The COVID-19 pandemic, an environmental neurology perspective.

Neurologists have a particular interest in SARS-CoV-2 because the nervous system is a major participant in COVID-19, both in its acute phase and in its persistent post-COVID phase. The global spread of SARS-CoV-2 infection has revealed most of the challenges and risk factors that humanity will face in the future. We review from an environmental neurology perspective some characteristics that have underpinned the pandemic. We consider the agent, SARS-CoV-2, the spread of SARS-CoV-2 as influenced by environmental factors, its impact on the brain and some containment measures on brain health. Several questions remain, including the differential clinical impact of variants, the impact of SARS-CoV-2 on sleep and wakefulness, and the neurological components of Long-COVID syndrome. We touch on the role of national leaders and public health policies that have underpinned management of the COVID-19 pandemic. Increased awareness, anticipation and preparedness are needed to address comparable future challenges.

Geoclimatology and sleep in Africa: A mini-review.

Sleeping habits and morningness-eveningness questionnaires (chronotype), and polysomnography (internal sleep organization) were proposed to healthy volunteers living under natural climates from different locations in West Africa (Niger, Côte d'Ivoire) and Central Africa (Angola, Congo). Under the Sahelian dry climate, 138 Niger medical students (130 had afternoon naps) completed 1792 sleep questionnaires during 7-day sessions in the cool-dry and hot-dry seasons. As everywhere else on Earth, daily sleep lasted 7 to 8hours. In Abidjan (hot-humid climate), 78 medical students reported shorter sleep time, because of course schedules. Also in Abidjan, 23 African sportsmen and Expatriate soldiers slept at night and in afternoon naps. They reported similar sleep amounts than Niger students. In Congo villages, during a 5-year human African trypanosomiasis (HAT) research campaign, 45 healthy volunteers expressed morning chronotypes. The 71 HAT patients shifted from the indifferent chronotype towards morningness type. Chronotyping such patients may help evaluating treatment efficacy on brain function alterations. French soldiers executing missions in Africa were typed for morningness-eveningness. Regarding malaria prophylaxis and mosquito control, morning chronotype was more compliant than evening type. Polysomnography demonstrated internal sleep organization differences in different geoclimatic zones. The Sahelian climate promoted N3 slow-wave sleep in Africans and Expatriates during both the cool-dry and hot-dry seasons, with higher amounts in the hot-dry season. Increasing heat load by physical exercise further augmented N3. Rapid-eye-movement R sleep was high compared with values from temperate and hot-humid climates. Supramaximal exercise triggered a surprising R stage increase in the hot-dry season. In Côte d'Ivoire, Caucasian and African volunteers fragmented their sleep, although internal sleep organization approached that of temperate climates. Sleep patterns were also similar in Angola high hills and on Congo River shores. Therefore, Africans and Caucasians living in Niger hot-dry Sahelian climate exhibited major differences with those exposed to hot-humid or temperate climates.

Environmental neurology in the tropics.

We address the impact of the tropical environment on the human nervous system using the multifaceted approach characteristic of environmental neurology. First, environmental factors are examined according to their nature (physical, chemical and biological) and in relation to human activity and behavior. Some factors are specific to the tropics (climate and infections), while others are non-specific (chemicals, human communities and their way of life). Second, we examine the major role of human adaptation to the success of Homo sapiens, with emphasis on the linkage between thermoregulation and sleep-wake regulation. Third, we examine the performance of environmental neurology as a clinical discipline in tropical climates, with focus on the diagnostic and therapeutic challenges posed by human African trypanosomiasis. Finally, the prevention, early detection and monitoring of environmental neurological diseases is examined, as well as links with political and economic factors. In conclusion, practitioners of environmental neurology seek a global, multidisciplinary and holistic approach to understanding, preventing and treating neurological disorders within their purview. Environmental neurology integrates an expanded One Health concept by linking health and wellness to the interaction of plants, animals, humans and the ecosystem. Recent epidemics and the current COVID-19 pandemic exemplify the need for worldwide action to protect human health and biodiversity.

Decreased heat tolerance is associated with hypothalamo-pituitary-adrenocortical axis impairment.

When rats are exposed to heat, they adapt themselves to the stressor with a wide inter-individual variability. Such differences in heat tolerance may be related to particularities in the hypothalamo-pituitary-adrenocortical (HPA) axis activation. To further this hypothesis, 80 rats instrumented with a telemetric device for abdominal temperature (Tabd) measurement were separated into two groups. Sixty-eight rats were exposed during 90 min at an ambient temperature of 40 degrees C, and 12 rats to an ambient temperature of 22 degrees C. Heat-exposed rats were then divided into three groups using the a posteriori k-means clustering method according to their Tabd level at the end of heat exposure. Heat tolerant rats (Tol, n=30) exhibiting the lowest Tabd showed a slight dehydration, a moderate triglyceride mobilization, but the highest plasma adrenocorticotropic-hormone (ACTH) and corticosterone levels. Conversely, heat exhausted rats (HE, n=14) presented the highest Tabd, a higher degree of dehydration, a greater metabolic imbalance with the lowest plasma triglyceride level and the highest lactate concentration, as well as a lowest plasma corticosterone and ACTH levels. The fact that the proopiomelanocortin (POMC) mRNA content within the pituitary was low despite of a high c-fos mRNA level is also relevant. Current inflammatory processes in HE rats were underlined by lower inhibitory factor kappaBalpha (IkappaBalpha) mRNA and higher tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA. In conclusion, data show that intolerance to heat exposure is associated to an HPA axis impairment, possibly related to changes occurring in the IkappaBalpha and TNF-alpha mRNA levels.

Harbouring in the brain: A focus on immune evasion mechanisms and their deleterious effects in malaria and human African trypanosomiasis.

Malaria and human African trypanosomiasis represent the two major tropical vector-transmitted protozoan infections, displaying different prevalence and epidemiological patterns. Death occurs mainly due to neurological complications which are initiated at the blood-brain barrier level. Adapted host-immune responses present differences but also similarities in blood-brain barrier/parasite interactions for these diseases: these are the focus of this review. We describe and compare parasite evasion mechanisms, the initiating mechanisms of central nervous system pathology and major clinical and neuropathological features. Finally, we highlight the common immune mediated mechanisms leading to brain involvement. In both diseases neurological damage is caused mainly by cytokines (interferon-gamma, tumour necrosis factor-alpha and IL-10), nitric oxide and endothelial cell apoptosis. Such a comparative analysis is expected to be useful in the comprehension of disease mechanisms, which may in turn have implications for treatment strategies.

Disruption of endocrine rhythms in sleeping sickness with preserved relationship between hormonal pulsatility and the REM-NREM sleep cycles.

In human African trypanosomiasis (sleeping sickness), sleep and wake episodes are sporadically distributed throughout the day and the night. To determine whether these sleep disturbances affect the 24-h hormone profiles and the normal relationships between hormone pulsatility and sleep stages, polygraphic sleep recordings and concomitant hormone profiles were obtained in 6 African patients with sleeping sickness and in 5 healthy African subjects selected from Abidjan on the Ivory Coast. Polysomnographic recordings were continuous, and blood was taken every 10 min throughout the 24-h period. Plasma was analyzed for cortisol, prolactin, and plasma renin activity (PRA). The 24-h rhythm of cortisol, considered to be an endogenous circadian rhythm, was attenuated in all of the patients except one. However, as in normal subjects, slow wave sleep (SWS) remained associated with the declining phases of the cortisol secretory episodes. Prolactin and PRA profiles, which are strongly influenced by the sleep-wake cycle, did not manifest the nocturnal increase normally associated with the sleep period; instead, they reflected a sporadic distribution of the sleep and wake episodes throughout the 24-h period. In patients with sleeping sickness as in normal subjects, rapid eye movement (REM) sleep began during the descending phases of prolactin pulses. In both groups, PRA reflected the sleep stage distribution with non REM (NREM) sleep occurring during the ascending phases and REM sleep during the descending phases of the PRA oscillations. However, in sleeping sickness patients, the marked sleep fragmentation often did not allow sufficient time for PRA to increase significantly, as is normally the case in subjects with regular NREM-REM sleep cycles. These results demonstrate that, together with the disruption of the sleep-wake cycle, there are profound differences in the temporal organization of the 24-h hormone profiles in humans with African trypanosomiasis. However, the relationship between hormonal pulses and specific sleep stages persists, indicating the existence of a robust link between hormonal release and the internal sleep structure.

Differences in prefrontal cortex GABA/glutamate ratio after acute restraint stress in rats are associated with specific behavioral and neurobiological patterns.

In patients suffering from stress-related pathologies and depression, frontal cortex GABA and glutamate contents are reported to decrease and increase, respectively. This suggests that the GABA and/or glutamate content may participate in pathological phenotype expression. Whether differences in frontal cortex GABA and glutamate contents would be associated with specific behavioral and neurobiological patterns remains unclear, especially in the event of exposure to moderate stress. We hypothesized that an increase in prefrontal cortex GABA/glutamate ratio would be associated with a blunted prefrontal cortex activation, an enhanced hypothalamo-pituitary-adrenocortical (HPA) axis activation and changes in behavior. Rats being restrained for 1-h were then tested in an open-field test in order to assess their behavior while under stress, and were sacrificed immediately afterward. The GABA/glutamate ratio was assessed by (1)H high-resolution magic angle spinning magnetic resonance spectroscopy ((1)H-HRMAS-MRS). The neurobiological response was evaluated through prefrontal cortex mRNA expression and plasma corticosterone levels. The stressed rats were distributed into two subgroups according to their high (H-G/g) or low (L-G/g) GABA/glutamate ratio. Compared to the L-G/g rats, the H-G/g rats exhibited a decrease in c-fos, Arc, Npas4, Nr4a2 mRNA expression suggesting blunted prefrontal cortex activation. They also showed a more pronounced stress with an enhanced rise in corticosterone, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), creatine kinase (CK) and lactate dehydrogenase (LDH) levels, as well as behavioral disturbances with decreased locomotion speed. These changes were independent from prefrontal cortex energetic status as mammalian target of rapamycin (mTOR) and adenosine monophosphate-activated protein kinase (AMPK) pathway activities were similar in both subpopulations. The differences in GABA/glutamate ratio in the frontal cortex observed in the stressed animals may participate in shaping individual differences in psychophysiological reactions.

Human sleep patterns in Antarctica.

Eight volunteers wintering in a French coastal station in Antarctica underwent 156 polysomnographic night recordings. The subjects, selected for their usual good sleeping habits, were recorded on 17-21 nights throughout the wintering in sessions of 2 to 3 consecutive nights. A two-way analysis of variance showed that most of the subjects' sleep characteristics were not similar, leading the authors to study the individual time course of sleep variables. As the subjects slept in their own comfortable quarters, there was no "polar insomnia," no first night effect, nor any relationship between sleep pattern variations and climatic changes. In all subjects, delta sleep tended to increase throughout the wintering, whereas stages 1 and 2 decreased. No significant variation was seen in paradoxical sleep (PS), neither between subjects nor with time. PS latency was also within normal range, but it was bimodally distributed in subjects S1, S2, and S8. Some other sleep variables also varied in certain subjects. Such was the case for sleeping time, which decreased throughout the wintering period in subject S8, the least adapted individual. However, due to the limited number of subjects, no statistical attempt could be made to link individual differences in sleep patterns and adaptation to life in Antarctica.

Heart blocks during sleep: a case report in a healthy subject.

Cardiac arrhythmia was fortuitously discovered during an experimental sleep recording in a healthy 50-year-old man. a 24 hr electrocardiographic (ECG) monitoring revealed the prevalence of these abnormalities during sleep and their absence during the awake period. Sleep and ECG were recorded during 4 consecutive nights. Numerous (500-1, 100 events/night) heart blocks and sinus pauses occurred 60-80 min after going to bed. They were never observed during awakenings and were exacerbated during paradoxical sleep. The atrioventricular blocks were of the Wenckebach-Luciani type. No other abnormality was found. These conduction abnormalities are discussed as possibly due to phasic increases in vagal firing, which during paradoxical sleep would be superimposed on the tonic increase in heart rate.

Effects of zopiclone on the rest/activity rhythm after a westward flight across five time zones.

The effects of zopiclone on the rest/activity rhythm were investigated after a westward flight with a 5-h phase delay (Grenoble-Martinique). The rest/activity rhythm was recorded continuously with an actigraph monitor during a 6-day baseline episode in Grenoble and a 6-day sojourn in Martinique. Rectal temperature was recorded before the flight on day 2 and after the flight on days 2 and 5. Subjective jet-lag score was assessed before the flight on days 1 and 2 and in Martinique on days 1, 2, 5 and 6. Zopiclone (7.5 mg) or placebo were administered double blind 30 min prior to bedtime during the first 4 post-flight days (D1-D4). Under zopiclone treatment, sleep was less fragmented on the first post-flight night and the curtailment of sleep duration observed on D2 and D3 under placebo was prevented. During day-time, subjects tended to be more active than with placebo. By contrast, subjective jet-lag scores did not differ between both groups. Zopiclone seemed to accelerate the readjustment of the rest/activity rhythm and the normalisation of the phase relationship between sleep and the temperature rhythm. Zopiclone probably exerts its "resetting" effects on jet-lag desynchronosis by facilitating sleep induction rather than via a chronobiotic action.

High frequency waking EEG: reflection of a slow ultradian rhythm in daytime arousal.

The ultradian dynamics of the human waking EEG was studied using a short visual fixation task repeated every 10 min throughout the daytime. The EEG spectra obtained from the tasks were assessed for time effect and ultradian periodicity. Fronto-central EEG high frequency powers (22.5-44.5 Hz) decreased at the time of the midafternoon vigilance dip (14.00-17.00 h) along with slight concomitant increases in parietal alpha (7.5-13.5 Hz) and delta (1-3 Hz) powers. A slow ultradian rhythm with a 3-4 h periodicity strongly modulated EEG power in all frequency bands between 1 and 44.5 Hz. The high frequency waking EEG may well reflect the activity of a brain arousal process underlying maintenance of the waking state probably throughout the 24 h cycle.

Contribution of exertional hyperthermia to sympathoadrenal-mediated lymphocyte subset redistribution.

The contribution of hyperthermia to the differential leukocytosis of exercise remains obscure. This study examined changes in circulating sympathoadrenal hormone concentrations and patterns of leukocyte and lymphocyte subset (CD3(+), CD4(+), CD8(+), CD19(+), CD3(-)16(+)/56(+)) redistribution during exercise, with and without a significant rise of rectal temperature (T(re)). Ten healthy men [age 26.9 +/- 5.7 (SD) yr, body mass 76.0 +/- 10.9 kg, body fat 13.9 +/- 4.6%, peak O(2) consumption: 48.0 +/- 12.4 ml x kg(-1) x min(-1)] exercised for 40 min (65% peak O(2) consumption) during water immersion at 39 or 18 degrees C. T(re) increased from 37.2 to 39.3 degrees C (P < 0.0001) after 40 min of exercise in 39 degrees C water but was held constant to an increment of 0.5 degrees C during exercise in 18 degrees C water. Application of this thermal clamp reduced exercise-associated increments of plasma epinephrine (Epi) and norepinephrine (NE) by >50% (P < 0.05) and abolished the postexercise increase in cortisol. Thermal clamping also reduced the exercise-induced leukocytosis and lymphocytosis. Multiple regression demonstrated that T(re) had no direct association with lymphocyte subset mobilization but was significantly (P < 0.0001) correlated with hormone levels. Epi was an important determinant of total leukocytes, lymphocytes, and CD3(+), CD4(+), CD8(+), and CD3(-)CD16(+)/56(+) subset redistribution. The relationship between NE and lymphocyte subsets was weaker than that with Epi, with the exception of CD3(-)CD16(+)/56(+) counts, which were positively (P < 0.0001) related to NE. Cortisol was negatively associated with leukocytes, CD14(+) monocytes, and CD19(+) B- and CD4(+) T-cell subsets but was positively related to granulocytes. We conclude that hyperthermia mediates exercise-induced immune cell redistribution to the extent that it causes sympathoadrenal activation, with alterations in circulating Epi, NE, and cortisol.

The effects of antimalarial drugs on ventricular repolarization.

Cardiotoxicity has become a major concern during treatment with antimalarial drugs. Lengthening of the QTc and severe cardiac arrhythmia have been observed, particularly after treatment with halofantrine for chloroquine-resistant Plasmodium falciparum malaria. The purpose of this prospective study was to evaluate whether antimalarial agents alter dispersion of the QTc and ventricular repolarization dynamicity. Sixty patients with uncomplicated falciparum malaria were randomly allocated in four groups of 15 patients and treated with quinine, mefloquine, artemether, or halofantrine at recommended doses. Patients in treatment groups were compared with a group including 15 healthy controls with no history of malaria and/or febrile illness within the last month. QTc dispersion was measured on surface electrocardiograms. Repolarization dynamicity was analyzed from Holter recordings, which allow automatic beat-to-beat measurement of QT and RR intervals. Plasma drug concentration was determined by reversed-phase high-performance liquid chromatography. No change in QTc dispersion was observed after treatment with quinine, mefloquine, or artemether. Treatment with halofantrine was followed by a significant increase in QTc dispersion at 9 hours (P < 0.0001) and 24 hours (P < 0.01). Assessment of QT heart rate variability by QT/RR nychtohemeral regression slope demonstrated no significant difference between the artemether (mean +/- SEM = 0.170 +/- 0.048), mefloquine (0.145 +/- 0.044), and the control groups (0.172 +/- 0.039). A significant decrease in the Q-eT/RR slope was observed in the quinine group compared with the control and artemether groups (0.135 +/- 0.057; P < 0.04). With halofantrine, a significant increase in the QT/RR regression slope (0.289 +/- 0.118) was observed (P < 0.0002). QTc interval, QT dispersion, and QT regression slope were significantly correlated with halofantrine and quinine plasma concentration. Mefloquine and artemether did not alter ventricular repolarization. Quinine induced a significant decrease in QT/RR slope of the same order of magnitude as those previously observed with quinidine. Both QTc dispersion and QT/RR slope were significantly modified by halofantrine. These repolarization changes were related to a class-III antiarrhythmic drug effect and may explain the occurrence of ventricular arrhythmia and/or sudden deaths reported after halofantrine intake.

Twenty-four-hour plasma cortisol and prolactin in human African trypanosomiasis patients and healthy African controls.

We have previously demonstrated that human African trypanosomiasis (sleeping sickness) at the stage of meningoencephalitis results in a major disruption of the circadian rhythmicity of sleep and wakefulness that is proportional to the severity of the disease. This paper examines the corresponding 24-hourly secretion in cortisol and prolactin and compares it with the hourly distribution of sleep composition in infected patients and healthy African subjects. The secretion of cortisol in humans follows a circadian rhythm relatively independent of the sleep-wake cycle, whereas that of prolactin exhibits fluctuations over the 24-hr day that are strongly related to the sleep-wake cycle. After the clinical classification of the patients according to the severity of the disease, hourly blood samples were taken over 24 hr via an indwelling catheter. Plasma cortisol and prolactin were analyzed by radioimmunoassay, and the variations in the hourly concentrations were analyzed for the presence of a potential 24-hr rhythm (circadian). All of the healthy African subjects showed significant circadian rhythms in both cortisol and prolactin secretion, similar to data on humans from temperate regions, and a sleep-related anamnestic afternoon peak of prolactin. Major disruptions in the circadian rhythms of plasma cortisol and prolactin were found in the three patients with the most severe illness, in contrast to the four who were less severely ill and the healthy controls. Thus, it appears that as the disease progresses in severity, major disruptions begin to occur in body circadian rhythms, not only in the sleep-wake cycle as reported elsewhere, but also in cortisol and prolactin secretion, suggesting that sleeping sickness affects the circadian timing system.

Sleep patterns of European expatriates in a dry tropical climate.

Night sleep in sedentary African subjects living in the sahelian zone lasts from 7 h to 8 h, with high amounts of slow-wave sleep (SWS) and paradoxical sleep (PS), SWS being present in each sleep cycle. We report here on sleep patterns in 6 healthy male European expatriates (aged 32-39 years) living in the same tropical climate. Polysomnography was taken for 3 consecutive nights in February (mean ambient temperature, Ta: 29.5 degrees C), March (Ta: 31.6 degrees C) and May (Ta: 33.3 degrees C). Comparisons between seasons were made with an analysis of variance, with P >/= 0.05. Because of a first night effect, the first nocturnal recording was discarded. Total sleep time (TST) increased in May vs February and March (P < 0.05). Stage 2 was shorter in March than in February (P < 0.001) and its proportion decreased from February to March (P < 0.02) and from March to May (P < 0.05). Conversely, SWS increased from February to March and March to May (duration, P < 0.001; proportion, P < 0.05), due to an augmentation in stage 4 with more numerous and longer stage 4 phases. Stage 3 was also increased in May vs March. The latency to SWS was shorter in March. SWS was present in each sleep cycle. PS was high, but did not vary. The sleep pattern changes were directly correlated with Ta. In conclusion, Caucasians living in the tropics slept similarly to Africans. The seasonal sleep variations favour the hypothesis that SWS is increased when thermoregulatory processes are triggered, either through passive climatic heating or exercise-induced hyperthermia.

Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. II. Effects on two nights of recovery sleep.

Polysomnograms were obtained from 37 volunteers, before (baseline) and after (two consecutive recovery nights) a 64-h sleep deprivation, with (d-amphetamine or modafinil) or without (placebo) alerting substances. The drugs were administered at 23.00 hours during the first sleep deprivation night (after 17.5 h of wakefulness), to determine whether decrements in cognitive performance would be prevented; at 05.30 hours during the second night of sleep deprivation (after 47.5 h of wakefulness), to see whether performance would be restored; and at 15.30 hours during the third day of continuous work, to study effects on recovery sleep. The second recovery night served to verify whether drug-induced sleep disturbances on the first recovery night would carry over to a second night of sleep. Recovery sleep for the placebo group was as expected: the debt in slow-wave sleep (SWS) and REM sleep was paid back during the first recovery night, the rebound in SWS occurring mainly during the first half of the night, and that of REM sleep being distributed evenly across REM sleep episodes. Recovery sleep for the amphetamine group was also consistent with previously published work: increased sleep latency and intrasleep wakefulness, decreased total sleep time and sleep efficiency, alterations in stage shifts, Stage 1, Stage 2 and SWS, and decreased REM sleep with a longer REM sleep latency. For this group, REM sleep rebound was observed only during the second recovery night. Results for the modafinil group exhibited decreased time in bed and sleep period time, suggesting a reduced requirement for recovery sleep than for the other two groups. This group showed fewer disturbances during the first recovery night than the amphetamine group. In particular, there was no REM sleep deficit, with longer REM sleep episodes and a shorter REM latency, and the REM sleep rebound was limited to the first REM sleep episode. The difference with the amphetamine group was also marked by less NREM sleep and Stage 2 and more SWS episodes. No REM sleep rebound occurred during the second recovery night, which barely differed from placebo. Hence, modafinil allowed for sleep to occur, displayed sleep patterns close to that of the placebo group, and decreased the need for a long recovery sleep usually taken to compensate for the lost sleep due to total sleep deprivation.

Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work. I. Effects on mood, fatigue, cognitive performance and body temperature.

Modafinil is an alerting substance that is considered safer than amphetamine with fewer side effects. Although modafinil has been used successfully to treat narcolepsy, relatively little is known about its ability to ameliorate fatigue and declines in mental performance due to sleep deprivation (SD) in a normal population. Forty-one military subjects received either 300 mg of modafinil, 20 mg of d-amphetamine, or placebo on 3 separate occasions during 64 hours of continuous cognitive work and sleep loss. Three drug treatments were given: at 23.30 hours and 05.30 hours during the first and second SD nights, respectively, and once at 15.30 hours during the third day of continuous work. Subjective estimates of mood, fatigue and sleepiness, as well as objective measures of reaction time, logical reasoning and short-term memory clearly showed better performance with both modafinil and amphetamine relative to placebo. Both modafinil and amphetamine maintained or increased body temperature compared to the natural circadian cycle observed in the placebo group. Also, from subject debriefs at the end of the study, modafinil elicited fewer side-effects than amphetamine, although more than the placebo group. Modafinil appears to be a good alternative to amphetamine for counteracting the debilitating mood and cognitive effects of sleep loss during sustained operations.

Time-related changes in the sleep-wake cycle of rats infected with Trypanosoma brucei brucei.

Patients with human African trypanosomiasis, sleeping sickness, show a major disturbance in the circadian distribution of sleeping and waking, with sleep and wake episodes equally distributed throughout the nycthemeron. In order to develop an animal model, polysomnography was taken continuously in 8 male OFA rats in a 12:12 h light-dark cycle, during 1 baseline week and for 2 weeks after infection with Trypanosoma brucei brucei. Considerable sleep fragmentation was observed in the infected rats, with numerous sleep-wake stage changes and an increased number of wakefulness and slow-wave sleep phases. Although the infection produced a progressive disruption of the sleep-wake cycle, the extensive disturbances of the circadian rhythm of the sleep-wake cycle observed in humans with sleeping sickness was not attained in the rats.

Inhibition of different types of nitric oxide synthase: effect on thermoregulation in the rat exposed to high ambient temperature.

Vascular and immunological mechanisms are both likely to be involved in heatstroke, this condition being preceded by a decrease in cerebral blood flow and an increase in brain cytokine concentrations. As the two mechanisms involve a nitridergic step, we analysed their respective role in heat tolerance by exposing vigil rats to heat after treatment with nitric oxide synthases (NOS) antagonists: non-specific inhibitors N(omega)-nitro-L-arginine (LNA) and N-nitro-L-arginine-methyl-ester (L-NAME); 7-nitroindazol (neuronal NOS inhibitor) and aminoguanidine (AG) (inducible NOS inhibitor). Heat exposure was interrupted when clinical signs occurred or when colonic temperature reached 43 degrees C. LNA and L-NAME dramatically reduced heat tolerance, while AG did not modify it. These results suggest the involvement of constitutive NOS in heat tolerance. Inducible NOS does not seem to be involved in the occurrence of heatstroke.

Voltametric assessment of brain nitric oxide during heatstroke in rats.

Anesthetized rats exposed to a high ambient temperature develop heatstroke with brain ischemia. Since nitric oxide (NO) plays an important role during normothermic ischemia, its cortical and cerebellar production were continuously assessed in pentobarbital anesthetized rats exposed to heat by using differential pulsed voltammetry. After 60 min at thermoneutrality, the rats were submitted to an ambient temperature of 40 degrees C until death. After 60 min in the heat, the rats were injected intraperitoneally with saline, MK801 (1 mg.kg(-1)), an antagonist of N-methyl-D-aspartate (NMDA) receptors, or L-arginine p-nitroanilide (L-ANA; 100 mg.kg(-1)), an inhibitor of NO synthase. Just before death, a 70% increase in NO production was observed in both the cerebellum and the cortex of saline-treated rats. The cortical increase in NO was not modified by MK801 while the NO signal was suppressed by L-ANA.