RESUMEN
Acetylcholine (ACh) is involved in the modulation of the inflammatory response. ACh levels are regulated by its synthesizing enzyme, choline acetyltransferase (ChAT), and by its hydrolyzing enzymes, mainly acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). A more comprehensive understanding of the cholinergic system in experimental autoimmune encephalomyelitis (EAE) disease progression could pave the path for the development of therapies to ameliorate multiple sclerosis (MS). In this work, we analyzed possible alterations of the CNS cholinergic system in the neuroinflammation process by using a MOG-induced EAE mice model. MOG- and vehicle-treated animals were studied at acute and remitting phases. We examined neuropathology and analyzed mRNA expression of ChAT, AChE and the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR), as well as AChE and BuChE enzyme activities, in brain and spinal cord sections during disease progression. The mRNA expression and enzyme activities of these cholinergic markers were up- or down-regulated in many cholinergic areas and other brain areas of EAE mice in the acute and remitting phases of the disease. BuChE was present in a higher proportion of astroglia and microglia/macrophage cells in the EAE remitting group. The observed changes in cholinergic markers expression and cellular localization in the CNS during EAE disease progression suggests their potential involvement in the development of the neuroinflammatory process and may lay the ground to consider cholinergic system components as putative anti-inflammatory therapeutic targets for MS.
Asunto(s)
Encéfalo/metabolismo , Colina O-Acetiltransferasa/metabolismo , Colinérgicos/farmacología , Encefalomielitis Autoinmune Experimental/metabolismo , Acetilcolina/metabolismo , Enfermedad Aguda , Animales , Astrocitos/metabolismo , Encéfalo/efectos de los fármacos , Colina O-Acetiltransferasa/efectos de los fármacos , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Femenino , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Microglía/metabolismo , Esclerosis Múltiple/inducido químicamente , Esclerosis Múltiple/metabolismo , Factores de TiempoRESUMEN
A neural network model has been developed to predict the inhibitory capacity of any chemical structure to be a phosphodiesterase 7 (PDE7) inhibitor, a new promising kind of drugs for the treatment of neurological disorders. The numerical definition of the structures was achieved using CODES program. Through the validation of this neural network model, a novel family of 5-imino-1,2,4-thiadiazoles (ITDZs) has been identified as inhibitors of PDE7. Experimental extensive biological studies have demonstrated the ability of ITDZs to inhibit PDE7 and to increase intracellular levels of cAMP. Among them, the derivative 15 showed a high in vitro potency with desirable pharmacokinetic profile (safe genotoxicity and blood brain barrier penetration). Administration of ITDZ 15 in an experimental autoimmune encephalomyelitis (EAE) mouse model results in a significant attenuation of clinical symptoms, showing the potential of ITDZs, especially compound 15, for the effective treatment of multiple sclerosis.
Asunto(s)
Simulación por Computador , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/antagonistas & inhibidores , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Encefalomielitis Autoinmune Experimental/enzimología , Inhibidores de Fosfodiesterasa/uso terapéutico , Animales , Línea Celular , Femenino , Ratones , Ratones Endogámicos C57BL , Red Nerviosa/efectos de los fármacos , Red Nerviosa/enzimología , Inhibidores de Fosfodiesterasa/química , Inhibidores de Fosfodiesterasa/farmacología , Distribución Aleatoria , Resultado del TratamientoRESUMEN
Phosphodiesterase (PDE) 7 is involved in proinflammatory processes, being widely expressed both on lymphocytes and on certain brain regions. Specific inhibitors of PDE7 have been recently reported as potential new drugs for the treatment of neurological disorders because of their ability to increase intracellular levels of cAMP and thus to modulate the inflammatory process, as a neuroprotective well-established strategy. Multiple sclerosis is an unmet disease in which pathologies on the immune system, T-cells, and specific neural cells are involved simultaneously. Therefore, PDE7 inhibitors able to interfere with all these targets may represent an innovative therapy for this pathology. Here, we report a new chemically diverse family of heterocyclic PDE7 inhibitors, discovered and optimized by using molecular modeling studies, able to increase cAMP levels in cells, decrease inflammatory activation on primary neural cultures, and also attenuate the clinical symptoms in the experimental autoimmune encephalomyelitis (EAE) mouse model. These results led us to propose the use of PDE7 inhibitors as innovative therapeutic agents for the treatment of multiple sclerosis.