RESUMO
The steroidal drug Tibolone is used for the treatment of climacteric symptoms and osteoporosis in post-menopausal women. Although Tibolone has been shown to exert neuroprotective actions after middle cerebral artery occlusion, its specific actions on glial cells have received very little attention. In the present study we have assessed whether Tibolone exerts protective actions in a human astrocyte cell model, the T98G cells, subjected to glucose deprivation. Our findings indicate that Tibolone decreases the effects of glucose deprivation on cell death, nuclear fragmentation, superoxide ion production, mitochondrial membrane potential, cytoplasmic calcium concentration and morphological parameters. These findings suggest that glial cells may participate in the neuroprotective actions of Tibolone in the brain.
Assuntos
Astrócitos/efeitos dos fármacos , Moduladores de Receptor Estrogênico/farmacologia , Glucose/metabolismo , Fármacos Neuroprotetores/farmacologia , Norpregnenos/farmacologia , Astrócitos/metabolismo , Astrócitos/fisiologia , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismoRESUMO
Cortical spreading depression (CSD) is a presumably pathophysiological phenomenon that interrupts local cortical function for periods of minutes to hours. This phenomenon is important due to its association with different neurological disorders such as migraine, malignant stroke and traumatic brain injury (TBI). Glial cells, especially astrocytes, play an important role in the regulation of CSD and in the protection of neurons under brain trauma. The correlation of TBI with CSD and the astrocytic function under these conditions remain unclear. This review discusses the possible link of TBI and CSD and its implication for neuronal survival. Additionally, we highlight the importance of astrocytic function for brain protection, and suggest possible therapeutic strategies targeting astrocytes to improve the outcome following TBI-associated CSD.
Assuntos
Astrócitos/fisiologia , Lesões Encefálicas/fisiopatologia , Depressão Alastrante da Atividade Elétrica Cortical , Animais , Lesões Encefálicas/metabolismo , Lesões Encefálicas/patologia , Sobrevivência Celular , Metabolismo Energético , Aminoácidos Excitatórios/metabolismo , Humanos , Neurônios/patologia , Neurônios/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Cortical spreading depression (CSD) is a depolarization wave associated with neurological disorders such as migraine, cerebral ischemia and traumatic brain injury. The mechanism of action of this phenomenon still remains unclear. Although it is suggested that extracellular K(+) accumulation contributes to CSD, other ions may play a relevant role in the mechanism of propagation of the wave. In this context, we hypothesize that Ca(2+) may play an important function in the wave propagation. Our results demonstrate that enhancing Ca(2+) influx into the cells by topical cortical application of the ionophore A23187 (10 µM, 50 µM and 100 µM solutions) increases the velocity of CSD propagation in a dose-dependent manner, and a much higher dose of this compound (2 mM) triggers CSD. In conclusion, increased Ca(2+) influx can be a key element in the induction mechanism of the CSD, and should be assessed in further experimental strategies targeting brain disorders related to CSD.
Assuntos
Cálcio/metabolismo , Depressão Alastrante da Atividade Elétrica Cortical , Animais , Calcimicina/farmacologia , Ionóforos de Cálcio/farmacologia , Masculino , Ratos WistarRESUMO
GRP78 participates in multiple functions in the cell during normal and pathological conditions, controlling calcium homeostasis, protein folding and Unfolded Protein Response. GRP78 is located in the endoplasmic reticulum, but it can change its location under stress, hypoxic and apoptotic conditions. NF-κB represents the keystone of the inflammatory process and regulates the transcription of several genes related with apoptosis, differentiation, and cell growth. The possible relationship between GRP78-NF-κB could support and explain several mechanisms that may regulate a variety of cell functions, especially following brain injuries. Although several reports show interactions between NF-κB and Heat Shock Proteins family members, there is a lack of information on how GRP78 may be interacting with NF-κB, and possibly regulating its downstream activation. Therefore, we assessed the computational predictions of the GRP78 (Chain A) and NF-κB complex (IkB alpha and p65) protein-protein interactions. The interaction interface of the docking model showed that the amino acids ASN 47, GLU 215, GLY 403 of GRP78 and THR 54, ASN 182 and HIS 184 of NF-κB are key residues involved in the docking. The electrostatic field between GRP78-NF-κB interfaces and Molecular Dynamic simulations support the possible interaction between the proteins. In conclusion, this work shed some light in the possible GRP78-NF-κB complex indicating key residues in this crosstalk, which may be used as an input for better drug design strategy targeting NF-κB downstream signaling as a new therapeutic approach following brain injuries.
Assuntos
Lesões Encefálicas/metabolismo , Proteínas de Choque Térmico/metabolismo , Modelos Biológicos , NF-kappa B/metabolismo , Biologia Computacional/métodos , Chaperona BiP do Retículo Endoplasmático , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular/métodos , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas/fisiologia , Mapeamento de Interação de Proteínas/métodos , Eletricidade EstáticaRESUMO
Glucose-regulated protein 78 (GRP78; 78 kDa) belongs to a group of highly conserved heat shock proteins (Hsp) with important functions at the cellular level. The emerging interest for GRP78 relies on its different functions, both in normal and pathological circumstances. GRP78 regulates intracellular calcium, protein shaping, endoplasmic reticulum (ER) stress and cell survival by an immediate response to insults, and that its expression may also be regulated by estrogens. Although these roles are well explored, the mechanisms by which GRP78 induces these changes are not completely understood. In this review, we highlight various aspects related to the GRP78 functioning in cellular protection and repair in response to ER stress and unfolded protein response by the regulation of intracellular Ca(2+) and other mechanisms. In this respect, the novel interactions between GRP78 and estrogens, such as estradiol and others, are analyzed in the context of the central nervous system (CNS). We also discuss the importance of GRP78 and estrogens in brain diseases including ischemia, Alzheimer's and Huntington's disorders. Finally, the main protective mechanisms of GRP78 and estrogens during ER dysfunction in the brain are described, and the prospective roles of GRP78 in therapeutic processes.