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Parkinson's disease motor disorders are strongly associated with the degeneration of dopaminergic neurons and dopamine depletion in the nigrostriatal pathway. However, earlier, patients may have olfactory disorders. Studies have shown an inverse relationship between the consumption of caffeine or nicotine and the risk of developing Parkinson's disease. This study investigated whether the treatment with caffeine and/or nicotine would be able to prevent olfactory impairment in an animal model. Adult male and female Wistar rats received intraperitoneal saline, caffeine and/or nicotine for 7 consecutive days after intranigral injury and were submitted to behavioral tests. The treatment with caffeine and double treatment (caffeine + nicotine) reversed the olfactory impairment caused by rotenone, in male rats.In females, olfactory disturbance was not present.Surprisingly, there was no olfactory bulb (OB)tyrosine hydroxylase (TH) increased phosphorylation by the caffeine administration, present only in a double treatment, for males. In addition, a trend to increased TH phosphorylation of the nicotine rotenone group was observed, indicating a negative influence of dopamine on olfaction, probably due to its action on OB D2 inhibitory receptors, which may explain the olfactory impairment not reversed by nicotine. Besides, nicotine presented dopaminergic neurons restoration for both male and female in the substantia nigra, indicating a neuroprotective effect against rotenone lesion. Caffeine and nicotine presented different benefits in the rotenone model, improving the olfactory disturbance and reducing the neuronal loss within the substantia nigra. Additionally, the intranigral rotenone presented sex differences related to olfactory function, also present in a human population.

To evaluate the sleep and circadian rest-activity pattern of critical COVID-19 survivors 3 months after hospital discharge.Observational, prospective study.Single-center study.One hundred seventy-two consecutive COVID-19 survivors admitted to the ICU with acute respiratory distress syndrome.Seven days of actigraphy for sleep and circadian rest-activity pattern assessment; validated questionnaires; respiratory tests at the 3-month follow-up.The cohort included 172 patients, mostly males (67.4%) with a median (25th-75th percentile) age of 61.0 years (52.8-67.0 yr). The median number of days at the ICU was 11.0 (6.00-24.0), and 51.7% of the patients received invasive mechanical ventilation (IMV). According to the Pittsburgh Sleep Quality Index (PSQI), 60.5% presented poor sleep quality 3 months after hospital discharge, which was further confirmed by actigraphy. Female sex was associated with an increased score in the PSQI (p0.05) and IMV during ICU stay was able to predict a higher fragmentation of the rest-activity rhythm at the 3-month follow-up (p0.001). Furthermore, compromised mental health measured by the Hospital Anxiety and Depression Scale was associated with poor sleep quality (p0.001).Our findings highlight the importance of considering sleep and circadian health after hospital discharge. Within this context, IMV during the ICU stay could aid in predicting an increased fragmentation of the rest-activity rhythm at the 3-month follow-up. Furthermore, compromised mental health could be a marker for sleep disruption at the post-COVID period.

Parkinson's disease (PD) is a neurodegenerative disorder classically associated with motor symptoms, but several nonmotor disturbances appear decades before the clinical diagnosis of the disease. A variety of hypotheses exist to explain the onset of PD, and neuroinflammation is one of the most investigated processes. In fact, strong evidence suggests that PD begins with an inflammatory process; currently, however, no anti-inflammatory therapy is clinically employed to alleviate the typical motor and the prodromal disturbances such as olfactory loss, cognitive impairments, depression and anxiety, sleep disturbances, and autonomic disorders. In fact, the classical dopaminergic therapies are not effective in alleviating these symptoms and there is no other specific therapy for these outcomes. Therefore, in this review, we will discuss novel potential pharmacological therapeutic strategies focusing on cannabinoids, caffeine, melatonin, and dietary compounds, which could act as adjuvants to regular PD therapy. These described chemicals have been extensively investigated as anti-inflammatory agents possibly promoting beneficial effects on nonmotor symptoms of PD. The investigation of the inflammatory process at different stages of PD progression should give us a better view of the therapeutic scenario and could improve our understanding of the mechanisms of this disease.

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.

Melatonin MT

Studies in Parkinson's disease (PD) reported an increased number of dopaminergic neurons within the olfactory bulb (OB), possibly resulting in a deficiency of the olfactory processing. It is hypothesized that such an increase in periglomerular neurons could elicit a massive inhibition of mitral cells in particular. Furthermore, the association of the substantia nigra pars compacta (SNpc) with PD olfactory disturbance has been demonstrated according to the description of a direct pathway from the SNpc to the OB. In addition, deficits of other neurotransmitter systems such as serotonergic, noradrenergic, and cholinergic projections to the OB are potentially associated with olfactory dysfunctions in PD. Moreover, the pronounced olfactory deficits in PD are associated with a higher risk for developing dementia, which strengthens the use of odor tests as possible early diagnostic methods. In addition, nonsteroidal antiinflammatory drugs potentially improve olfaction; hence, they may constitute potential candidates for the treatment of olfactory disorders in PD.

Sleep disturbances are among the most disabling non-motor symptoms in Parkinson's disease. They are represented by rapid eye movement behavior disorder, restless legs syndrome, excessive daytime sleepiness, and insomnia. Neurodegeneration that occurs with the progression of the disease is an important factor for the appearance of these symptoms. In fact, the olfactory bulb, locus coeruleus, dorsal raphe nucleus, pedunculopontine tegmental nucleus, and substantia nigra pars compacta are reportedly associated to sleep and are affected in Parkinson's disease. Drugs targeting neurotransmitter systems and receptors associated with these nuclei are constantly reported, but there remains a lack of proper treatment for these symptoms. In this chapter, we first describe the most common sleep disturbances in Parkinson's disease. Then, we discuss the neuronal mechanisms underlying these dysfunctions. Finally, a detailed description is provided regarding potential therapeutic targets and current therapy.

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.

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.

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.

Several efforts have been made to understand the involvement of rapid eye movement (REM) sleep for cognitive processes. Consolidation or retention of recognition memories is severely disrupted by REM sleep deprivation (REMSD). In this regard, pedunculopontine tegmental nucleus (PPT) and other brainstem nuclei, such as pontine nucleus (Pn) and oculomotor nucleus (OCM), appear to be candidates to take part in this REM sleep circuitry with potential involvement in cognition. Therefore, the objective of this study was to investigate a possible association between the performance of Wistar rats in a declarative memory and PPT, Pn, and OCM activities after different periods of REMSD. We examined c-Fos and choline acetyltransferase (ChaT) expressions as indicators of neuronal activity as well as a familiarity-based memory test. The animals were distributed in groups: control, REMSD, and sleep rebound (REB). At the end of the different REMSD (24, 48, 72, and 96 h) and REB (24 h) time points, the rats were immediately tested in the object recognition test and then the brains were collected. Results indicated that OCM neurons presented an increased activity, due to ChaT-labeling associated with REMSD that negatively correlated (r = −0.32) with the cognitive performance. This suggests the existence of a cholinergic compensatory mechanism within the OCM during REMSD. We also showed that 24 h of REMSD impacted similarly in memory, compared to longer periods of REMSD. These data extend the notion that REM sleep is influenced by areas other than PPT, i.e., Pn and OCM, which could be key players in both sleep processes and cognition.