Usha Panjwani

Hypobaric hypoxia modulates brain biogenic amines and disturbs sleep architecture

Sojourners to high altitude experience poor-quality of sleep due to hypobaric hypoxia (HH). Brain neurotransmitters are the key regulators of sleep wakefulness. Scientific literature has limited information on the role of brain neurotransmitters involved in sleep disturbance in HH. The present study aimed to investigate the time dependent changes in neurotransmitter levels and enzymes involved in the biosynthesis of brain neurotransmitters in frontal cortex, brain stem, cerebellum, pons and medulla and the effect of these alterations on sleep architecture in HH. Thirty adult Sprague-Dawley rats, body weight of 230-250 g were exposed to simulated altitude ∼7620 m, 282 mm Hg, partial pressure of O(2) 59 mm Hg for 7 and 14 days continuously in an animal decompression chamber. After 7 and 14 days of HH, brain nor-epinephrine and dopamine levels were significantly increased in frontal cortex, brain stem, cerebellum and pons and medulla whereas serotonin level was significantly reduced in frontal cortex and pons and medulla after 14 days of HH. Tyrosine hydroxylase level in locus coeruleus (LC) was significantly increased whereas Choline Acetyl Transferase and Glutamic Acid Decarboxylase (GAD) levels were significantly reduced in laterodorsal-tegmentum and pedunculopontine-tegmentum after 7 days of HH. GAD was also reduced in LC after 7 days HH. Alteration in these neurotransmitters and enzyme levels was accompanied with reduction in quality and quantity of sleep. There was a significant increase in sleep latency, rapid eye movement (REM) latency, duration of active awake, quiet awake, quiet sleep and a significant decrease in duration of REM sleep and deep sleep on day 7 and 14 of HH. It was concluded that HH alters the expression of enzymes linked to sleep neurotransmitter synthesis pathway and subsequent loss of homeostasis at neurotransmitter level disrupts the sleep pattern in hypobaric hypoxia.

Effect of Sahaja yoga meditation on auditory evoked potentials (AEP) and visual contrast sensitivity (VCS) in epileptics.

The effect of Sahaja yoga meditation on 32 patients with primary idiopathic epilepsy on regular and maintained antiepileptic medication was studied. The patients were randomly divided into 3 groups: group I practiced Sahaja Yoga meditation twice daily for 6 months under proper guidance; group II practiced postural exercises mimicking the meditation for the same duration; and group III was the control group. Visual Contrast Sensitivity (VCS), Auditory Evoked Potentials (AEP), Brainstem Auditory Evoked Potentials (BAEP), and Mid Latency Responses (MLR) were recorded initially (0 month) and at 3 and 6 months for each group. There was a significant improvement in VCS following meditation practice in group I participants. Na, the first prominent negative peak of MLR and Pa, the positive peak following Na did not register changes in latency. The Na-Pa amplitude of MLR also showed a significant increase. There were no significant changes in the absolute and interpeak latencies of BAEP. The reduced level of stress following meditation practice may make patients more responsive to specific stimuli. Sahaja Yoga meditation appears to bring about changes in some of the electrophysiological responses studied in epileptic patients.

Effect of l-Carnitine Supplementation on Endurance Exercise in Normobaric/Normoxic and Hypobaric/Hypoxic Conditions

Abstract Objective.—To evaluate the effect of l-carnitine supplementation on improving endurance exercise in normobaric/normoxic and hypobaric/hypoxic environments. Methods.—Six-week–endurance-trained male Sprague-Dawley rats (n = 24) were randomly divided into 2 groups: control and experimental; the latter group was supplemented with l-carnitine, administered orally in a dose of 100 mg·kg−1 body weight. The animals were supplemented for 25 days under ambient normobaric/normoxic conditions and thereafter were exposed to 72 hours of hypobaric hypoxia equivalent to 6100 m. The supplementation was continued during the exposure. “Run to exhaustion” was recorded on day 1 (R1) (presupplementation) and on days 7 (R2), 14 (R3), 21 (R4), and 28 (R5, which followed the last 72 hours of hypoxic exposure) of supplementation. Food intake, body weight, and the biochemical measures of plasma glucose, total cholesterol, and high-density lipoprotein (HDL) cholesterol were recorded. Results.—There was a significant improvement in endurance exercise, as indicated by an increase in run to exhaustion following l-carnitine supplementation under normobaric normoxia (36%–39%) and hypobaric hypoxia (50%). l-carnitine supplementation had no effect on plasma glucose levels either at sea level or after hypoxic exposure. Total cholesterol was decreased in normoxic and HDL cholesterol was increased in normoxic and hypoxic conditions, indicating a beneficial effect of exercise. Conclusion.—l-carnitine supplementation improved exercise endurance in rats exposed to normobaric normoxic and hypobaric hypoxic conditions. Such supplementation would be beneficial in delaying the onset of fatigue during prolonged exercise in both conditions, indicating its potentially beneficial use at high altitude.

Guanfacine is an effective countermeasure for hypobaric hypoxia-induced cognitive decline

Hypobaric hypoxia (HH), an environmental stress resulting from ascent to high altitude, affects perception, memory, judgment, and attention, resulting in degradation of many aspects of normal functioning. Alpha 2A adrenergic agonist, guanfacine proved to be beneficial in the amelioration of neurological outcomes of many neuropsychiatric disorders involving adrenergic imbalance and neurodegeneration. Adrenergic dysregulation and neuronal damage have been implicated in hypoxia-induced cognitive deficits, however, efficacy of guanfacine as a countermeasure for HH-induced cognitive decline remains to be evaluated. We, therefore, have studied the effect of this drug on the HH-induced cognitive deficits, adrenergic dysfunction and neuronal damage. Rats were exposed to HH at a simulated altitude of 25,000 feet for 7days and received an IM injection of either saline or guanfacine at a dose of 1mg/kg. Adrenergic transmission was evaluated by biomarkers i.e. norepinephrine (NE), dopamine (DA) and tyrosine hydroxylase (TH) in medial prefrontal cortex (PFC) by biochemical and immunohistochemical assays. Spine and dendritic morphology of pyramidal neurons in layer II of medial PFC was studied using Golgi-Cox staining and Neurolucida neuronal tracing. The cognitive performance was assessed by Delayed Alternation Task using a T-Maze. There was a significant reduction in HH-induced increases in NE, DA and TH levels with guanfacine treatment. Guanfacine rescued HH-induced dendritic atrophy and mushroom type spine loss. The spatial working memory deficits induced by HH were significantly ameliorated with guanfacine treatment. Furthermore, the cognitive performance showed a positive correlation with dendritic arbors and spine numbers. These results showed that the HH-induced cognitive decline is associated with adrenergic dysregulation and neuronal damage in layer II of medial PFC, and that guanfacine treatment during HH ameliorated these functional and morphological deficits. The study suggests a potential role of the alpha-2A adrenergic agonist, guanfacine, in amelioration of PFC dysfunction caused by high altitude exposure.

Caffeine and modafinil given during 48 h sleep deprivation modulate object recognition memory and synaptic proteins in the hippocampus of the rat

We aimed to evaluate the effect of caffeine/modafinil on sleep deprivation (SD) induced alterations in recognition memory and synaptic proteins. The data revealed a beneficial effect of caffeine/modafinil against deficit in the familiar object retrieval performance and object exploration ratio after 48 h SD. Caffeine treatment prevented the SD induced down-regulation of synaptophysin and synapsin I proteins with no change in PSD-95 protein in hippocampus. However, modafinil administration improved the down-regulation of synaptophysin, synapsin I and PSD-95 proteins in hippocampus. Hence, caffeine/modafinil can serve as counter measures in amelioration of SD induced consequences at behavioural and protein levels.

Valeriana wallichii root extract improves sleep quality and modulates brain monoamine level in rats

The present study was performed to investigate the effects of Valeriana wallichi (VW) aqueous root extract on sleep-wake profile and level of brain monoamines on Sprague-Dawley rats. Electrodes and transmitters were implanted to record EEG and EMG in freely moving condition and the changes were recorded telemetrically after oral administration of VW in the doses of 100, 200 and 300 mg/kg body weight. Sleep latency was decreased and duration of non-rapid eye movement (NREM) sleep was increased in a dose dependent manner. A significant decrease of sleep latency and duration of wakefulness were observed with VW at doses of 200 and 300 mg/kg. Duration of NREM sleep as well as duration of total sleep was increased significantly after treatment with VW at the doses of 200 and 300 mg/kg. VW also increased EEG slow wave activity during NREM sleep at the doses of 200 and 300 mg/kg. Level of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT) and hydroxy indole acetic acid (HIAA) were measured in frontal cortex and brain stem after VW treatment at the dose of 200mg/kg. NE and 5HT level were decreased significantly in both frontal cortex and brain stem. DA and HIAA level significantly decreased only in cortex. DOPAC level was not changed in any brain region studied. In conclusion it can be said that VW water extract has a sleep quality improving effect which may be dependent upon levels of monoamines in cortex and brainstem.

Guanfacine ameliorates hypobaric hypoxia induced spatial working memory deficits

Hypobaric hypoxia (HH) observed at high altitude causes mild cognitive impairment specifically affecting attention and working memory. Adrenergic dysregulation and neuronal damage in prefrontal cortex (PFC) has been implicated in hypoxia induced memory deficits. Optimal stimulation of alpha 2A adrenergic receptor in PFC facilitates the spatial working memory (SWM) under the conditions of adrenergic dysregulation. Therefore the present study was designed to test the efficacy of alpha 2A adrenergic agonist, Guanfacine (GFC), to restore HH induced SWM deficits and PFC neuronal damage. The rats were exposed to chronic HH equivalent to 25,000ft for 7days in an animal decompression chamber and received daily treatment of GFC at a dose of 1mg/kg body weight via the intramuscular route during the period of exposure. The cognitive performance was assessed by Delayed Alternation Task (DAT) using T-Maze and PFC neuronal damage was studied by apoptotic and neurodegenerative markers. Percentage of correct choice decreased significantly while perseverative errors showed a significant increase after 7days HH exposure, GFC significantly ameliorated the SWM deficits and perseveration. There was a marked and significant increase in chromatin condensation, DNA fragmentation, neuronal pyknosis and fluoro Jade positive cells in layer II of the medial PFC in hypoxia exposed group, administration of GFC significantly reduced the magnitude of these changes. Modulation of adrenergic mechanisms by GFC may serve as an effective countermeasure in amelioration of prefrontal deficits and neurodegenerative changes during HH.

Modafinil improves event related potentials P300 and contingent negative variation after 24 h sleep deprivation

AIMS The efficacy of modafinil as a countermeasure in the reduction of cognitive decline following 24 h of sleep deprivation (SD) on subjective sleepiness scales, event-related potential (ERP) P300, and contingent negative variation (CNV) was evaluated. MAIN METHODS Eleven healthy males, age 25-30 years participated. The experiment was performed in five sessions on different days between 7 and 8a.m. Session 1, baseline recordings; Session 2, after one nights SD; Session 3, 48 h of recovery from SD; Session 4, after 1 week of Session 1, following one nights SD along with modafinil (400mg/day); Session 5, 48 h of recovery after SD+modafinil. KEY FINDINGS Subjective sleepiness scores increased significantly after SD as compared to baseline (P<0.01), but remained unaltered after modafinil supplementation. There was an increase in N100 and P300 peak latencies of ERP following SD (P<0.01), which was reduced with modafinil (P<0.05). There was an increase in CNV M100 and P300 peak latencies after SD (P<0.01) which decreased with the use of modafinil (P<0.05). The CNV reaction time increased following SD (P<0.01) and decreased with the use of modafinil (P<0.05). No significant effects on ERP N200, P200 latencies and P200, P300 amplitudes and CNV N100, M200 peak latencies and M100, M200 amplitudes were observed. SIGNIFICANCE The results strongly suggest that modafinil in a dose of 400mg/day, reduces the subjective sleepiness and cognitive decline following 24 h of SD.

Adenosine A1 receptor antagonist mitigates deleterious effects of sleep deprivation on adult neurogenesis and spatial reference memory in rats.

Sleep deprivation (SD) upsurges intracellular levels of adenosine, impairs adult neuronal cell proliferation (NCP) and cognition while caffeine, a non-selective adenosine A1 receptor (A1R) antagonist improves cognition and adult NCP during SD. We examined the selective antagonistic effects of adenosine A1R using 8-cyclopentyl-1,3-dimethylxanthine (8-CPT) on impairment of spatial reference memory and adult NCP during 48h SD. Adult male Sprague Dawley rats were sleep deprived for 48h, using an automatic cage vibrating stimulus based on animal activity. Spatial reference memory was tested as a measure of cognitive performance employing Morris Water Maze. Rats were given 8-CPT dissolved in 50% dimethyl sulfoxide (DMSO), twice daily (10mg/kg, i.p.) along with 5-bromo-2-deoxyuridine (BrdU) (50mg/kg/day, i.p.). The rats treated with 8-CPT showed significantly short mean latency and path-length to reach the platform compared to the SD rats. Consistent with these findings, 8-CPT-treated group was found to have significantly increased the number of BrdU, Ki-67 and doublecortin (DCX) positive cells. However, no significant difference was seen in NeuN expression in the Dentate Gyrus (DG). Brain-derived neurotropic factor (BDNF) expression in the DG and CA1 region was observed to decrease significantly after SD and be rescued by 8-CPT treatment. Furthermore, latency to reach platform showed a negative correlation with number of BrdU, DCX type-1 cells and BDNF expression in DG. Thus, it may be concluded that treatment with 8-CPT, an adenosine A1R antagonist during SD mitigates SD induced decline in spatial reference memory and adult NCP possibly via up regulation of BDNF levels in DG and CA1 regions.

Effect of a carbohydrate supplement on feeding behaviour and exercise in rats exposed to hypobaric hypoxia

The effect of a carbohydrate supplement, offered as a diet option, on feeding behaviour, body weight gain, and endurance exercise was studied in rats exposed to hypobaric hypoxia. Male albino rats (n = 35) were randomly divided into 5 groups; hypoxic supplemented and control groups; normoxic supplemented and control groups, and an untreated control group. After treadmill training for 5 days, the hypoxic groups were exposed to simulated high altitude equivalent to 6960 m for 18 days continuously. Food and water intakes, body weight and endurance exercise were recorded before and during the exposure period. Blood glucose, insulin, muscle and liver glycogen were assayed at the end of the exposure period. Hypobaric hypoxia resulted in a significant decrease in food and water intake, and body weight, and reduced endurance exercise capacity compared to the basal and normoxic group values. The carbohydrate supplement did not ameliorate the hypoxia-induced loss in body weight, but however, significantly delayed the onset of fatigue during exercise in the supplemented rats compared to the hypoxic control group.