Wii-based exercise program to improve physical fitness, motor proficiency and functional mobility in adults with Down syndrome.

BACKGROUND: People with Down syndrome (DS) usually display reduced physical fitness (aerobic capacity, muscle strength and abnormal body composition), motor proficiency impairments (balance and postural control) and physical functional limitations. Exergames can be an appealing alternative to enhance exercise engagement and compliance, whilst improving physical fitness and motor function. This study aims to analyse the effects of a Wii-based exercise program on physical fitness, functional mobility and motor proficiency of adults with DS. METHODS: Twenty-seven adults with DS were randomly allocated to an experimental group (Wii; n = 14) or control group (n = 13). Participants in the experimental group completed a 2-month Wii-based exercise program, with three 1-h sessions per week that included training games for aerobic endurance, balance and isometric strength. Participants completed assessments regarding anthropometric measures, physical fitness, functional mobility and motor proficiency. RESULTS: Mixed ANOVA analysis showed a significant group by time interaction for aerobic endurance, explosive leg power and flexibility. Independent samples t-test for change scores indicated significant between-group differences favouring the experimental group regarding speed of limb movement, trunk strength and functional mobility, as well as a trend towards significance on body weight. Mann-Whitney's U test for change scores demonstrated between-group differences favouring the experimental group for visceral fat as well as running speed and agility. Large within-group effect sizes were observed for explosive leg power (d = 1.691), body weight (d = 1.281), functional mobility (d = 1.218), aerobic endurance (d = 1.020), speed of limb movement (d = 0.867) and flexibility (d = 0.818) in the experimental group. CONCLUSIONS: Our findings suggest that Wii-based exercise can be an effective tool to improve physical fitness, functional mobility and motor proficiency of adults with DS, including crucial measures such as aerobic capacity and lower limb strength. Exergames using Wii Fit or other equipment can be appealing alternatives for adults with DS to engage in regular physical activity, preventing sedentary behaviour and decreasing the risk to develop cardiovascular diseases.

Retracted: Hypocretin (orexin) cell transplantation diminishes narcoleptic-like sleep behavior in rats.

Arias-Carrión, O.; Drucker-Colín, R.; Murillo-Rodríguez, E. "Hypocretin (orexin) cell transplantation diminishes narcoleptic-like sleep behavior in rats." CNS Neurol. Disord. Drug Targets, 2011,11(7). The above-cited paper has been retracted from CNS & Neurological Disorders-Drug Targets at the request of the authors. The authors advised the Journal of their intention to perform additional experiments in order to strengthen their initial results, at which time an amended manuscript may be submitted.

The anandamide membrane transporter inhibitor, VDM-11, modulates sleep and c-Fos expression in the rat brain.

Endogenous cannabinoids or endocannabinoids are lipid molecules that have a variety of biological actions, most notably via activation of the cannabinoid receptors. The family of endocannabinoids includes arachidonoylethanolamide (ANA) which modulates different behaviors, such as sleep. However, it is unknown whether pharmacological elevation of ANA endogenous levels might induce sleep. VDM 11 [(5 Z,8 Z,11 Z,14 Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide] is commonly used as an inhibitor of ANA cellular uptake, and thereby to potentiate its actions. In this study we have examined whether VDM-11 exerts any effect on the sleep-wake cycle and c-Fos expression in brain areas. When assayed alone in rats, VDM-11 (10 or 20 microg/5 microL, i.c.v.) at the beginning of the lights-off period, reduced wakefulness and increased sleep. The CB(1) cannabinoid receptor antagonist, SR141716A, partially reversed the effects of VDM-11 on sleep. Additionally, VDM-11 enhanced c-Fos expression in sleep-related brain areas such as the anterior hypothalamic area, paraventricular thalamic nucleus, and pedunculopontine tegmental nucleus. It is concluded that VDM-11 displays sleep-inducing properties and these effects slightly, albeit significantly, are reversed using SR141716A. Furthermore, c-Fos data suggest a possible underlying neuroanatomical substrate of the sleep-inducing properties of VDM-11. We report evidence suggesting that VDM-11 might be considered for the development of new pharmacological and pharmaceutical approaches to treat sleep disorders such as insomnia.

[The modulatory role of endocannabinoids in sleep]. / Papel modulador de los endocanabinoides en el sueno.

INTRODUCTION: The endogenous cannabinoid, or endocannabinoid, system is present in the central nervous system (CNS) of rodents and humans. This system includes receptors, endogenous ligands and enzymes. The presence of cannabinoid receptors, called CB1, in the CNS has been reported in the cerebral cortex, the hippocampus, the cerebellum and the brain stem. This neuroanatomical location suggests that this receptor could modify several physiological functions, such as the consolidation of memory, motor control and the generation of sleep. DEVELOPMENT: Recent reports have described the presence of lipids in the CNS that bind to the CB1 receptor. Administration of said molecules induces cannabimimetic effects, and hence it has been suggested that these lipids are endogenous cannabinoids or endocannabinoids. Anandamide, 2-arachidonylglycerol, virodhamine, noladin ether and N-arachidonyldopamine are molecules that belong to the endocannabinoid family. Anandamide has received more attention from researchers because it was the first endocannabinoid to be reported. Pharmacological experiments have shown that this endocannabinoid induces several different intracellular and behavioural changes. CONCLUSIONS: In this study, we review the most important pharmacological aspects of exogenous cannabinoids and the neurobiological role played by the endocannabinoid system, including endogenous and exogenous ligands and receptors. We also examine their pharmacological effects on different behaviours, with particular attention given to the modulation of sleep.

Papel modulador de los endocanabinoides en el sueño / The modulatory role of endocannabinoids in sleep

El sistema de canabinoides endógenos, o endocanabinoides, está presente en el sistema nervioso central (SNC) tanto de roedores como en humanos. Este sistema incluye receptores, ligandos endógenos y enzimas. La presencia en el SNC de receptores para canabinoides, denominados CB1, se ha descrito en la corteza cerebral, el hipocampo, el cerebeloy el tallo cerebral. Dicha localización neuroanatómica sugiere que este receptor podría modular diversas funciones fisiológicas como la consolidación de la memoria, el control motor y la generación del sueño. Desarrollo. En la actualidad se ha comunicadola presencia en el SNC de lípidos que se unen al receptor CB1. La administración de dichas moléculas induce efectos canabimiméticos, de tal forma que se han sugerido estos lípidos como canabinoides endógenos o endocanabinoides. Anandamida, 2-araquidonilglicerol, virodamina, noladin-éter y N-araquidonildopamina son moléculas que pertenecen a la familia de losendocanabinoides. Dado que la anandamida fue el primer endocanabinoide descrito, ha sido el más estudiado. Experimentos farmacológicos han demostrado que este endocanabinoide induce diversos cambios intracelulares y conductuales. Conclusiones. En este trabajo se revisan los aspectos farmacológicos más importantes de los canabinoides exógenos y el papel neurobiológicodel sistema de endocanabinoides, incluyendo ligandos endógenos y exógenos y receptores, así como sus efectos farmacológicos en diversas conductas, especialmente en la modulación del sueño

The endogenous cannabinoid, or endocannabinoid, system is present in the central nervous system(CNS) of rodents and humans. This system includes receptors, endogenous ligands and enzymes. The presence of cannabinoid receptors, called CB1, in the CNS has been reported in the cerebral cortex, the hippocampus, the cerebellum and the brain stem.This neuroanatomical location suggests that this receptor could modify several physiological functions, such as the consolidation of memory, motor control and the generation of sleep. Development. Recent reports have described the presence of lipids in the CNS that bind to the CB1 receptor. Administration of said molecules induces cannabimimetic effects, and henceit has been suggested that these lipids are endogenous cannabinoids or endocannabinoids. Anandamide, 2-arachidonylglycerol, virodhamine, noladin ether and N-arachidonyldopamine are molecules that belong to the endocannabinoid family. Anandamidehas received more attention from researchers because it was the first endocannabinoid to be reported. Pharmacological experiments have shown that this endocannabinoid induces several different intracellular and behavioural changes.Conclusions. In this study, we review the most important pharmacological aspects of exogenous cannabinoids and theneurobiological role played by the endocannabinoid system, including endogenous and exogenous ligands and receptors. We also examine their pharmacological effects on different behaviours, with particular attention given to the modulation of sleep

The diurnal rhythm of adenosine levels in the basal forebrain of young and old rats.

There are significant decrements in sleep with age. These include fragmentation of sleep, increased wake time, decrease in the length of sleep bouts, decrease in the amplitude of the diurnal rhythm of sleep, decrease in rapid eye movement sleep and a profound decrease in electroencephalogram Delta power (0.3-4 Hz). Old rats also have less sleep in response to 12 h-prolonged wakefulness (W) indicating a reduction in sleep drive with age. The mechanism contributing to the decline in sleep with aging is not known but cannot be attributed to loss of neurons implicated in sleep since the numbers of neurons in the ventral lateral preoptic area, a region implicated in generating sleep, is similar between young (3.5 months) and old (21.5 months) rats. One possibility for the reduced sleep drive with age is that sleep-wake active neurons may be stimulated less as a result of a decline in endogenous sleep factors. Here, we test this hypothesis by focusing on the purine, adenosine (AD), one such sleep factor that increases after prolonged W. In experiment 1, microdialysis measurements of AD in the basal forebrain at 1 h intervals reveal that old (21.5 months) rats have more extracellular levels of AD compared with young rats across the 24 h diurnal cycle. In experiment 2, old rats kept awake for 6 h (first half of lights-on period) accumulated more AD compared with young rats. If old rats have more AD then why do they sleep less? To investigate whether changes in sensitivity of the AD receptor contribute to the decline in sleep, experiments 3 and 4 determined that for the same concentration of AD or the AD receptor 1 agonist, cyclohexyladenosine, old rats have less sleep compared with young rats. We conclude that even though old rats have more AD, a reduction in the sensitivity of the AD receptor to the ligand does not transduce the AD signal at the same strength as in young rats and may be a contributing factor to the decline in sleep drive in the elderly.

Potential role of the cannabinoid receptor CB1 in rapid eye movement sleep rebound.

Sleep is an unavoidable activity of the brain. The delay of the time to sleep (sleep deprivation), induces an increase of slow-wave sleep and rapid-eye-movement (REM) sleep (rebound) once the subject is allowed to sleep. This drive to sleep has been hypothesized to be dependent on the accumulation of sleep-inducing molecules and on the high expression of these molecule receptors. In this study we selectively deprived rats of REM sleep for 24 h by using the flowerpot technique. One group deprived of REM sleep was treated with SR141716A, a cannabinoid receptor 1 (CB1) receptor antagonist and then allowed to sleep for the next 4 h. Two other groups were killed, one immediately after the REM sleep deprivation period and the other after 2 h of REM sleep rebound (REM sleep deprivation plus 2 h of rebound). In both groups we determined the expression of the CB1 receptor and its mRNA. Results indicated that SR141716A prevents REM sleep rebound and REM sleep deprivation does not modify the expression of the CB1 protein or mRNA. However, REM sleep deprivation plus 2 h of sleep rebound increased the CB1 receptor protein and, slightly but significantly, decreased mRNA expression. These results suggest that endocannabinoids may be participating in the expression of REM sleep rebound.

Sleep modulates cannabinoid receptor 1 expression in the pons of rats.

Endocannabinoids seem to play a role in the modulation of alertness. Therefore, we measured cannabinoid receptor 1 (CB1R) protein by Western blot and messenger RNA (mRNA) by reverse transcription-polymerase chain reaction in the pons of rats across the 24-h period. We performed evaluations every 4 h beginning at 09:00 h. Rats were under a controlled light/dark cycle 12:12 (lights on at 08:00 h). Our data suggest that the expression of CB1R gene depends on diurnal variations, with maximum expression at 13:00 h for protein and 21:00 h for mRNA, and minimum expression at 01:00 and 09:00 h, respectively. We also analyzed CB1R protein and mRNA levels in the pons of rats deprived of total sleep for 24 h and in rats with a 24-h period of sleep deprivation plus a 2-h period of sleep rebound. Unlike sleep deprivation, sleep rebound significantly increased CB1R protein while decreasing mRNA. Despite the fact that we used gentle manipulation to deprive the animals of sleep, there may be a potential influence of stress on this effect, too. However, these facts suggest that CB1R gene expression is modulated by the light/dark cycle and by sleep.

An anorexic lipid mediator regulated by feeding.

Oleylethanolamide (OEA) is a natural analogue of the endogenous cannabinoid anandamide. Like anandamide, OEA is produced in cells in a stimulus-dependent manner and is rapidly eliminated by enzymatic hydrolysis, suggesting a function in cellular signalling. However, OEA does not activate cannabinoid receptors and its biological functions are still unknown. Here we show that, in rats, food deprivation markedly reduces OEA biosynthesis in the small intestine. Administration of OEA causes a potent and persistent decrease in food intake and gain in body mass. This anorexic effect is behaviourally selective and is associated with the discrete activation of brain regions (the paraventricular hypothalamic nucleus and the nucleus of the solitary tract) involved in the control of satiety. OEA does not affect food intake when injected into the brain ventricles, and its anorexic actions are prevented when peripheral sensory fibres are removed by treatment with capsaicin. These results indicate that OEA is a lipid mediator involved in the peripheral regulation of feeding.

Oleamide modulates memory in rats.

Oleamide is a recently described lipid, obtained from the cerebrospinal fluid of sleep-deprived cats. It has been observed that oleamide possesses several biological effects, such as sleep induction, and immunological suppression as well as serotonin and gamma-aminobutyric acid receptors activation. In addition, oleamide also binds to the cannabinoid receptors. In this study, we have observed that oleamide facilitates memory extinction in a passive avoidance paradigm, reduces core temperature and pain perception, but does not affect significantly locomotion. These results suggest that oleamide modulates memory processes. However, we do not know if oleamide impairs the retrieval of the memory associated to the "not go" behavior, or facilitates the fast re-learning of the "go" behavior. In addition, since these effects are also induced by marijuana and anandamide, it is very likely that oleamide may be affecting the cerebral cannabinoid system to induce its effects.

Anandamide-induced sleep is blocked by SR141716A, a CB1 receptor antagonist and by U73122, a phospholipase C inhibitor.

Anandamide (ANA) alters sleep by increasing the amount of time spent in slow wave sleep 2 (SWS2) and rapid eye movement sleep (REMS) at the expense of wakefulness (W) in rats. In this report, we describe a similar effect of ANA when injected itracerebroventricularly (i.c.v.) or into the peduriculopontine tegmental nucleus (PPTg) and the lack of an effect when ANA is administered into the medial preoptic area (MPOA). Furthermore, the i.c.v. or PPTg administration of SR141716A, a CB1 antagonist, or U73122, a PLC inhibitor, 15 min prior to ANA, readily prevents the ANA induced changes in sleep. The present results suggest that a cannabinoid system in the PPTg may be involved in sleep regulation and that the cannabinoid effect is mediated by the CB1 receptor coupled to a PLC second messenger system.

HIV- and FIV-derived gp120 alter spatial memory, LTP, and sleep in rats.

Human immunodeficiency virus (HIV)-associated dementia (HAD) has been detected in 20-30% of patients suffering AIDS. The envelope glycoprotein 120 (gp120) derived from HIV seems to play a critical role in the pathophysiology of this dementia. Likewise, the feline immunodeficiency virus (FIV)-derived gp120 causes neurological and electrophysiological abnormalitites in cats. We have studied the effects of gp120 derived from HIV or FIV on learning and memory processing, hippocampal long-term potentiation (LTP), hippocampal neuronal cAMP production, the sleep-waking cycle, and locomotor activity and equilibrium in rats. Results showed that while both HIV- and FIV-gp120 impaired the rat's performance in the Barnes maze task, only HIVgp120 impaired the induction and maintenance of LTP. However, both glycoproteins induced a significant decrease in the posttetanic potentiation. HIVgp120 also caused a significant reduction in cAMP production in the hippocampus. Regarding the sleep-waking cycle, HIV- and FIV-gp120 increased the waking state and slow-wave sleep 1 (SWS1), while decreasing both SWS2 and REM sleep. Locomotor activity and equilibrium were significantly altered by these glycoproteins. These results suggest that HIVgp120 causes neurophysiological abnormalities and therefore may facilitate HAD development in AIDS patients.

Cortistatin modulates memory processes in rats.

Cortistatin (CST) is a recently described neuropeptide with high structural homology with somatostatin. Its mRNA is restricted to gamma amino butyric acid (GABA)-containing cells in the cerebral cortex and hippocampus. CST modulates the electrophysiology of the hippocampus and cerebral cortex of rats; hence, it may be modulating mnemonic processes. In this study, we have evaluated the effect of CST and somatostatin (SS) on short- and long-term memory (STM and LTM, respectively), as well as on the extinction of the behavior by using the footshock passive avoidance behavioral test. In addition, we tested the ability of both neuropeptides to affect the generation of cAMP in hippocampal neurons in culture. Results showed that the administration of either CST or SS into the hippocampal CA1 deteriorates memory consolidation in a dose-response fashion and facilitates the extinction of the learned behavior. CST was more potent than SS. Likewise, CST increases cAMP while SS decreases it. These results strongly support a modulatory role for CST in memory processes.

Anandamide modulates sleep and memory in rats.

In this study we have assessed the effect of the intracerebroventricular administration of anandamide (ANA) as well as its precursor metabolite arachidonic acid (AA), on the sleep-wakefulness cycle, memory formation, locomotor activity and pain perception. Our results have indicated that ANA strikingly increases slow-wave sleep (SWS)2 and rapid-eye movement (REM) sleep at the expense of wakefulness (W); while deteriorating memory consolidation. ANA also increases locomotor activity but does not modify pain perception threshold. In contrast, AA increases W and reduces SWS2, while deteriorating memory consolidation and increasing locomotor activity. AA has no effect on pain perception. These results suggest that the brain cannabinoid system participates in the modulation of the vigilance states and mnemonic processes. Additionally, they suggest that the effect on pain perception may be a peripheral rather than a central effect.