RESUMEN
The aim of this study was to explore the neurobiological background of individual susceptibility and resistance to the development of posttraumatic stress disorder (PTSD)-like behaviours. Rats were divided into susceptible, PTSD(+), and resistant, PTSD(-), groups based on freezing duration during exposure to aversive context and the time spent in the central area in open field test one week after threefold stress experience (modified single prolonged stress). PTSD(-) rats showed increased concentrations of corticosterone in plasma and changes in GAD67 expression: decreased in the infralimbic cortex (IL) and increased in the lateral amygdala (LA), dentate gyrus (DG), and CA1 area of the hippocampus. Moreover, in this group, we found an increase in the number of CRF-positive nuclei in the parvocellular neurons of the paraventricular hypothalamic nucleus (pPVN). The PTSD(+) group, compared to PTSD(-) rats, had decreased concentrations of corticosterone in plasma and reduced CRF expression in the pPVN, higher CRF expression in the CA1, increased expression of CRF-positive nuclei and GR receptors in the CA3 area of the hippocampus, and increased expression of GR receptors in the DG and the central amygdala (CeA). Biochemical analysis showed higher concentrations of noradrenaline, glutamic acid in the dorsal hippocampus and amygdala and lower levels of dopamine and its metabolites in the amygdala of the PTSD(+) group than in the PTSD(-) group. The study revealed different behavioural and biochemical profiles of PTSD(+) and PTSD(-) rats and suggested that individual differences in hypothalamic-pituitary-adrenal (HPA) axis activity may determine hippocampal- and amygdala-dependent memory and fear processing.
Asunto(s)
Susceptibilidad a Enfermedades/metabolismo , Trastornos por Estrés Postraumático/fisiopatología , Estrés Psicológico/fisiopatología , Amígdala del Cerebelo/metabolismo , Animales , Encéfalo/metabolismo , Corticosterona/análisis , Corticosterona/sangre , Hormona Liberadora de Corticotropina/metabolismo , Giro Dentado/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/psicología , Miedo/fisiología , Expresión Génica/genética , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad/genética , Glutamato Descarboxilasa/genética , Glutamato Descarboxilasa/metabolismo , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Masculino , Memoria , Núcleo Hipotalámico Paraventricular/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Trastornos por Estrés Postraumático/genética , Trastornos por Estrés Postraumático/metabolismoRESUMEN
In our study, we assessed the potency of the brain-derived proteins ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), matrix metalloproteinase 9 (MMP-9), glial fibrillary acidic protein (GFAP) and the immune activation indicators interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) as peripheral biomarkers of different susceptibilities to kindling in a preclinical model. We observed increased plasma UCH-L1 levels in kindled vs. control animals. Furthermore, MMP-9 and IL-1ß concentrations were the lowest in rats resistant to kindling. In summary, UCH-L1 is an indicator of neuronal loss and BBB disruption after seizure. MMP-9 and IL-1ß may indicate resistance to kindling. UCH-L1, MMP-9 and IL-1ß may have utility as peripheral biomarkers with translational potency in the clinic.
Asunto(s)
Química Encefálica , Proteína Ácida Fibrilar de la Glía/sangre , Metaloproteinasa 9 de la Matriz/sangre , Convulsiones/sangre , Ubiquitina Tiolesterasa/sangre , Animales , Biomarcadores , Convulsivantes/toxicidad , Susceptibilidad a Enfermedades , Interleucina-1beta/sangre , Interleucina-6/sangre , Excitación Neurológica/efectos de los fármacos , Excitación Neurológica/metabolismo , Masculino , Modelos Animales , Pentilenotetrazol/toxicidad , Ratas , Ratas Wistar , Convulsiones/inducido químicamenteRESUMEN
Because the contribution of inflammatory mediators to seizure disorders is unclear, we investigated the changes in the expression of interleukin-1ß (IL-ß) and its receptor - IL-1 receptor type 1 (IL-1R1), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the rat hippocampus at different stages of pentylenetetrazole (PTZ)-induced kindling. The occurrence and progressive development of seizures were induced by repeated systemic administration of PTZ, a non-competitive antagonist of the γ-aminobutyric acid type A (GABAA) receptor at a subconvulsive dose of 30 mg/kg. We also examined the effects of continuous intracerebroventricular administration of IL-1ß and lipopolysaccharide (LPS) in this model of epilepsy using subcutaneously implanted osmotic mini-pumps. We observed enhanced IL-1R1 expression in the dentate gyrus (DG) at different stages of kindling, whereas the elevated IL-1ß level was distinctive to fully kindled seizures. We did not detect significant changes in the concentration of IL-6 or TNF-α throughout the kindling process. LPS accelerated transiently the process of kindling, while IL-1ß showed a predisposition to delay kindling acquisition. Our study supports the concept of seizure-related modifications in brain cytokine production during epileptogenesis. Although some evidence indicates a proconvulsant property of IL-1ß activity, it cannot be ruled out that the alterations in IL-1 system reflect the activation of endogenous protective mechanisms with respect to the kindling of seizures.