RESUMEN
Alzheimer's disease is marked by the presence of amyloid-beta (Aß) plaques, elevated central cytokine levels, dysregulation of BDNF-related gene expression, and cognitive decline. Previously, our laboratory has demonstrated that repeated administration of peripheral LPS is sufficient to significantly increase the presence of central Aß in the hippocampus, and that this upregulation corresponds with deficits in learning and memory. We have also previously demonstrated that the inverse benzodiazepine agonist MRK-016 (MRK) can protect against memory acquisition and consolidation errors in mice. To extend these findings, the current study explored the protective effects of MRK in the context of LPS-induced hippocampal Aß accumulation. Hippocampal Aß was significantly elevated, relative to saline-treated animals, following seven days of peripheral LPS injections. Animals were then trained in a contextual fear conditioning paradigm and were immediately treated with MRK or saline once training was complete. Behavioral testing occurred the day after training. Results from this study demonstrate that repeated injections of LPS significantly elevate hippocampal Aß, and inhibit acquisition of contextual fear. Post-training treatment with MRK restored behavioral expression of fear in LPS-treated animals, despite elevated hippocampal Aß, an effect that may be attributed to increased BDNF mRNA expression. Therefore, our data indicate that MRK can prevent LPS- induced cognitive deficits associated with elevated Aß, and restore hippocampal BDNF expression.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Trastornos del Conocimiento/prevención & control , Agonistas del GABA/uso terapéutico , Hipocampo/metabolismo , Isoxazoles/uso terapéutico , Triazinas/uso terapéutico , Péptidos beta-Amiloides/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/genética , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/patología , Condicionamiento Psicológico/efectos de los fármacos , Miedo/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Lipopolisacáridos/toxicidad , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Memoria/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Fragmentos de Péptidos/metabolismo , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , ARN Mensajero/metabolismoRESUMEN
Peripheral administration of lipopolysaccharide (LPS) elevates production of pro-inflammatory cytokines, and motivates the expression of sickness behaviors. In this study, we tested the ability of an LPS-derived adjuvant, monophosphoryl lipid A (MPLA), to prevent LPS-induced sickness behaviors in a burrowing paradigm. Testing occurred over a three-day period. Animals received a single injection of either MPLA or saline the first two days of testing. On day three, animals received either LPS or saline. Tissue from the dorsal hippocampus was collected for qRT-PCR to assess expression of IL-1ß and IL-4. Results indicate that, during the pre-treatment phase, administration of MPLA induces an immune response sufficient to trigger sickness behaviors. However, we observed that animals pre-treated with MPLA for two days were resistant to LPS-induced sickness behaviors on day three. Results from the qRT-PCR analysis indicated that LPS-treated animals pre-treated with MPLA expressed significantly less IL-1ß compared to LPS-treated animals pre-treated with saline. However, we did not observe a significant difference in IL-4 expression between groups. Therefore, results indicate that under the given parameters of the study, MPLA pre-treatment protects against LPS-induced sickness behaviors, at least in part, by decreasing expression of the pro-inflammatory cytokine IL-1ß.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Conducta de Enfermedad/efectos de los fármacos , Interleucina-1beta/metabolismo , Lípido A/análogos & derivados , Adyuvantes Inmunológicos/administración & dosificación , Animales , Modelos Animales de Enfermedad , Esquema de Medicación , Interleucina-1beta/genética , Interleucina-4/genética , Interleucina-4/metabolismo , Lípido A/administración & dosificación , Lípido A/farmacología , Lipopolisacáridos/toxicidad , Ratones , Ratones Endogámicos C57BL , ARN Mensajero/metabolismoRESUMEN
Recent evidence suggests that inflammation-induced decrements in cognitive function can be mitigated via manipulation of excitatory or inhibitory transmission. We tested the ability of the inverse benzodiazepine agonist, MRK-016 (MRK) to protect against LPS-induced deficits in memory acquisition and consolidation, using a contextual fear conditioning (CFC) paradigm. In Experiment One, mice received lipopolysaccharide (LPS) and/or MRK injections prior to CFC training, and were then tested 24h after training. In Experiment Two, animals received similar treatment injections immediately after training, and were tested 24h later. Additionally, hippocampal samples were collected 4h after LPS injections and immediately after testing, to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) mRNA expression. Results indicate that MRK can protect against LPS-induced learning/memory decrements in both paradigms. We also found, in both paradigms, that animals treated with LPS/Saline expressed significantly less BDNF mRNA when compared to Saline/Saline-treated animals 4h after LPS administration, but that MRK did not restore BDNF expression levels. Further, treatment administrations had no effect on IGF-1 mRNA expression at any collection time-point. In summary, MRK-016 can protect against LPS-induced deficits in memory acquisition and consolidation, in this hippocampus-dependent paradigm, though this protection occurs independently of recovery of BDNF expression.