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BACKGROUND: The existing data about language recovery in bilingual patients come from few studies on acute lesional deficits like stroke or traumatic injury. Still, little is known about the neuroplasticity potential of bilingual patients who undergo resection of gliomas affecting language-eloquent brain regions. In this study, we prospectively evaluated the pre- and postoperative language functions among bilinguals with eloquent region gliomas. METHODS: We have prospectively collected the preoperative, 3-month and 6-month postoperative data from patients with tumors infiltrating the dominant hemisphere language areas during a 15-month period. Validated Persian/Turkish version of Western Aphasia Battery test and Addenbrooke Cognitive Examination were assessed for main language (L1) and second acquired languages (L2) in each visit. RESULTS: Twenty-two right-handed bilingual patients were enrolled, and language proficiencies were assessed using mixed model analysis. On baseline and postoperative points, L1 had higher scores in all Addenbrooke Cognitive Examination and Western Aphasia Battery subdomains than L2. Both languages had deterioration at 3-month visit; however, L2 was significantly more deteriorated in all domains. At 6-month visit, both L1 and L2 showed recovery; however, L2 recovered to a less extent than L1. The single most parameter affecting the ultimate language outcome in this study was the preoperative functional level of L1. CONCLUSIONS: This study shows L1 is less vulnerable to operative insults and L2 may be damaged even when L1 is preserved. We would suggest the more sensitive L2 be used as the screening tool and L1 be used for confirmation of positive responses during language mapping.
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Afasia , Glioma , Multilingüismo , Humanos , Habla , Lenguaje , Afasia/etiología , Afasia/patología , Glioma/cirugíaRESUMEN
Based on previous studies, seizure has been reported to accompany coronavirus disease 2019 (COVID-19). Underlying mechanisms are those leading to the direct central nervous system (CNS) invasion through hematogenous spread or trans-synaptic retrograde invasion, causing meningoencephalitis. On the other hand, there are pathophysiologic mechanisms that seizure would be one of their early consequences, such as cytokine storm, hypoxemia, metabolic derangement, and structural brain lesions. Herein, we focused on available evidence to provide an insight into the pathophysiologic mechanisms that link seizure and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, as a better understanding of pathophysiology would lead to better diagnosis and treatment.
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BACKGROUND: Socioeconomic status (SES) is associated with stroke incidence and mortality. Distribution of stroke risk factors is changing worldwide; evidence on these trends is crucial to the allocation of resources for prevention strategies to tackle major modifiable risk factors with the highest impact on stroke burden. METHODS: We extracted data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. We analysed trends in global and SES-specific age-standardised stroke incidence, prevalence, mortality, and disability-adjusted life years (DALYs) lost from 1990 to 2017. We also estimated the age-standardised attributable risk of stroke mortality associated with common risk factors in low-, low-middle-, upper-middle-, and high-income countries. Further, we explored the effect of age and sex on associations of risk factors with stroke mortality from 1990 to 2017. RESULTS: Despite a growth in crude number of stroke events from 1990 to 2017, there has been an 11.3% decrease in age-standardised stroke incidence rate worldwide (150.5, 95% uncertainty interval [UI] 140.3-161.8 per 100,000 in 2017). This has been accompanied by an overall 3.1% increase in age-standardised stroke prevalence rate (1300.6, UI 1229.0-1374.7 per 100,000 in 2017) and a 33.4% decrease in age-standardised stroke mortality rate (80.5, UI 78.9-82.6 per 100,000 in 2017) over the same time period. The rising trends in age-standardised stroke prevalence have been observed only in middle-income countries, despite declining trends in age-standardised stroke incidence and mortality in all income categories since 2005. Further, there has been almost a 34% reduction in stroke death rate (67.8, UI 64.1-71.1 per 100,000 in 2017) attributable to modifiable risk factors, more prominently in wealthier countries. CONCLUSIONS: Almost half of stroke-related deaths are attributable to poor management of modifiable risk factors, and thus potentially preventable. We should appreciate societal barriers in lower-SES groups to design tailored preventive strategies. Despite improvements in general health knowledge, access to healthcare, and preventative strategies, SES is still strongly associated with modifiable risk factors and stroke burden; thus, screening of people from low SES at higher stroke risk is crucial.
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Carga Global de Enfermedades , Clase Social , Accidente Cerebrovascular/epidemiología , Adulto , Anciano , Preescolar , Personas con Discapacidad/estadística & datos numéricos , Femenino , Carga Global de Enfermedades/métodos , Carga Global de Enfermedades/estadística & datos numéricos , Carga Global de Enfermedades/tendencias , Salud Global/estadística & datos numéricos , Salud Global/tendencias , Humanos , Incidencia , Masculino , Prevalencia , Años de Vida Ajustados por Calidad de Vida , Factores de Riesgo , Accidente Cerebrovascular/mortalidad , Tasa de SupervivenciaRESUMEN
OBJECTIVES: The endoscopic approach increasingly is used to treat third ventricular colloid cysts. Our objective was to assess the results of endoscopic resection of colloid cysts of the third ventricle. METHODS: A retrospective study was designed, and a series of 112 consecutive patients (76 male, 36 female) with third ventricular colloid cyst treated by endoscopic surgery was undertaken. RESULTS: We found that the most common clinical presentations in patients with third ventricular colloid cyst were headache, vomiting, and impaired vision. Complete resection was obtained in majority of patients (92%). Meningitis, hemiparesis, and memory deficits occurred most commonly as postoperative complications. CONCLUSIONS: High rates of complete resection of third ventricular colloid cysts, with low morbidity and mortality, are possible with an endoscopic approach. The results of this study support the role of endoscopic resection in the treatment of patients with third ventricular colloid cysts as a safe and effective modality and show how endoscopic resection of third ventricular colloid cysts can produce favorable results.
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Quiste Coloide/cirugía , Neuroendoscopía/métodos , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neuroendoscopía/efectos adversos , Complicaciones Posoperatorias/epidemiología , Estudios Retrospectivos , TiempoRESUMEN
Anxiety-related disorders are complex illnesses that underlying molecular mechanisms need to be understood. Mitochondria stand as an important link between energy metabolism, oxidative stress, and anxiety. The nuclear factor, erythroid-derived 2,-like 1(Nrf1) is a member of the cap "n" collar subfamily of basic region leucine zipper transcription factors and plays the major role in regulating the adaptive response to oxidants and electrophiles within the cell. Here, we injected small interfering RNA (siRNA) targeting Nrf1 in dorsal third ventricle of adult male albino Wistar rats and subsequently examined the effect of this silencing on anxiety-related behavior. We also evaluated apoptotic markers and mitochondrial biogenesis factors, along with electron transport chain activity in three brain regions: hippocampus, amygdala, and prefrontal cortex. Our data revealed that in the group that received Nrf1-siRNA, anxiety-related behavior did not show any significant changes compared to the control group. Caspase-3 did not increase in Nrf1-siRNA-injected rats even though Bax/Bcl2 ratio markedly elevated in Nrf1-knockdown rats in all three mentioned regions compared to control rats. Also, Nrf1 silencing of complex I and II-III did not alter, generally. In addition, Nrf1-knockdown affected mitochondrial biogenesis markers. The level of peroxisome proliferator-activated receptor gamma coactivator-1α and cytochrome-c increased, which indicates a possible role for mitochondrial biogenesis in anxiety.
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Ansiedad/patología , Conducta Animal , Técnicas de Silenciamiento del Gen , Mitocondrias/patología , Factor Nuclear 1 de Respiración/metabolismo , Estrés Oxidativo , Animales , Apoptosis , Western Blotting , Encéfalo/enzimología , Encéfalo/metabolismo , Encéfalo/patología , Caspasa 3/metabolismo , Transporte de Electrón , Silenciador del Gen , Masculino , Mitocondrias/metabolismo , Factor Nuclear 1 de Respiración/genética , Biogénesis de Organelos , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/metabolismo , Ratas Wistar , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Several pathways involved in regulation of intracellular protein integrity are known as the protein quality control (PQC) system. Molecular chaperones as the main players are engaged in various aspects of PQC system. According to the importance of these proteins in cell survival, in the present study, we traced endoplasmic reticulum-specific markers and chaperone-mediated autophagy (CMA)-associated factors as two main arms of PQC system in intra-hippocampal amyloid beta (Aß)-injected rats during 10 days running. Data analysis from Western blot indicated that exposure to Aß activates immunoglobulin heavy-chain-binding protein (Bip) which is the upstream regulator of unfolded protein responses (UPR). Activation of UPR system eventually led to induction of pro-apoptotic factors like CHOP, calpain, and caspase-12. Moreover, our data revealed that protein disulfide isomerase activity dramatically decreased after Aß injection, which could be attributed to the increased levels of nitric oxide. Besides, Aß injection induced levels of 2 members of heat shock proteins (Hsp) 70 and 90. Elevated levels of Hsps family members are accompanied by increased levels of lysosome-associated membrane protein type-2A (Lamp-2A) that are involved in CMA. Despite the reduction in CHOP, calpain, caspase-12, and Lamp-2A protein levels, the levels of molecular chaperones Bip, Hsps70, and 90 increased 10 days after Aß injection in comparison to the control group. Based on our results, 10 days after Aß injection, despite the activation of protective chaperones, markers associated with neurotoxicity were still elevated.
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Péptidos beta-Amiloides/metabolismo , Hipocampo/metabolismo , Óxido Nítrico/metabolismo , Proteína Disulfuro Isomerasas/metabolismo , Desplegamiento Proteico , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Masculino , Unión Proteica/fisiología , Ratas WistarRESUMEN
Although percutaneous dilatational tracheostomy (PDT) is more accessible and less time-demanding compared with surgical tracheostomy (ST), it has its own limitations. We introduced a modified PDT technique and brought some surgical knowledge to the bedside to overcome some standard percutaneous dilatational tracheostomy relative contraindications. PDT uses a blind route of tracheal access that usually requires perioperational imaging guidance to protect accidental injuries. Moreover, there are contraindications in certain cases, limiting widespread PDT application. Different PDT modifications and devices have been represented to address the problem; however, these approaches are not generally popular among professionals due to limited accessibility and/or other reasons.We prospectively analyzed the double-blinded trial, patient and nurse head evaluating the complications, and collected data from 360 patients who underwent PDT, ST, or our modified mini-surgical PDT (msPDT, Hashemian method). These patients were divided into 2 groups-contraindicated to PDT-and randomization was done for msPDT or PDT in PDT-indicated group and msPDT or ST for PDT-contraindicated patients. The cases were compared in terms of pre and postoperational complications.Data analysis demonstrated that the mean value of procedural time was significantly lower in the msPDT group, either compared with the standard PDT or the ST group. Paratracheal insertion, intraprocedural hypoxemia, and bleeding were also significantly lower in the msPDT group compared with the standard PDT group. Other complications were not significantly different between msPDT and ST patients.The introduced msPDT represented a semiopen incision, other than blinded PDT route of tracheal access that allowed proceduralist to withdraw bronchoscopy and reduced the total time of procedure. Interestingly, the most important improvement was performing msPDT on PDT-contraindicated patients with the complication rate comparable to surgical procedure. Supplements citation missing in the text. Please check supplements video in original manuscript.
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Procedimientos Quirúrgicos Mínimamente Invasivos , Insuficiencia Respiratoria/cirugía , Traqueostomía , APACHE , Adulto , Anciano , Contraindicaciones , Dilatación/efectos adversos , Dilatación/métodos , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos/efectos adversos , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/etiología , Traqueostomía/efectos adversos , Traqueostomía/métodos , Resultado del TratamientoRESUMEN
Choroid plexus epithelial cells (CPECs) as a secretory epithelium are responsible for the secretion of cerebrospinal fluid (CSF). Beyond this classical tenet, CPECs also synthesize and release many neurotrophic factors such as antioxidants into the CSF, participating in brain homeostasis. In this study, CPECs were isolated from rat's brain and encapsulated in alginate microcapsules. Firstly, functional properties of alginate microcapsules and encapsulated CPECs were examined in vitro. Following, micro-encapsulated CPECs were grafted into rats' brains that were pretreated with Aß. The in vivo studies include western blotting against Caspase-3 and Terminal-Transferase dUTP Nick End Labeling test that were performed to detect apoptosis in brain tissues. The in vivo part also included immunohistochemistry against Iba-1, glial fibrillary acidic protein, and Brdu to detect microglial migration, gliosis, and neurogenesis, respectively. Moreover, the activity of superoxide dismutase enzyme in hippocampi also was measured, and the memory was assessed by shuttle box apparatus. Our data suggest that transplantation of encapsulated CPECs resulted in a significant decrease in apoptosis, reduced migration microglia, diminished gliosis, increased neurogenesis, and improved long-term memory as well as upregulated antioxidant activity. Since microencapsulated CPECs do not need immunosuppression following implantation, and also we showed their neuroprotective effects against Aß toxicity and oxidative stress, this may be a suitable candidate for cell therapy in neurological disorders.
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Apoptosis , Células Epiteliales/trasplante , Hipocampo/patología , Trastornos de la Memoria/terapia , Memoria a Largo Plazo , Neurogénesis , Alginatos , Péptidos beta-Amiloides/toxicidad , Animales , Cápsulas/química , Plexo Coroideo/citología , Hipocampo/fisiopatología , Masculino , Trastornos de la Memoria/etiología , Ratas , Ratas Wistar , Regulación hacia ArribaRESUMEN
One of the neuropathological hallmarks of Alzheimer's disease (AD) is the accumulation of beta-amyloid peptides (Aß) in senile plaques. Aß-induced oxidative stress is believed to be responsible for degeneration and apoptosis of neurons and consequent cognitive and memory deficits. Here, we investigated the possible neuroprotective effect of the heat shock protein 90 (Hsp90) inhibitor geldanamycin (GA) against amyloid pathogenesis in adult male Wistar rats. GA or vehicle was injected into the lateral cerebral ventricles of rats 24 h before injection of Aß (1-42) in CA1 area of hippocampus. The learning and memory of the rats were assessed 7 days after injection of Aß using passive avoidance (PA) task. As potential contributing factors in Aß-induced memory decline, we evaluated apoptotic markers and also used terminal-transferase UTP nick end labeling (TUNEL) technique to detect apoptosis in the hippocampus of Aß-injected rats. Our behavioral data suggest that GA pretreatment can significantly suppress memory deficits in Aß-injected rats. There was also not only a marked increase in Hsp70 level but also upregulated 70 kDa ribosomal protein S6 kinase (p70S6K) in the hippocampus of GA-treated groups with a reduction in apoptotic factors including caspase-3, poly (ADP-ribose) polymerase, Bax/Bcl-2 ratio, and TUNEL-positive cells as well. Thus, we conclude that GA exerts its protective effects against Aß (1-42) toxicity and memory deficits, at least in part, by upregulating of Hsp70 and P70S6K.
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Péptidos beta-Amiloides/toxicidad , Apoptosis/efectos de los fármacos , Benzoquinonas/farmacología , Proteínas HSP70 de Choque Térmico/metabolismo , Hipocampo/metabolismo , Lactamas Macrocíclicas/farmacología , Memoria a Largo Plazo/efectos de los fármacos , Fragmentos de Péptidos/toxicidad , Proteínas Quinasas S6 Ribosómicas 70-kDa/metabolismo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Animales , Conducta Animal/efectos de los fármacos , Caspasa 3/metabolismo , Modelos Animales de Enfermedad , Glutatión/metabolismo , Proteínas HSP90 de Choque Térmico/metabolismo , Hipocampo/efectos de los fármacos , Masculino , Fosforilación/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Ratas , Ratas Wistar , Regulación hacia Arriba/efectos de los fármacos , Proteína X Asociada a bcl-2/metabolismoRESUMEN
By the current study, we tried to find out the interactive mechanisms enrolled by Hsp70 and Hsp90 following the 6-hydroxydopamine (6-OHDA)-induced oxidative stress. Of heat shock protein (Hsp) family, we have previously evaluated the effects of Hsp90 gene silencing on in vitro model of Parkinson's disease and its influence on controlling the mechanisms of cell survival. Here, we extended our study to Hsp70 silencing short interfering RNA (siRNA) oligonucleotides, transfected into Pheochromocytoma (PC12) cells with/without exposure to 6-OHDA stress. In order to determine the probable effects of Hsp70 silencing on apoptotic factors, we assessed Bcl2/Bax ratio, nuclear level of PARP, and cleavage of caspase-3 under 6-OHDA stress condition. The results showed deteriorated effect of Hsp70 siRNA on apoptosis in cells exposed to only 6-OHDA. This is, at least in part, in consequence of upregulation of Hsp90, both at messenger RNA (mRNA) and protein levels. These data highlight the critical role of Hsp70 for cell survival under 6-OHDA stress condition. It could be a suggestive issue for supervision of caspase cascades by survival roles of Hsps as Hsp70 silencing resulted in apoptosis phenomenon. Convergence of Hsp70 anti-apoptotic and 6-OHDA pro-apoptotic pathways may explain intensified apoptosis following Hsp70 silencing. In addition, nuclear factor erythroid-2-related factor 2 (Nrf2), a transcription factor, has been previously studied in detoxification of oxidative stress. For this issue, we tried to elucidate Hsp70 silencing impact on Nrf2, which has been shown to regulate the transcription of Hsp70, unspecifically. Besides, our investigations revealed that Hsp70 siRNA did not affect the level of Nrf2 during 6-OHDA exposure. But, it is still a dealing question and other investigations are needed to have a comprehensive perception of Hsp family signaling functions.
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Apoptosis , Proteínas HSP70 de Choque Térmico , Proteínas HSP90 de Choque Térmico , Regulación hacia Arriba , Animales , Ratas , Silenciador del Gen , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/genética , Proteínas HSP90 de Choque Térmico/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Oxidopamina/farmacología , Células PC12 , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
Anxiety-related disorders are complex illnesses that underlying molecular mechanisms of these complicated emotional disorders are poorly understood. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the most important regulator of the antioxidant defense system. Its protective actions are not only limited to antioxidative transactivation, but also plays important roles in encountering various physiological and pathological stresses. In this study, we evaluated whether silencing of Nrf2 plays a role in development of anxiety-related behavior. In this regard, we exerted small interfering RNA (siRNA) targeting Nrf2 in dorsal third ventricle and subsequently examined the effect of this silencing on anxiety-related behavior along with supposed molecular mechanisms. Therefore, we evaluated apoptotic markers and mitochondrial electron transport chain (ETC) activity in three brain regions: hippocampus, amygdala, and prefrontal cortex. Based on our result, Nrf2-silenced rats exhibited greater anxiety-like behavior compared to control group. Furthermore, Nrf2 silencing increased activity of ETC complexes. Also, Bax/Bcl2 ratio of all mentioned areas of the brain and cleavage of caspase-3 in hippocampus increased in Nrf2 silenced group, however, with a distinct pattern.
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Amígdala del Cerebelo/metabolismo , Ansiedad/metabolismo , Hipocampo/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fosforilación Oxidativa , Corteza Prefrontal/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Animales , Apoptosis , Proteínas del Complejo de Cadena de Transporte de Electrón/metabolismo , Masculino , Factor 2 Relacionado con NF-E2/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Ratas , Ratas Wistar , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
Protein aggregation is impacted by many factors including temperature, pH, and the presence of surfactants, electrolytes, and metal ions. The addition of sodium dodecyl sulphate (SDS) at different concentrations may play a significant role in the human serum albumin (HSA) fibrillation pathway. Here the heat induction of HSA fibrillation incubated with different concentrations of SDS was evaluated using a variety of techniques. These included ThT fluorescence, Congo red absorbance, circular dichroism, dynamic light scattering, and atomic force microscopy (AFM). To explore HSA surface properties, the surface tension of solutions was measured using Du Noüy Ring method tensiometry. In addition, the criteria of neurite outgrowth and complexity were monitored by exposing PC12 cells to different forms of HSA amyloid intermediates. ThT fluorescence kinetic studies indicated that SDS at low concentrations induced more fibrillation of HSA, while SDS at high concentrations inhibited the fibrillation of HSA. At higher SDS concentrations hydrophobic forces had a significant role whereas at lower SDS concentrations electrostatic forces were dominant. The cell culture studies demonstrated the significant impact of SDS concentration on HSA fibrillation and subsequent neuronal cell morphology. The HSA incubated with low concentrations of SDS inhibited neurite outgrowth and complexity of the PC12 cells, whereas high concentrations of SDS had lesser effect. Thus, SDS acts as a salt at lower concentrations, while at higher concentrations acts as a chaperon, with significant impact on fibrillation of HSA.
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Albúmina Sérica/metabolismo , Dodecil Sulfato de Sodio/farmacología , Animales , Dicroismo Circular , Relación Dosis-Respuesta a Droga , Fluorescencia , Humanos , Cinética , Microscopía de Fuerza Atómica , Células PC12 , Ratas , Tensión SuperficialRESUMEN
Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder that has been shown to be associated with oxidative stress. This phenomenon occurs primarily via generation of 6-hydroxydopamine(6-OHDA) in catecholaminergic neurons leading to activation of apoptosis. The 90-kDa heat shock protein (Hsp90) functions as a chaperone in maintaining the functional stability and viability of cells under a transforming pressure. Since Hsp90 binds to inactive transcription factor heat shock factor-1 (HSF-1), inhibition of Hsp90 could activate HSF-1 and transcription of heat shock element containing genes subsequently, like Hsp70 as an anti-apoptotic factor. Our trial of silencing Hsp90 expression through transfection of Hsp90 siRNAs into neuronal PC12 cells being exposed to 6-OHDA resulted in the inhibition of pro-apoptotic factors, Bax, caspase-3, and PARP and upregulation of anti-apoptotic factor, Bcl2. In this manner,our data suggest a protective role for Hsp70 as it was observed to be induced upon Hsp90 knockdown. Furthermore, our results showed that Hsp90 silencing against 6-OHDA-induced oxidative stress may associate with upregulation of nuclear factor-erythroid 2-related factor 2. In summary, we found that silencing of Hsp90 expression leads to induction of cytoprotective pathways which can protect neurons against apoptosis in a PD model.
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Proteínas HSP90 de Choque Térmico/metabolismo , Neuronas/metabolismo , Interferencia de ARN , Animales , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Supervivencia Celular , Proteínas HSP70 de Choque Térmico/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP90 de Choque Térmico/genética , Neuronas/efectos de los fármacos , Oxidopamina/toxicidad , Células PC12 , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/genética , RatasRESUMEN
Interrelation between oxidative stress and neuro-inflammation has been discussed extensively to contribute to neuronal dysfunction in neurodegenerative disorders. In this manner, it seems that there is an intriguing link between protein kinase A (PKA), neuronal apoptosis and inflammation. Rat PC12 pheochromocytoma cell can be induced to differentiate into neuron-like cells possessing elongated neurites by nerve growth factor. In this study, we investigated the effect of H-89, a selective inhibitor of PKA, on the neurite retraction along with evaluation of cell death and inflammatory markers in the differentiated PC12 cells, exposed to H2O2. We found that dose-dependent inhibition of PKA by low and medium concentrations of H-89 (5, 7 and 10 µM) enhanced the parameters of neurite outgrowth and complexity in the cells co-treated with H2O2 as an oxidative stress. Similar concentrations of H-89 significantly inhibited cell death and neurite retraction induced by oxidative stress. Components of TNF-α-NFκB-COX-2 axis, a discussed pathway in neuroinflammation, downregulated dose-dependently by administration of H-89 in H2O2-induced PC12 cells. In this condition, PKA inhibition by the high concentrations of H-89 (15 and 20 µM) led to enhanced cell death and inflammation with decreased neurite outgrowth. These findings indicate that H-89 has a dual contradictory effect on oxidative stress and inflammation that affect neurite outgrowth and complexity in differentiated PC12 cells.
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Neuritas/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Animales , Apoptosis , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Relación Dosis-Respuesta a Droga , Peróxido de Hidrógeno/toxicidad , FN-kappa B/genética , FN-kappa B/metabolismo , Neuritas/metabolismo , Estrés Oxidativo , Células PC12 , Ratas , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The endoplasmic reticulum (ER) lumen is chemically complex and crowded with polypeptides in different stages of assembly. ER quality control monitors chaperone-assisted protein folding, stochastic errors and off-pathway intermediates. In acute conditions, potentially toxic polypeptides overflow the capacity of the chaperone system and lead to ER stress. Activation of the unfolded protein response (UPR) following ER stress buys time for non-native polypeptides to refold or be eliminated; otherwise cell death occurs. The clearance routes for deleterious proteins are endoplasmic reticulum-associated degradation (ERAD) and ER stress-activated autophagy. The ERAD pathway is a chaperone and proteasome-mediated polypeptide degradation, while autophagy applies to wider range of substances. ER stress signal transduction recruits diverse molecules and pathways upon UPR induction to compensate stress condition. NF-E2-related factor 1 (Nrf1) and Nrf2 are two transcription factors mostly known by their induction through an antioxidant response; they can also be activated by UPR machinery. Discovery of diverse molecules downstream of Nrf1 and Nrf2 has expanded our understanding of the biological impacts of these transcription factors beyond classic antioxidant activation. In this review, we summarize our current understanding of mutual relationships between Nrf1, Nrf2, and ER stress clearance mechanisms and highlight the crosstalk of specific molecules mediating these correlations.