RESUMO
The contribution of the various subcellular compartments in the induction of cell injury triggered by spinal cord trauma has not been clearly elucidated yet. In the present study, we investigated changes in mRNA levels of processed xbp1, ho-1, and hsp70 induced in mice by hemisection or contusion of the spinal cord. The expression of these genes is upregulated under conditions associated with endoplasmic reticulum (ER; xbp1, ho-1) dysfunction or impairment of cytoplasmic function (hsp70) respectively. When the functioning of the ER or the cytoplasm is impaired, unfolded proteins accumulate in these compartments. This is the warning signal for activation of the unfolded protein response (ER) and heat-shock response (cytoplasm) respectively. Spinal cord trauma activated the expression of these genes starting at 3 h and peaking at 6 h of recovery (processed xbp1, 12-fold and fivefold increase; ho-1, fourfold and eightfold increase; hsp70, fourfold, no increase, after contusion and hemisection, respectively). After 6 h of recovery, the rise in hsp70 mRNA levels was confined to the traumatized segment (fourfold), whereas a significant increase in processed xbp1 and ho-1 mRNA levels was also observed in the adjacent segments. This suggests a spread of the pathological process from the site of the primary impact into the surrounding tissue. After induction of spinal cord trauma processed xbp1 mRNA levels rose in a delayed fashion. This implies that the pathological process that causes impairment of ER functioning, starts with a delay of a few hours after induction of trauma and may therefore be amenable to therapeutic intervention.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Retículo Endoplasmático/patologia , Proteínas Nucleares/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Animais , Proteínas de Ligação a DNA/genética , Expressão Gênica , Regulação da Expressão Gênica , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Camundongos , Proteínas Nucleares/genética , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , Fatores de Transcrição de Fator Regulador X , Traumatismos da Medula Espinal/genética , Traumatismos da Medula Espinal/metabolismo , Fatores de Tempo , Fatores de Transcrição , Proteína 1 de Ligação a X-BoxRESUMO
Preconditioning is a process where a preceding non-lethal form of stress activates a stress response that protects cells against an otherwise lethal form of stress. Preconditioning can be induced in various ways including short-term ischemia or spreading depression. Here we investigated the effect of 1 h repetitive spreading depression on the unfolded protein response (UPR), a stress response activated under conditions associated with endoplasmic reticulum (ER) dysfunction. Spreading depression induced processing of xbp1 mRNA, indicative of an activation of UPR. Processing of xbp1 was paralleled by a rise in grp78 mRNA levels resulting from an activation of a signal transduction pathway that depends on protein synthesis. Preconditioning-induced activation of UPR may preserve ER functioning under pathological conditions interfering with ER functions.