que desencadenan procesos de muerte neuronal en la epilepsia del lóbulo temporal farmacorresistente

Abstract: Introduction. In relation to drug-resistant temporal lobe epilepsy (DRTLE), the interrelation between inflammation, oxidative stress, and neuronal death constitutes a topic increasingly researched into. Objectives: To expand the knowledge of the molecular mechanisms that participate in the pathophysiology of DRTLE by correlating clinical variables with immunological ones, oxidative stress and neuronal death. Methods. Immunocytochemistry techniques were used to measure the markers CD3, CD4, CD8, CD19, CD25, HLA-DR; Nephelometry was used for IgG, IgM, IgA, and Albumin; immunoenzymatic tests for IL-1β, IL-6, TNF-α, and nitric oxide. By means of western blot: NFκB, JNK, 4-hydroxy-2-nonenal, 3-nitrotyrosine; by means of spectrophotometry: malonildialdehyde, advanced glycation products, advanced protein oxidation products, uric acid, superoxide dismutase, glutathione, and vitamin C; by means of immunohistochemistry: Annexin V, TUNEL, synaptophysin, caspase 3, p53, and bcl-2; by means of HPLC: glutamate and by means of autorradiography: 5-HT, 5-HT1A, 5-HT7. Results. It is shown that seizures are the pathogenic substrate of immunological, inflammatory and oxidative stress disorders in DRTLE. The clinical variables are related to the molecular and protein studies conducted and all together show the neuronal death in the DRTLE.

Efecto de la deficiencia transitoria de glutatión sobre el funcionamiento de la vía nigro-estriatal y la conducta motora de ratas

Abstract: La enfermedad de Parkinson (EP) es una enfermedad neurodegenerativa que afecta aproximadamente 9,5/1000 personas mayores de 65 anos. Es una enfermedad con una incidencia creciente en Cuba y una de las primeras causas de atencion medica en el CIREN. Debido a su caracter progresivo se hace necesaria la comprension de los mecanismos moleculares involucrados en el dano neuronal que en la actualidad no estan bien dilucidados. Trabajos recientes han demostrado que el mantenimiento de la concentracion de GSH es esencial para proteger a la SNpc de la neurodegeneracion. Sin embargo, el efecto directo de la disminucion del GSH sobre la supervivencia de la celula dopaminergica y la conducta motora no ha sido esclarecido in vivo . De ahi que el objetivo de este trabajo fue determinar el efecto de la disminucion transitoria de la concentracion de glutation sobre el funcionamiento de la substantia nigra pars compacta (SNpc) y la conducta motora de ratas. La administracion unica por cirugia estereotactica de L-butionina sulfoximina en la SNpc produjo disminucion transitoria de la concentracion de glutation nigral y estriatal, lo que constituye un modelo valido para estudiar el papel de esta molecula en el sistema nervioso central. La evaluacion conductual demostro, por primera vez, que la disminucion transitoria de la concentracion de glutation nigral produce alteraciones en la conducta motora de ratas, lo que evidencio la importancia de este antioxidante para el funcionamiento del sistema motor de ratas. Estos cambios conductuales se acompanaron de muerte de neuronas dopaminergicas en la SNpc y cambios en la expresion de genes relacionados con la plasticidad del sistema nigro-estriatal. Por otra parte, la disminucion transitoria de la concentracion de glutation resulta en una acumulacion de oxido nitrico y alteracion de la senalizacion redox hacia la activacion de los mecanismos de apoptosis, asi como un desbalance en los mecanismos de neuroinflamacion que pueden contribuir a perpetuar el dano en esta estructura.

Cyclooxygenase-2 (COX-2) inhibitors: future therapeutic strategies for epilepsy management

Abstract: Epilepsy, a common multifactorial neurological disease, affects about 69 million people worldwide constituting nearly 1% of the world population. Despite decades of extensive research on understanding its underlying mechanism and developing the pharmacological treatment, very little is known about the biological alterations leading to epileptogenesis. Due to this gap, the currently available antiepileptic drug therapy is symptomatic in nature and is ineffective in 30% of the cases. Mounting evidences revealed the pathophysiological role of neuroinflammation in epilepsy which has shifted the focus of epilepsy researchers towards the development of neuroinflammation-targeted therapeutics for epilepsy management. Markedly increased expression of key inflammatory mediators in the brain and blood-brain barrier may affect neuronal function and excitability and thus may increase seizure susceptibility in preclinical and clinical settings. Cyclooxygenase-2 (COX-2), an enzyme synthesizing the proinflammatory mediators, prostaglandins, has widely been reported to be induced during seizures and is considered to be a potential neurotherapeutic target for epilepsy management. However, the efficacy of such therapy involving COX-2 inhibition depends on various factors viz., therapeutic dose, time of administration, treatment duration, and selectivity of COX-2 inhibitors. This article reviews the preclinical and clinical evidences supporting the role of COX-2 in seizure-associated neuroinflammation in epilepsy and the potential clinical use of COX-2 inhibitors as a future strategy for epilepsy treatment.

Role of the Angiotensin Pathway and its Target Therapy in Epilepsy Management

Abstract: Despite extensive research on epileptogenesis, there is still a need to investigate new pathways and targeted therapeutic approaches in this complex process. Inflammation, oxidative stress, neurotoxicity, neural cell death, gliosis, and blood–brain barrier (BBB) dysfunction are the most common causes of epileptogenesis. Moreover, the renin–angiotensin system (RAS) affects the brain’s physiological and pathological conditions, including epilepsy and its consequences. While there are a variety of available pharmacotherapeutic approaches, information on new pathways is in high demand and the achievement of treatment goals is greatly desired. Therefore, targeting the RAS presents an interesting opportunity to better understand this process. This has been supported by preclinical studies, primarily based on RAS enzyme, receptor-inhibition, and selective agonists, which are characterized by pleiotropic properties. Although there are some antiepileptic drugs (AEDs) that interfere with RAS, the main targeted therapy of this pathway contributes in synergy with AEDs. However, the RAS-targeted treatment alone, or in combination with AEDs, requires clinical studies to contribute to, and clarify, the evidence on epilepsy management. There is also a genetic association between RAS and epilepsy, and an involvement of pharmacogenetics in RAS, so there are possibilities for the development of new diagnostic and personalized treatments for epilepsy.

Oxidative Stress in Patients with Drug Resistant Partial Complex Seizure.

Abstract: Oxidative stress (OS) has been implicated as a pathophysiological mechanism of drug-resistant epilepsy, but little is known about the relationship between OS markers and clinical parameters, such as the number of drugs, age onset of seizure and frequency of seizures per month. The current study’s aim was to evaluate several oxidative stress markers and antioxidants in 18 drug-resistant partial complex seizure (DRPCS) patients compared to a control group (age and sex matched), and the results were related to clinical variables. We examined malondialdehyde (MDA), advanced oxidation protein products (AOPP), advanced glycation end products (AGEs), nitric oxide (NO), uric acid, superoxide dismutase (SOD), glutathione, vitamin C, 4-hydroxy-2-nonenal (4-HNE) and nitrotyrosine (3-NT). All markers except 4-HNE and 3-NT were studied by spectrophotometry. The expressions of 4-HNE and 3-NT were evaluated by Western blot analysis. MDA levels in patients were significantly increased (p ≤ 0.0001) while AOPP levels were similar to the control group. AGEs, NO and uric acid concentrations were significantly decreased (p ≤ 0.004, p ≤ 0.005, p ≤ 0.0001, respectively). Expressions of 3-NT and 4-HNE were increased (p ≤ 0.005) similarly to SOD activity (p = 0.0001), whereas vitamin C was considerably diminished (p = 0.0001). Glutathione levels were similar to the control group. There was a positive correlation between NO and MDA with the number of drugs. The expression of 3-NT was positively related with the frequency of seizures per month. There was a negative relationship between MDA and age at onset of seizures, as well as vitamin C with seizure frequency/month. We detected an imbalance in the redox state in patients with DRCPS, supporting oxidative stress as a relevant mechanism in this pathology. Thus, it is apparent that some oxidant and antioxidant parameters are closely linked with clinical variables.