RESUMEN
Accumulating evidence suggests that modulating the sigma 2 receptor (Sig2R) can provide beneficial effects for neurodegenerative diseases. Herein, we report the identification of a novel class of Sig2R ligands and their cellular and in vivo activity in experimental models of Alzheimer's disease (AD). We report that SAS-0132 and DKR-1051, selective ligands of Sig2R, modulate intracellular Ca2+ levels in human SK-N-SH neuroblastoma cells. The Sig2R ligands SAS-0132 and JVW-1009 are neuroprotective in a C. elegans model of amyloid precursor protein-mediated neurodegeneration. Since this neuroprotective effect is replicated by genetic knockdown and knockout of vem-1, the ortholog of progesterone receptor membrane component-1 (PGRMC1), these results suggest that Sig2R ligands modulate a PGRMC1-related pathway. Last, we demonstrate that SAS-0132 improves cognitive performance both in the Thy-1 hAPPLond/Swe+ transgenic mouse model of AD and in healthy wild-type mice. These results demonstrate that Sig2R is a promising therapeutic target for neurocognitive disorders including AD.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Trastornos del Conocimiento/metabolismo , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Fármacos Neuroprotectores/metabolismo , Receptores sigma/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/prevención & control , Animales , Línea Celular Tumoral , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/prevención & control , Relación Dosis-Respuesta a Droga , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/metabolismo , Mediadores de Inflamación/antagonistas & inhibidores , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/uso terapéutico , Unión Proteica/fisiología , Receptores sigma/antagonistas & inhibidores , Receptores sigma/genéticaRESUMEN
Many animals, including humans, select alternate forms of motion (gaits) to move efficiently in different environments. However, it is unclear whether primitive animals, such as nematodes, also use this strategy. We used a multifaceted approach to study how the nematode Caenorhabditis elegans freely moves into and out of water. We demonstrate that C. elegans uses biogenic amines to switch between distinct crawling and swimming gaits. Dopamine is necessary and sufficient to initiate and maintain crawling after swimming. Serotonin is necessary and sufficient to transition from crawling to swimming and to inhibit a set of crawl-specific behaviors. Further study of locomotory switching in C. elegans and its dependence on biogenic amines may provide insight into how gait transitions are performed in other animals.
