Adriano D.S. Targa

Does Parkinson's disease and type-2 diabetes mellitus present common pathophysiological mechanisms and treatments?

Parkinsons disease (PD) is the second most common neurodegenerative disease afflicting about 1% of people over 65 years old and 4-5% of people over 85 years. It is proposed that a cascade of deleterious factors is set in motion within that neuron made not of one, but rather of multiple factors such as free radicals, excitotoxicity, neuroinflammation, and apoptosis to cite only some of the most salient. In this scenario, chronic systemic inflammation, as well as impaired mitochondrial metabolism, have also been suspected of playing a role in the development of type-2 diabetes, and the possibility of a shared pathophysiology of PD and type-2 diabetes has been proposed. The discussion about the interactions between PD and type-2 diabetes mellitus began in the 1960s and there is still controversy. Insulin and dopamine may exert reciprocal regulation hence; hypoinsulinemia induced by streptozotocin decreased the amounts of dopamine transporter and tyrosine hydroxylase transcripts in the substantia nigra pars compacta. Accordingly, dopamine depletion in the striatum is able to decreases insulin signaling in basal ganglia, indicating that, perhaps, PD may be considered as a risk factor for the development of type-2 diabetes mellitus. In this sense, it is described that peroxisome proliferator-activated receptor-γ, ATP-sensitive K(+) channels, AMP-activated protein kinase, glucagon-like peptide-1 and dipeptidyl peptidase-4 are important therapeutic targets for PD and reinforces the association with diabetes. Therefore, the objective of the present review is to contextualize the mutual pathophysiological interactions between PD and type-2 diabetes mellitus, as well as the potential common treatments.

REM Sleep Deprivation Reverses Neurochemical and Other Depressive-Like Alterations Induced by Olfactory Bulbectomy

There is compelling evidence that sleep deprivation (SD) is an effective strategy in promoting antidepressant effects in humans, whereas few studies were performed in relevant animal models of depression. Acute administration of antidepressants in humans and rats generates a quite similar effect, i.e., suppression of rapid eye movement (REM) sleep. Then, we decided to investigate the neurochemical alterations generated by a protocol of rapid eye movement sleep deprivation (REMSD) in the notably known animal model of depression induced by the bilateral olfactory bulbectomy (OBX). REMSD triggered antidepressant mechanisms such as the increment of brain-derived neurotrophic factor (BDNF) levels, within the substantia nigra pars compacta (SNpc), which were strongly correlated to the swimming time (r = 0.83; P < 0.0001) and hippocampal serotonin (5-HT) content (r = 0.66; P = 0.004). Moreover, there was a strong correlation between swimming time and hippocampal 5-HT levels (r = 0.70; P = 0.003), strengthen the notion of an antidepressant effect associated to REMSD in the OBX rats. In addition, REMSD robustly attenuated the hippocampal 5-HT deficiency produced by the OBX procedure. Regarding the rebound (REB) period, we observed the occurrence of a sustained antidepressant effect, indicated mainly by the swimming and climbing times which could be explained by the maintenance of the increased nigral BDNF expression. Hence, hippocampal 5-HT levels remained enhanced in the OBX group after this period. We suggested that the neurochemical complexity inflicted by the OBX model, counteracted by REMSD, is directly correlated to the nigral BDNF expression and hippocampal 5-HT levels. The present findings provide new information regarding the antidepressant mechanisms triggered by REMSD.

Olfactory impairment in the rotenone model of Parkinson's disease is associated with bulbar dopaminergic D2 activity after REM sleep deprivation

Olfactory and rapid eye movement (REM) sleep deficits are commonly found in untreated subjects with a recent diagnosis of Parkinson’s disease (PD). Additionally, different studies report declines in olfactory performance during a short period of sleep deprivation. Mechanisms underlying these clinical manifestations are poorly understood, and impairment of dopamine (DA) neurotransmission in the olfactory bulb and the nigrostriatal pathway may have important roles in olfaction and REM sleep disturbances. Therefore, we hypothesized that modulation of the dopaminergic D2 receptors in the olfactory bulb could provide a more comprehensive understanding of the olfactory deficits in PD and REM sleep deprivation (REMSD). We decided to investigate the olfactory, neurochemical, and histological alterations generated through the administration of piribedil (a selective D2 agonist) or raclopride (a selective D2 antagonist) within the glomerular layer of the olfactory bulb, in rats subjected to intranigral rotenone and REMSD. Our findings provide evidence of the occurrence of a negative correlation (r = −0.52, P = 0.04) between the number of periglomerular TH-ir neurons and the bulbar levels of DA in the rotenone, but not sham, groups. A significant positive correlation (r = 0.34, P = 0.03) was observed between nigrostriatal DA levels and olfactory discrimination index (DI) for the sham groups, indicating that increased DA levels in the substantia nigra pars compacta (SNpc) are associated with enhanced olfactory discrimination performance. Also, increased levels in bulbar and striatal DA were induced by piribedil in the rotenone control and rotenone REMSD groups, consistent with reductions in the DI. The present evidence reinforce the idea that DA produced by periglomerular neurons, particularly the bulbar dopaminergic D2 receptors, is an essential participant in olfactory discrimination processes, as the SNpc, and the striatum.

Putative role of monoamines in the antidepressant-like mechanism induced by striatal MT2 blockade.

It has been observed that the secretion pattern of melatonin is modified in Parkinsons disease (PD). Hence, it is hypothesized that dysregulations of melatonin MT2 receptors may be involved in the installation of depression in PD patients. Together with recent evidence based on the use of the intranigral rotenone model of PD, have led to the hypothesis that modulating the striatal MT2 receptor could provide a more comprehensive understanding of the antidepressant properties triggered. To further investigate this issue, male Wistar rats were infused with intranigral rotenone (12μg/μL) and seven days later subjected to a rapid eye movement sleep deprivation (REMSD) for 24h. After, we injected within the striatum the MT2 selective agonist, 8-M-PDOT (10μg/μL), the MT2 selective antagonist, 4-P-PDOT (5μg/μL) or vehicle. Subsequently, they were tested in the forced swimming test and were allowed to perform the sleep rebound (REB). Then, the rats were re-tested, and the striatum, hippocampus and substantia nigra pars compacta (SNpc) were collected for neurochemical purposes. Results indicated substantial antidepressant effects promoted by the blockade of striatal MT2 receptors that were potentiated by REMSD. MT2 activation increased DA levels in the striatum and hippocampus, while MT2 blockade increase DA in the SNpc. 4-P-PDOT treatment of the rotenone REMSD group generated a decrement in 5-HT levels within the striatum, hippocampus and SNpc. However, increased 5-HT turnover was observed among these structures. Therefore, we demonstrated the neurochemical antidepressant effect induced by striatal MT2 blockage associated with REMSD in the rotenone model of PD.

REM sleep deprivation promotes a dopaminergic influence in the striatal MT2 anxiolytic-like effects

The aim of this study was to investigate the possible anxiolytic-like effects of striatal MT2 activation, and its counteraction induced by the selective blockade of this receptor. Furthermore, we analyzed this condition under the paradigm of rapid eye movement (REM) sleep deprivation (REMSD) and the animal model of Parkinson’s disease (PD) induced by rotenone. Male Wistar rats were infused with intranigral rotenone (12 μg/μL), and 7 days later were subjected to 24 h of REMSD. Afterwards the rats underwent striatal micro-infusions of selective melatonin MT2 receptor agonist, 8-M-PDOT (10 μg/μL) or selective melatonin MT2 receptor antagonist, 4-P-PDOT (5 μg/μL) or vehicle. Subsequently, the animals were tested in the open-field (OP) and elevated plus maze (EPM) tests. Results indicated that the activation of MT2 receptors produced anxiolytic-like effects. In opposite, the MT2 blockade did not show an anxiogenic-like effect. Besides, REMSD induced anxiolytic-like effects similar to 8-M-PDOT. MT2 activation generated a prevalent locomotor increase compared to MT2 blockade in the context of REMSD. Together, these results suggest a striatal MT2 modulation associated to the REMSD-induced dopaminergic supersensitivity causing a possible dopaminergic influence in the MT2 anxiolytic-like effects in the intranigral rotenone model of PD.

A circuitry for sleep in Parkinson´s disease

Parkinson ́s disease (PD) is a neurodegenerative condition that usually begins in the fifth or sixth decade of life with an overall crude prevalence (including males and females across the entire age range) between 100 and 200 per 100 000 persons [1]. Considering the United Nations projections, the number of people aged 65 or older in 2010, estimated in 524 million, will grow to nearly 1.5 billion in 2050, with most of the increase in developing countries [2]. With this scenario, it is expected an increasing number of PD cases worldwide that invariably will be associated with movement disorders including asymmetric onset of bradykinesia, rigidity, rest tremor and disturbances in balance. Such afflictions were originally described 200 years ago by James Parkinson, and are, still today, the classical features for the clinical diagnosis. However, a multitude of premotor, that is, earlyphase disturbances, have been recently and richly described as neuropathological hallmarks of the disease progression serving as new diagnostic assessments. In view of that, sleep disturbances usually emerge early in the disease course as a product of the degeneration of nondopaminergic regions, like pedunculopontine tegmental nucleus (PPT), lower raphe nuclei and locus coeruleus [3]. Besides, the occurrence of a dopaminergic lesion within the substantia nigra pars compacta (SNpc), typically impacting in motor disability, is also reported to promote a selective impairment in the generation and maintenance of rapid eye movement (REM) sleep [4]. Also, the PPT and the basal ganglia share substantial amount of anatomical and functional similarities. Among these, there are reports of a role in locomotion, memory consolidation and sleep regulation [5, 6]. Therefore, the conjuncture of elements described at that time engaged us to propose a hypothesis aiming to explain sleep disturbances in PD based on the degeneration of the reciprocal connections between PPT and SNpc during the evolution of the disease [7]. Accordingly, our recent study published in Neuropharmacology proposed a physiological association between PPT and SNpc that was tested by a protocol of neurotoxic lesions and pharmacological modulation of striatal D2 receptors in Wistar rats [8]. These results showed that D2 striatal receptors have a relevant influence in non-REM sleep regulation because raclopride (a selective antagonist) administration increased the percentage of time spent in non-REM sleep compared to piribedil (a selective agonist). We demonstrated that a punctual PPT lesion (inflicted by ibotenic acid) blocked the compensatory manifestation of REM sleep, after 24 h of REM sleep deprivation. However, this effect was prevented when the animals were treated with intra-striatal piribedil. Thus, these results showed that striatal D2 receptors activation reinforced the pathway and, consequently, prevented sleep disturbances, when cholinergic tone within PPT was decreased. The SNpc lesion (inflicted by the neurotoxin rotenone) prevented the manifestations of REM sleep rebound and this effect was more intense than the ibotenic acid induced lesions, since the striatal activation did not reverse it. Furthermore, the most striking result was that rotenone lesion decreased the time spent in non-REM sleep. Moreover, we found a positive correlation between the percentage of time spent in non-REM sleep and dopamine levels within the SNpc and striatum in the sham REM sleep deprived animals. Hence, we suggested that dopamine is a keyplayer in non-REM sleep regulation. Such result was unexpected, since dopamine was mostly associated with REM sleep. Thus, the occurrence of non-REM sleep deficits, perhaps prior to REM sleep dysfunction, could be an important clue for novel diagnostic strategies in PD. Our findings, collectively, suggest a new circuitry for sleep regulation in PD, involving the so called triad of nuclei composed by PPT, SNpc and striatum, evidencing not only a potential therapeutic target for the sleep disturbances associated to this pathology, but also a remarkable opportunity of premotor diagnosis. Since originally described by Parkinson in 1817, a lot was accomplished regarding diagnosis and treatment, but certainly the last 15 years were accompanied by the most extraordinary advances, galvanizing sleep disturbances as the main source of prodromal markers.

Fish oil supplementation reverses behavioral and neurochemical alterations induced by swimming exercise in rats

Diet and exercise are known to affect learning and memory. However, the effects of these interventions in the brain under development remains to be better investigated as the effects of high-intensity exercise. Moreover, it is still unclear how long the influence of diet and exercise lasts after the interventions are ceased. To investigate this, juvenile Wistar rats (30 days old) were supplemented with fish oil rich in polyunsaturated fatty acids (PUFAs) and performed swimming training for 50 days, 45 min per day, 5 times/week. The animals were assessed for locomotor activity with the open field test and for spatial memory with the object location task. To investigate neurochemical parameters such as fatty acids incorporation within the plasma membrane and brain-derived neurotrophic factor (BDNF) levels, the animals were euthanized, and the hippocampus dissected. These investigations were made at the end of the supplementation and exercise protocols and 21 days after the protocol has ended. Results indicate that high-intensity exercise impaired the spatial memory and decreased the levels of BDNF. Although supplementation led to PUFAs incorporation in plasma membrane, it did not prevent the harmful effect of exercise on memory. After 21 days of interruption, we observed that the supplementation reversed not only the deleterious effect of exercise on memory but also increased the BDNF levels. These results point to a complex influence of diet and exercise on spatial memory of juvenile rats, persisting after 21 days of interruption.

REM sleep deprivation and dopaminergic D2 receptors modulation increase recognition memory in an animal model of Parkinson’s disease

HIGHLIGHTSD2 receptors blockade, SNpc and PPT lesion impaired object recognition memory.REMSD prevented/reversed the deleterious effects induced by these manipulations.Raclopride had a dual effect, improving memory in the rotenone group. ABSTRACT Cognitive impairment is an important non‐motor symptom of Parkinsons disease (PD). The neuronal death in nigrostriatal pathway is the main factor for motor symptoms and recent studies indicate a possible influence in non‐motor symptoms as well. The pedunculopontine tegmental nucleus (PPT) and basal ganglia are closely related anatomically and functionally and, since they are affected by neurodegeneration in PD, they might be involved in recognition memory. To investigate this, we promoted an ibotenic acid lesion within the PPT or a rotenone lesion within substantia nigra pars compacta (SNpc) of Wistar rats, followed by 24 h of REM sleep deprivation (REMSD). Then, we administered a dopaminergic D2 receptor agonist (piribedil, 3 &mgr;g/&mgr;l), antagonist (raclopride, 10 &mgr;g/&mgr;l) or vehicle (dimethylsulfoxide) directly in the striatum and the animals were submitted to the object recognition test (ORT). We observed that raclopride administration impaired object recognition memory as well as rotenone and ibotenic acid lesion. Interestingly, REMSD reversed the deleterious effects induced by these drugs. Also, raclopride administration after rotenone lesion allowed the animal to explore the new object for a longer time compared to the familiar object, suggesting that raclopride has a dual effect, dependent of the treatments. These findings suggest a role for PPT, SNpc and striatum in recognition memory and points the D2 receptors modulation and REMSD as possible targets for cognitive deficits in Parkinsons disease.

Olfactory impairment is related to REM sleep deprivation in rotenone model of Parkinson's disease

Introduction Olfactory dysfunction affects about 85-90% of Parkinsons disease (PD) patients with severe deterioration in the ability of discriminate several types of odors. In addition, studies reported declines in olfactory performances during a short period of sleep deprivation. Besides, PD is also known to strongly affect the occurrence and maintenance of rapid eye movement (REM) sleep. Methods Therefore, we investigated the mechanisms involved on discrimination of a social odor (dependent on the vomeronasal system) and a non-social odor (related to the main olfactory pathway) in the rotenone model of PD. Also, a concomitant impairment in REM sleep was inflicted with the introduction of two periods (24 or 48 h) of REM sleep deprivation (REMSD). Rotenone promoted a remarkable olfactory impairment in both social and non-social odors, with a notable modulation induced by 24 h of REMSD for the non-social odor. Results Our findings demonstrated the occurrence of a strong association between the density of nigral TH-ir neurons and the olfactory discrimination capacity for both odorant stimuli. Specifically, the rotenone-induced decrease of these neurons tends to elicit reductions in the olfactory discrimination ability. Conclusions These results are consistent with the participation of the nigrostriatal dopaminergic system mainly in the olfactory discrimination of a non-social odor, probably through the main olfactory pathway. Such involvement may have produce relevant impact in the preclinical abnormalities found in PD patients.