Marcelo Marques de Souza Lima

The Role of the Substantia Nigra Pars Compacta in Regulating Sleep Patterns in Rats

Background As of late, dopaminergic neurotransmission has been recognized to be involved in the generation of sleep disturbances. Increasing evidence shows that sleep disturbances in Parkinsons disease (PD) patients are mostly related to the disease itself, rather than being a secondary phenomenon. Evidence contained in the literature lends support to the hypothesis that the dopaminergic nigrostriatal pathway is closely involved in the regulation of sleep patterns. Methodology/Principal Findings To test this hypothesis we examined the electrophysiological activity along the sleep-wake cycle of rats submitted to a surgically induced lesion of the SNpc by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We demonstrated that a 50% lesion of the substantia nigra pars compacta (SNpc) suffices to produce disruptions of several parameters in the sleep-wake pattern of rats. A robust and constant decrease in the latency to the onset of slow wave sleep (SWS) was detected throughout the five days of recording in both light [F(22.16) = 72.46, p<0.0001] and dark [F(22.16) = 75.0, p<0.0001] periods. Also found was a pronounced increase in the percentage of sleep efficiency during the first four days of recording [F(21.15) = 21.48, p<0.0001], in comparison to the sham group. Additionally, the reduction in the SNpc dopaminergic neurons provoked an ablation in the percentage of rapid eye movement sleep (REM) during three days of the sleep-wake recording period with a strong correlation (r = 0.91; p<0.0001) between the number of dopaminergic neurons lost and the percentage decrease of REM sleep on the first day of recording. On day 4, the percentage of REM sleep during the light and dark periods was increased, [F(22.16) = 2.46, p<0.0007], a phenomenon consistent with REM rebound. Conclusions/Significance We propose that dopaminergic neurons present in the SNpc possess a fundamental function in the regulation of sleep processes, particularly in promoting REM sleep.

Blockage of dopaminergic D2 receptors produces decrease of REM but not of slow wave sleep in rats after REM sleep deprivation

Dopamine (DA) has, as of late, become singled out from the profusion of other neurotransmitters as what could be called a key substance, in the regulation of the sleep-wake states. We have hypothesized that dopaminergic D(2) receptor blockage induced by haloperidol could generate a reduction or even an ablation of rapid eye movement (REM) sleep. Otherwise, the use of the selective D(2) agonist, piribedil, could potentiate REM sleep. Electrophysiological findings demonstrate that D(2) blockage produced a dramatic reduction of REM sleep during the rebound (REB) period after 96 h of REM sleep deprivation (RSD). This reduction of REM sleep was accompanied by an increment in SWS, which is possibly accounted for the observed increase in the sleep efficiency. Conversely, our findings also demonstrate that the administration of piribedil did not generate additional increase of REM sleep. Additionally, D(2) receptors were found down-regulated, in the haloperidol group, after RSD, and subsequently up-regulated after REB group, contrasting to the D(1) down-regulation at the same period. In this sense, the current data indicate a participation of the D(2) receptor for REM sleep regulation and consequently in the REM sleep/SWS balance. Herein, we propose that the mechanism underlying the striatal D(2) up-regulation is due to an effect as consequence of RSD which originally produces selective D(2) supersensitivity, and after its period probably generates a surge in D(2) expression. In conclusion we report a particular action of the dopaminergic neurotransmission in REM sleep relying on D(2) activation.

Modulation of sickness behavior by sleep: The role of neurochemical and neuroinflammatory pathways in mice

Activation of the immune system elicits several behavioral changes that are collectively called sickness behavior and consists in a strategy to overcome infection. Sleep deprivation can increase susceptibility to pathogens and to behavioral alterations. Thus, the present study aimed to determine how paradoxical sleep deprivation (PSD) affects the behavioral and neurochemical responses to lipopolysaccharide (LPS, potent activator of the immune response). Adult inbred mice were paradoxical sleep deprived (72 h), whereas the control group was kept in their home cages. Both groups received either an injection of saline or LPS (5, 10 or 20 microg/animal ip) before behavioral tasks and tissue collection. During the recovery sleep period, LPS provoked a strong inhibition of sleep rebound due to a suppression of paradoxical sleep. PSD increased the susceptibility of mice to LPS-induced immobility in the open field, which was capable of affecting the anxiety-like behavior also. These altered behavioral responses to LPS were accompanied by reduction in dopamine turnover within the striatum and increased expression of cyclooxygenase-2 in the cortex. The study provides some insights into how the sleep-wake cycle affects the expression of sickness behavior induced by LPS.

Motor and Non-Motor Features of Parkinson’s Disease – A Review of Clinical and Experimental Studies

Classically, Parkinsons disease (PD) is considered to be a motor system affliction and its diagnosis is based on the presence of a set of cardinal motor signs (e.g. rigidity, bradykinesia, rest tremor and postural reflex disturbance). However, there is considerable evidence showing that non-motor alterations (e.g. anxiety, depression, sleep, gastrointestinal and cognitive functions) precede the classical motor symptoms seen in PD. The management of these nonmotor symptoms remains a challenge. A pattern of regional neurodegeneration that varies considerably depending upon the neuronal population affected may explain the different symptoms. In fact, differential mechanisms of neuronal vulnerability within the substantia nigra pars compacta (SNpc) suggests that factors other than location contribute to the susceptibility of these neurons. In this review we discuss how these factors interact to ultimately target the SNpc. Remarkably, this region consists of approximately 95% of the tyrosine hydroxylase (TH)-immunoreactive neurons in both human and rat brains, and consequently this implicates elevated levels of dopamine metabolites, free radicals and other hazard species in these neurons. An understanding of how these factors promote neuronal death may be useful for the development of novel neuroprotective and/or neurorestorative strategies for PD.

Intermittent hypoxia and sleep restriction: motor, cognitive and neurochemical alterations in rats.

The present study evaluated the effects of intermittent hypoxia (IH) and sleep restriction (SR) upon motor and cognitive function in rats. Also evaluated were catecholamine concentrations and tyrosine hydroxylase (TH) protein expression in different regions of the forebrain. Wistar Hannover rats were submitted to IH for 4 days or 21 days (2 min room air to 2 min 10% O(2) for 10:00-16:00 h), followed by SR for 18 h (16:00-10:00 h). Rats were randomly assigned into four experimental groups: (1) control (2) IH (3) SR and (4) IH-SR. In the inhibitory avoidance task, an additional group of rats was submitted to paradoxical sleep deprivation (PSD) for 96 consecutive hours. Results showed that SR induced an increase in motor activity without modifying catecholaminergic turnover in the frontal cortex and striatum. The increase in exploratory activity in SR rats could be the result of impaired habituation. Neither SR periods induced cognitive deficits in the inhibitory avoidance task after 5 or 21 days. However, 96 h of PSD impaired acquisition/retention in rats. Exposure to IH did not affect motor and cognitive function but IH was associated with SR in increased motor activity. After 21 days, IH and IH-SR reduced striatal norepinephrine concentration although neither SR nor IH affected TH protein expression. The results presented here suggest that hypoxia and sleep loss exert distinct deleterious effects upon the central nervous system.

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.

Paradoxical Sleep Deprivation Modulates Tyrosine Hydroxylase Expression in the Nigrostriatal Pathway and Attenuates Motor Deficits Induced by Dopaminergic Depletion

The nigrostriatal pathway is very likely involved in sleep regulation, considering the occurrence and high prevalence of sleep-related disorders in patients with Parkinsons disease. Indeed, dopaminergic neurons in the ventral tegmental area were recently shown to fire in bursts during paradoxical sleep (PS), but little is known about the activity of the nigrostriatal dopamine (DA) cells in relation to PS. In view of that we hypothesized that paradoxical sleep deprivation (PSD) may play a relevant role in nigrostriatal tyrosine hydroxylase (TH) expression and, subsequently, in sleep rebound. The present study was designed to determine the effects of PSD in the nigrostriatal pathway in mice by means of neurochemical and behavioral approaches. Intraperitoneal reserpine (1 mg/kg) associated to α-methyl-p-tyrosine (αMT) (250 mg/kg) to produce catecholamine depletion, or rotenone (10 mg/kg) to increase striatal DA turnover were injected 30 min before the 24 h of PSD. Catalepsy and open-field tests indicated that motor deficits induced by reserpine-αMT were counteracted by PSD, which, in contrast, potentiated the motor impairment induced by rotenone. Besides, PSD produced down-regulation on TH expression within the substantia nigra pars compacta and striatum, without affecting the number or the optical density of dopaminergic neurons present in the respective areas. Interestingly, PSD potentiated the downregulation of TH expression in the substantia nigra pars compacta and striatum induced by the co-administration of reserpine-αMT. These results reinforce the notion of a strong participation of DA in PS, as a consequence of the modulation of TH protein expression in the nigrostriatal pathway.

Effect of the Loading Dose of Magnesium Sulfate (MgSO4) on the Parameters of Doppler Flow Velocity in the Uterine, Umbilical and Middle Cerebral Arteries in Severe Preeclampsia

Objective. To evaluate Doppler velocimetry parameters (resistance index [RI], pulsatility index [PI] and systolic/diastolic [S/D] ratio) of maternal-fetal circulation before and after magnesium sulfate administration in pregnant women with severe preeclampsia. Methods. A prospective observational cohort analysis of 40 women with severe preeclampsia was performed. Doppler ultrasonography scans were performed before and 20 minutes after intravenous administration of magnesium sulfate. Maternal parameters such as heart rate, and systolic, diastolic and mean arterial pressure were recorded. Doppler flow velocity parameters (RI, PI and S/D ratio) were evaluated in the uterine, umbilical and middle cerebral arteries. The different mean values obtained before and after magnesium sulphate were analyzed using the paired t-test. Results. There was a statistically significant increase in mean maternal heart rate and a statistically significant decrease in systolic, diastolic and mean maternal blood pressure before and after administration of magnesium sulphate (p < 0.001). Resistance index decreased in the umbilical (p = 0.003; 95% CI: 0.008 - 0.03) and middle cerebral artery (p = 0.001; 95% CI: 0.01 - 0.05) and in both uterine arteries. Likewise, there was a significant reduction in the PI and S/D ratio in all the arteries assessed. Conclusions. Maternal administration of intravenous magnesium sulfate in preeclampsia leads to an increase in maternal heart rate and a decrease in systolic, diastolic and mean arterial blood pressure. A reduction in the resistance index, pulsatility index and S/D ratio was recorded in the uterine, umbilical and cerebral arteries.

Doppler das artérias umbilicais e cerebral média fetal após sulfato de magnésio na pré-eclâmpsia

OBJETIVO: Comparar a relacao da arteria umbilical e arteria cerebral media fetal atraves dos indices dopplervelocimetricos (indice de resistencia, indice de pulsatilidade e relacao S/D) antes e apos a utilizacao do sulfato de magnesio nas gestantes com pre-eclâmpsia grave (pura ou superposta). METODOS: Foi desenvolvido um estudo do tipo coorte prospectivo, no qual cada sujeito serviu como seu proprio controle. Foram selecionadas 40 gestantes com pre-eclâmpsia grave, submetidas ao exame dopplervelocimetrico antes e apos 20 minutos da administracao intravenosa de 6 g do sulfato de magnesio. As variaveis estudadas foram os indices dopplervelocimetricos da relacao arteria umbilical e cerebral media fetal. A comparacao das medias entre as duas medidas (antes e depois) de cada individuo foi realizada atraves do teste t student pareado. A comparacao entre a distribuicao de frequencia de diagnostico fetal (normal, reducao isolada na resistencia da arteria cerebral media e centralizado) foi realizada atraves do teste Qui quadrado (c2) de Stuart-Maxwell. RESULTADOS: Nao foi observada diferenca estatisticamente significativa das medias da relacao arteria umbilical/cerebral media nos indices dopplervelocimetricos antes e apos o sulfato de magnesio. Verificou-se aumento da frequencia de reducao isolada na resistencia da arteria cerebral media apos o sulfato de magnesio (25,0% x 47,5%; p = 0,01). CONCLUSAO: A administracao intravenosa do sulfato de magnesio nas gestantes com pre-eclâmpsia grave resultou em um aumento significativo na frequencia de fetos com diagnostico de reducao da resistencia da arteria cerebral media na dopplervelocimetria.

Ultrasound and Doppler assessment of uterus during puerperium after normal delivery

Abstract Objective: To describe the biometric and morphological characteristics of the uterus through ultrasound (US) and Doppler on the uterine arteries in the initial and late puerperium after normal delivery. Methods: This was a prospective longitudinal study on full-term singleton pregnancies without complications. The patients were divided into two groups: 31 primiparous and 28 multiparous women. Two US exams were carried out with Doppler evaluation: firstly, within the initial 48 h; and secondly, between 31 and 50 days after childbirth. The US assessed the position and biometry of the uterus, appearance of the myometrium, measurement and content of the uterine cavity, and Doppler velocimetry indices of uterine arteries. To compare the groups at the two times, the paired Student t-test, Fisher’s exact test and chi-square test were used. Results: In the initial puerperium, the position of the uterus was retroversion (98.3%); the appearance of the myometrium was heterogeneous (96.6%); the uterine cavity was filled with some type of material (72.9%). After the 30th day, a position was anteversion (74.6%); the appearance of the myometrium was homogeneous (91.5%); and the uterine cavity was empty (81.3%). There was an evolution in the pulsatility index between the two US exams, with an increase of 52.03% among the primiparous and 53.13% among the multiparous for the right uterine artery. Conclusion: Significant changes were observed in the morphological and biometric characteristics of the uteruses evaluated through US, as well as in the uterine arteries Doppler, between the initial and late puerperium.