RESUMEN
Melatonin MT1 and MT2 receptors are expressed in the glomerular layer of the olfactory bulb (OB); however, the role of these receptors has not been evaluated until now. Considering the association of the OB with olfactory and depressive disorders in Parkinson's disease (PD), we sought to investigate the involvement of melatonin receptors in these non-motor disturbances in an intranigral 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD. We demonstrate the presence of functional melatonin receptors in dopaminergic neurons of the glomerular layer. Local administration of melatonin (MLT, 1 µg/µl), luzindole (LUZ, 5 µg/µl) or the MT2-selective receptor drug 4-P-PDOT (5 µg/µl) reversed the depressive-like behavior elicited by 6-OHDA. Sequential administration of 4-P-PDOT and MLT (5 µg/µl, 1 µg/µl) promoted additive antidepressant-like effects. In the evaluation of olfactory discrimination, LUZ induced an olfactory impairment when associated with the nigral lesion-induced impairment. Thus, our results suggest that melatonin MT2 receptors expressed in the glomerular layer are involved in depressive-like behaviors and in olfactory function associated with PD.
Asunto(s)
Anosmia/metabolismo , Conducta Animal , Trastorno Depresivo/metabolismo , Neuronas Dopaminérgicas/metabolismo , Bulbo Olfatorio/metabolismo , Trastornos Parkinsonianos/metabolismo , Receptor de Melatonina MT2/metabolismo , Animales , Anosmia/etiología , Anosmia/fisiopatología , Anosmia/psicología , Conducta Animal/efectos de los fármacos , Trastorno Depresivo/etiología , Trastorno Depresivo/fisiopatología , Trastorno Depresivo/psicología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Melatonina/farmacología , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/fisiopatología , Percepción Olfatoria/efectos de los fármacos , Oxidopamina , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatología , Trastornos Parkinsonianos/psicología , Ratas Wistar , Receptor de Melatonina MT2/efectos de los fármacos , Transducción de Señal , Olfato/efectos de los fármacos , Natación , Tetrahidronaftalenos/farmacología , Triptaminas/farmacologíaRESUMEN
Parkinson's disease (PD) is a chronic disorder that presents a range of premotor signs, such as sleep disturbances and cognitive decline, which are key non-motor features of the disease. Increasing evidence of a possible association between sleep disruption and the neurodegenerative process suggests that sleep impairment could produce a detectable metabolic signature on the disease. In order to integrate neurocognitive and metabolic parameters, we performed untargeted and targeted metabolic profiling of the rotenone PD model in a chronic sleep restriction (SR) (6 h/day for 21 days) condition. We found that SR combined with PD altered several behavioural (reversal of locomotor activity impairment; cognitive impairment; delay of rest-activity rhythm) and metabolic parameters (branched-chain amino acids, tryptophan pathway, phenylalanine, and lipoproteins, pointing to mitochondrial impairment). If combined, our results bring a plethora of parameters that represents reliable early-phase PD biomarkers which can easily be measured and could be translated to human studies.
Asunto(s)
Biomarcadores/metabolismo , Enfermedad de Parkinson/patología , Trastornos del Sueño-Vigilia/diagnóstico , Aminoácidos de Cadena Ramificada/sangre , Animales , Área Bajo la Curva , Biomarcadores/sangre , Cromatografía Líquida de Alta Presión , Enfermedad Crónica , Análisis Discriminante , Modelos Animales de Enfermedad , Análisis de los Mínimos Cuadrados , Masculino , Espectrometría de Masas , Metaboloma/efectos de los fármacos , Enfermedad de Parkinson/etiología , Curva ROC , Ratas , Ratas Wistar , Rotenona/toxicidad , Trastornos del Sueño-Vigilia/metabolismoRESUMEN
Olfactory impairments and depressive behavior are commonly reported by individuals with Parkinson's disease (PD) being observed before motor symptoms. The mechanisms underlying these clinical manifestations are not fully elucidated. However, the imbalance in dopaminergic neurotransmission seems to play an important role in this context. In patients and animal models of PD, an increase in the dopaminergic interneurons of the glomerular layer in olfactory bulb (OB-gl) is observed, which may contribute to the olfactory impairment. In addition, neuronal imbalance in OB is related to depressive symptoms, as demonstrated by chemical olfactory bulbectomy. In view of that, we hypothesized that a reduction in the number or density of dopaminergic neurons present in OB could promote an olfactory improvement and, in contrast, would accentuate the depressive-like behaviors in the 6-hydroxydopamine (6-OHDA) model of PD. Therefore, we performed single or double injections of 6-OHDA within the substantia nigra pars compacta (SNpc) and/or in the OB-gl. We observed that, after 7 days, the group with nigral lesion exhibited olfactory impairment, as well as the group with the lesion in the OB-gl. However, the combination of the lesions prevented the occurrence of hyposmia. In relation to depressive-like behaviors, we observed that the SNpc injury promoted depressive-like behavior, being accentuated after a double injury. Our results demonstrated the importance of the dopaminergic neurons of the OB-gl in different non-motor features of PD, since the selective reduction of these periglomerular neurons was able to induce olfactory impairment and depressive-like behaviors.
Asunto(s)
Conducta Animal/efectos de los fármacos , Depresión/inducido químicamente , Bulbo Olfatorio/efectos de los fármacos , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Dopamina/metabolismo , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Masculino , Bulbo Olfatorio/lesiones , Bulbo Olfatorio/patología , Enfermedad de Parkinson/patología , Ratas Wistar , Sustancia Negra/efectos de los fármacos , Sustancia Negra/patologíaRESUMEN
Excitotoxicity has been related to play a crucial role in Parkinson's disease (PD) pathogenesis. Pedunculopontine tegmental nucleus (PPT) represents one of the major sources of glutamatergic afferences to nigrostriatal pathway and putative reciprocal connectivity between these structures may exert a potential influence on rapid eye movement (REM) sleep control. Also, PPT could be overactive in PD, it seems that dopaminergic neurons are under abnormally high levels of glutamate and consequently might be more vulnerable to neurodegeneration. We decided to investigate the neuroprotective effect of riluzole administration, a N-methyl-D-aspartate (NMDA) receptor antagonist, in rats submitted simultaneously to nigrostrial rotenone and 24h of REM sleep deprivation (REMSD). Our findings showed that blocking NMDA glutamatergic receptors in the SNpc, after REMSD challenge, protected the dopaminergic neurons from rotenone lesion. Concerning rotenone-induced hypolocomotion, riluzole reversed this impairment in the control groups. Also, REMSD prevented the occurrence of rotenone-induced motor impairment as a result of dopaminergic supersensitivity. In addition, higher Fluoro Jade C (FJC) staining within the SNpc was associated with decreased cognitive performance observed in rotenone groups. Such effect was counteracted by riluzole suggesting the occurrence of an antiapoptotic effect. Moreover, riluzole did not rescue cognitive impairment impinged by rotenone, REMSD or their combination. These data indicated that reductions of excitotoxicity, by riluzole, partially protected dopamine neurons from neuronal death and appeared to be effective in relieve specific rotenone-induce motor disabilities.