Is there a link between headache and cognitive disorders? A systematic review.

BACKGROUND: The overall prevalence of headaches decreases with age; however headaches remain frequent in aged individuals who are also affected by other disorders such as cognitive decline. Despite the high frequency of both conditions in these persons, the association between headaches and cognitive decline is underexplored, underdiagnosed and poorly understood. OBJECTIVE: In the present article, we aim to provide a comprehensive review of existing data concerning the link between headache and cognitive decline. METHODS: We undertook a systematic literature review to report articles that focus on headaches (including all types of headaches) and neurocognitive disorders of degenerative causes. RESULTS: Only 9 studies have explored the association between headaches and neurocognitive decline. Methods were highly variable from population-based study to short series of patients using either database or questionnaire during consultation. Studies focusing on Familial Alzheimer's Disease revealed a very high prevalence of headaches in mutation carrier patients compared to non-carrier patients. CONCLUSION: The association between headaches and cognitive decline is underexplored. Future studies are needed to address the pathophysiological mechanisms to improve the treatment of these underestimated headaches.

Decompression models: review, relevance and validation capabilities.

INTRODUCTION/BACKGROUND: For more than a century, several types of mathematical models have been proposed to describe tissue desaturation mechanisms in order to limit decompression sickness. These models are statistically assessed by DCS cases, and, over time, have gradually included bubble formation biophysics. This paper proposes to review this evolution and discuss its limitations. METHODS: This review is organized around the comparison of decompression model biophysical criteria and theoretical foundations. Then, the DCS-predictive capability was analyzed to assess whether it could be improved by combining different approaches. RESULTS: Most of the operational decompression models have a neo-Haldanian form. Nevertheless, bubble modeling has been gaining popularity, and the circulating bubble amount has become a major output. By merging both views, it seems possible to build a relevant global decompression model that intends to simulate bubble production while predicting DCS risks for all types of exposures and decompression profiles. CONCLUSIONS: A statistical approach combining both DCS and bubble detection databases has to be developed to calibrate a global decompression model. Doppler ultrasound and DCS data are essential: i. to make correlation and validation phases reliable; ii. to adjust biophysical criteria to fit at best the observed bubble kinetics; and iii. to build a relevant risk function.

Cognitive function after several years of antiretroviral therapy with stable central nervous system penetration score.

OBJECTIVES: Previous studies in HIV-infected populations have yielded conflicting results on the effect of antiretroviral therapy (ART) on cognition. Our objective was to investigate the effect of several years of ART with stable central nervous system penetration effectiveness (CPE) score on neuropsychological performance in HIV-infected individuals. METHODS: We analysed a clinical cohort of HIV-infected patients who initiated ART between June 2003 and December 2006 and maintained stable CPE scores. Patients were evaluated with a short neuropsychological battery. Using linear regression, we examined the relationship between results of cognitive tests and CPE scores in all patients. RESULTS: Patients were divided into three similarly sized groups (CPE ≤ 1, CPE between 1.5 and 2.5, and CPE ≥ 2.5). We found that ART with high CPE scores was associated with poorer executive performances in HIV-1-infected patients. CONCLUSION: These results suggest that cognitive performance in treated HIV-infected patients could be influenced by ART.

A new biophysical decompression model for estimating the risk of articular bends during and after decompression.

The biophysical models that intend to predict the risk of decompression sickness after a change of pressure are not numerous. Few approaches focus in particular on joints as target tissues, with the aim to describe properly the mechanisms inducing pain. Nevertheless, for this type of decompression incidents, called articular bends, no model proved to fit the empirical results for a broad range of exposures and decompression procedures. We present here an original biophysical decompression model for describing the occurrence of articular bends. A target joint is broken down into two parts that exchange inert gases with the blood by perfusion and with each other by diffusion over distances of a few millimetres. This diffusion pathway allows the slow amplification of microbubbles growing during and after decompression, consistent with the possible delayed occurrence of bends. The diffusion coefficients introduced into this model are larger than those introduced into most modern decompression models. Their value remains physical (#10(-9)m(2)/s). Inert gas exchanges and the formation, amplification and resorption of microbubbles during and after decompression were simulated. We used a critical gas volume criterion for predicting the occurrence of bends. A risk database extracted from COMEX experience and other published studies were used for the correlation of model parameters not known a priori. We considered a large range of exposure, and the commonly used inert gases nitrogen and helium. This correlation phase identified the worst biophysical conformations most likely to lead to the formation, in tissues such as tendons, of a large number of microbubbles recruited from pre-existing gas nuclei during decompression. The risk of bends occurrence was found to be linked to the total separated gas volume generated during and after decompression. A clamping phenomenon occurs soon after the start of decompression, greatly slowing the gas exchanges controlled especially by the oxygen window. This model, which reproduces many empirical findings, may be considered both descriptive and predictive.

Chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repeated traumatic brain injury (TBI). This disorder is mainly observed in subjects at risk for brain traumatisms including boxers, American football and European football (soccer) players, as well as war veterans. Neuropathological findings are marked by abnormally phosphorylated tau accumulations at the depth of cerebral sulci, as well as TDP43, Aß and α-synuclein positive staining. It has been described 3 clinical variants: the behavioural/mood variant, the cognitive variant and the mixed behavioural/cognitive variant. Cerebral MRI revealed signs of diffuse atrophy with abnormal axonal findings using the diffusion tensor imaging methods. Cerebral PET tau revealed increased standardised uptake value ratio (SUVR) levels in various brain regions of CTE patients compared to controls. The place of CTE among other neurodegenerative diseases is still debated. The focus of CTE management must be on prevention. The best way to prevent CTE in athletes is to put in place strict and appropriate measures by physicians. An individual with concussion should not be allowed to play again immediately (and sometimes never) in cases of abnormal neurological symptoms or imaging abnormalities.

Guam amyotrophic lateral sclerosis-parkinsonism-dementia linked to a plant excitant neurotoxin.

The decline in the high incidence of amyotrophic lateral sclerosis, parkinsonism, and Alzheimer-type dementia among the Chamorro population of the western Pacific islands of Guam and Rota, coupled with the absence of demonstrable viral and hereditable factors in this disease, suggests the gradual disappearance of an environmental factor selectively associated with this culture. One candidate is seed of the neurotoxic plant Cycas circinalis L., a traditional source of food and medicine which has been used less with the Americanization of the Chamorro people after World War II. Macaques were fed the Cycas amino acid beta-N-methylamino-L-alanine, a low-potency convulsant that has excitotoxic activity in mouse brain, which is attenuated by N-methyl-D-aspartate receptor antagonists. These animals developed corticomoto-neuronal dysfunction, parkinsonian features, and behavioral anomalies, with chromatolytic and degenerative changes of motor neurons in cerebral cortex and spinal cord. In concert with existing epidemiological and animal data, these findings support the hypothesis that cycad exposure plays an important role in the etiology of the Guam disease.

The pathway to drive decompression microbubbles from the tissues to the blood and the lymphatic system as a part of this transfer.

The formation sites of the microbubbles that are routinely detected in the bloodstream at precordial level by Doppler after a decompression are reviewed and discussed here. First, microbubbles could form on the endothelium lumen wall of the capillaries, at specific nanometric sites, but the release mechanism of such small emerging entities remains puzzling. They could be also formed from pre-existing gas nuclei present in the blood when favorable local hydrodynamic/supersaturation conditions generate microcavitation and tribonucleation phenomena. Finally, tissues could represent large pools for microbubble formation and amplification. Nevertheless, it remains to explain what the potential pathways are to drive them to the blood. Knowing that the permeability of most of the blood capillary network is quite low, an alternative is proposed for such transport. The lymphatic system, which drains the interstitial fluid to guarantee the fluid balance of tissues, could allow the transfer of micrometric elements like stabilized microbubbles formed in tissues on long distances. A final rejection in the bloodstream at the termination of both right lymphatic and thoracic ducts can be expected. The characteristics of this slow transport, activated by the muscular pump, could explain the detection on long periods of massive venous gas emboli.

Diagnosis associated with Tau higher than 1200 pg/mL: Insights from the clinical and laboratory practice.

CONTEXT: Cerebrospinal fluid (CSF) biomarkers are valuable tools for the diagnosis of neurological diseases. We aimed to investigate within a retrospective multicentric study the final diagnosis associated with very high CSF Tau levels and to identify patterns of biomarkers that would differentiate them in clinical practice, to help clinical biologists into physicians' counseling. PATIENTS AND METHODS: Within the national multicentric network ePLM, we included 1743 patients from January 1, 2008, to December 31, 2013, with CSF biomarkers assayed by the same Innotest assays (protein Tau, phospho-Tau [pTau], and Aß 1-42). We identified 205 patients with protein Tau concentration higher than 1200 pg/mL and final diagnosis. RESULTS: Among those patients, 105 (51.2%) were suffering from Alzheimer's disease, 37 (18%) from sporadic Creuztfeldt-Jakob disease, and 63 (30.7%) from other neurological diseases including paraneoplastic/ central nervous system tumor, frontotemporal dementia, other diagnoses, amyloid angiopathy, Lewy body dementia, and infections of the central nervous system. Phospho-Tau, Aß1-42 and Aß1-42/pTau values differed significantly between the three groups of patients (p < .001). An Aß1-42/pTau ratio between 4.7 and 9.7 was suggestive of other neurological diseases (threshold in AD: 8.3). CSF 14-3-3 was useful to discriminate Alzheimer's disease from Creuztfeldt-Jakob disease in case of Aß1-42 concentrations <550 pg/mL or pTau>60 pg/mL. CONCLUSION: This work emphasizes the interest of a well-thought-out interpretation of CSF biomarkers in neurological diseases, particularly in the case of high Tau protein concentrations in the CSF.

Semi-quantification and grading of amyloid PET: A project of the European Alzheimer's Disease Consortium (EADC).

BACKGROUND: amyloid-PET reading has been classically implemented as a binary assessment, although the clinical experience has shown that the number of borderline cases is non negligible not only in epidemiological studies of asymptomatic subjects but also in naturalistic groups of symptomatic patients attending memory clinics. In this work we develop a model to compare and integrate visual reading with two independent semi-quantification methods in order to obtain a tracer-independent multi-parametric evaluation. METHODS: We retrospectively enrolled three cohorts of cognitively impaired patients submitted to 18F-florbetaben (53 subjects), 18F-flutemetamol (62 subjects), 18F-florbetapir (60 subjects) PET/CT respectively, in 6 European centres belonging to the EADC. The 175 scans were visually classified as positive/negative following approved criteria and further classified with a 5-step grading as negative, mild negative, borderline, mild positive, positive by 5 independent readers, blind to clinical data. Scan quality was also visually assessed and recorded. Semi-quantification was based on two quantifiers: the standardized uptake value (SUVr) and the ELBA method. We used a sigmoid model to relate the grading with the quantifiers. We measured the readers accord and inconsistencies in the visual assessment as well as the relationship between discrepancies on the grading and semi-quantifications. CONCLUSION: It is possible to construct a map between different tracers and different quantification methods without resorting to ad-hoc acquired cases. We used a 5-level visual scale which, together with a mathematical model, delivered cut-offs and transition regions on tracers that are (largely) independent from the population. All fluorinated tracers appeared to have the same contrast and discrimination ability with respect to the negative-to-positive grading. We validated the integration of both visual reading and different quantifiers in a more robust framework thus bridging the gap between a binary and a user-independent continuous scale.

[Alzheimer's disease cerebro-spinal fluid biomarkers: A clinical research tool sometimes useful in daily clinical practice of memory clinics for the diagnosis of complex cases]. / Les biomarqueurs du liquide cérébro-spinal dans la maladie d'Alzheimer : un outil de recherche utile dans la pratique clinique courante des consultations mémoire pour les cas complexes.

The role of biomarkers in clinical research was recently highlighted in the new criteria for the diagnosis of Alzheimer's disease. Cerebro-spinal fluid (CSF) biomarkers (total Tau protein, threonine 181 phosphorylated Tau protein and amyloid Aß1-42 peptide) are associated with cerebral neuropathological lesions observed in Alzheimer's disease (neuronal death, neurofibrillary tangle with abnormal Tau deposits and amyloid plaque). Aß1-40 amyloid peptide dosage helps to interpret Aß1-42 results. As suggested in the latest international criteria and the French HAS (Haute Autorité de santé) recommendations, using theses CSF biomarkers should not be systematic but sometimes could be performed to improve confidence about the diagnostic of Alzheimer's disease in young subjects or in complex clinical situations. Future biomarkers actually in development will additionally help in diagnostic process (differential diagnosis) and in prognostic evaluation of neurodegenerative diseases.

Activated double-stranded RNA-dependent protein kinase and neuronal death in models of Alzheimer's disease.

Neuronal death is a pathological hallmark of Alzheimer's disease. We have shown previously that phosphorylated double-stranded RNA-dependent protein kinase is present in degenerating hippocampal neurons and in senile plaques of Alzheimer's disease brains and that genetically down-regulating double-stranded RNA-dependent protein kinase activity protects against in vitro beta-amyloid peptide neurotoxicity. In this report, we showed that two double-stranded RNA-dependent protein kinase blockers attenuate, in human neuroblastoma cells, beta-amyloid peptide toxicity evaluated by caspase 3 assessment. In addition, we have used the newly engineered APP(SL)/presenilin 1 knock-in transgenic mice, which display a severe neuronal loss in hippocampal regions, to analyze the activation of double-stranded RNA-dependent protein kinase. Western blots revealed the increased levels of activated double-stranded RNA-dependent protein kinase and the inhibition of eukaryotic initiation factor 2 alpha activity in the brains of these double transgenic mice. Phosphorylated RNA-dependent protein kinase-like endoplasmic reticulum-resident kinase was also increased in the brains of these mice. The levels of activated double-stranded RNA-dependent protein kinase were also increased in the brains of patients with Alzheimer's disease. At 3, 6 and 12 months, hippocampal neurons display double stranded RNA-dependent protein kinase labelings in both the nucleus and the cytoplasm. Confocal microscopy showed that almost constantly activated double-stranded RNA-dependent protein kinase co-localized with DNA strand breaks in apoptotic nuclei of CA1 hippocampal neurons. Taken together these results demonstrate that double-stranded RNA-dependent protein kinase is associated with neurodegeneration in APP(SL)/presenilin 1 knock-in mice and could represent a new therapeutic target for neuroprotection.

In vitro efficacy of three lazaroids in a model of acute chemical neuronal hypoxia.

Free radicals are highly reactive chemicals containing an unpaired electron and are normally produced by the cellular metabolism. But the excessive production of free radicals by oxidative stress is engaged in a large variety of diseases. The goal of this work was to determine the neuroprotective effect of free radical scavengers in an acute in vitro model of neuronal hypoxia. Primary cultures of cortical neurons of rats were exposed to 0.5 mM sodium cyanide for 6 h. Neuron death was evaluated with a lactate dehydrogenase assay. This mortality was up to 66.5% in cultures exposed to 0.5 mM sodium cyanide compared to non-exposed control cultures. Three lazaroids (U-74500A, U-74389G, U-83836E), were added to cultures, at different concentrations (10(-7)-10(-5) M), simultaneously with cyanide, during 6h. These agents caused a reduction in neuronal death, compared to exposed cultures. Efficacy varied with lazaroid compounds and U-74500A decreased neuronal death to 37-23.5%, U-74389G to 37-32%, and U-83836E to 42-33%. These results suggest a partial neuroprotective effect of free radical scavengers since lipid peroxidation is a key cellular event in neuronal injury, and its inhibition with lazaroids could help to reduce brain ischaemic lesions.

[Automatic recall of didactic knowledge in semantic memory during normal aging and in Alzheimer's disease]. / Réactivation automatique en mémoire sémantique de connaissances didactiques au cours du vieillissement normal et dans la maladie d'Alzheimer.

INTRODUCTION: The goal of our work is to study the most consolidated items of semantic memory in normal subjects and in patients with Alzheimer's disease (AD). PATIENTS AND METHOD: The first test is based on automatic recall of didactic knowledge. This test is made of 250 automatic verbal expressions exploring general knowledge. It as been validated according to age and cultural levels in 219 normal subjects (20-90 years old). Another simplified test called EVA including only 50 of the 250 previously chosen items was also used. The EVA scores found in a normal population have been classified by centilages according to age and cultural levels. The EVA was also tested in 20 patients with AD and the results compared with MMSE and "Pyramids and Palm Trees Test" (semantic memory testing). RESULTS: The results reveal that the scores observed with the first test in a normal population with comparable cultural levels are correlated with age. EVA test scores found in control subjects show that the median value, for a same age group, is positively correlated with cultural levels. In patients with AD, scores for EVA test and MMSE are associated, the low results being linked to the severity of dementia. In addition, scores for EVA test and "Pyramids and Palm Trees Test" are also significantly correlated. Seven patients with mild dementia (MMSE>20) have abnormal scores for the "Pyramids and Palm Trees Test". CONCLUSION: Our study confirms that changes linked to aging do not involve all aspects of cognition. The most consolidated items of semantic memory assessed by EVA test seem to resist at the beginning of AD but later decline similarly to the other items of semantic memory. Normal results for EVA tests do not imply that semantic memory is not affected in the early phases of AD. We propose this new test which assesses the semantic memory stock without involving an active process of recuperation. This test is not suitable for an early diagnosis of AD but could help to evaluate the severity of the disease during the evolution.

Turnover of mouse intestinal brush border membrane proteins and enzymes in organ culture. A direct evaluation from studies on the evolution of enzyme activities during the culture.

The turnover of mouse intestinal brush border membrane enzymes has been studied by kinetic analysis of the evolution of enzyme activities during organ culture. By comparing the results obtained in these studies with the predictions from a mathematical model of enzyme synthesis and degradation in organ cultures, it has been possible to reach the following conclusions: (1) There is no degradation of brush border membrane enzymes during culture and the rate of synthesis of each enzyme is directly measurable from the kinetics of total enzyme accumulation (tissue + media). (2) Brush border membrane enzymes are released in culture media by two complementary processes. The first one involves a differential solubilization of enzymes but its exact nature cannot be exactly stated. The second one involves a microvesiculation of brush border membranes, the importance of which in vivo is seen in the possible conciliation between urinary membrane synthesis and heterogeneous turnover of membrane components.

Cortical cell elution by sedimentation field-flow fractionation.

As a cell sorter, Sedimentation field-flow fractionation (SdFFF) can be defined as an effective tool for cell separation and purification, respecting integrity and viability as well as providing enhanced recovery and purified sterile fraction collection. The complex cell suspension containing both neurons and glial cells of all types, obtained from cerebral cortices of 17-day-old rat fetuses, is routinely used as a model of primary neuronal culture. Using SdFFF, this complex cell mixture was eluted in sterile fractions which were collected and cultured. SdFFF cell elution was conducted under strictly defined conditions: rapid cell elution, high recovery (negligible cell trapping), short- and long-term cell viability, sterile collection. After immunological cellular type characterization (neurons and glial cells) of cultured cells, our results demonstrated the effectiveness of SdFFF to provide, in less than 6 min, viable and enriched neurons which can be cultured for further investigations.

Therapeutic advances in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive and rapidly fatal neurodegenerative disease in which both upper and lower motoneurones are involved. The recent discovery of mutations affecting the superoxide dismutase (SOD) gene has given impetus to research on the role of oxidative stress in the pathogenesis of familial ALS, while further evidence for a role of excitotoxicity in the disease process has arisen. In this review, Erik Louvel, Jacques Hugon and Adam Doble discuss these findings and, in addition, describe how a number of large, well-controlled clinical trials have taken place to test potential therapies suggested by different aetiological hypotheses, including immunosuppressive therapies, neurotrophic factors, antioxidants and anti-excitotoxic drugs. These trials have led to the first modest steps in the treatment of this devastating neurological disease.

PKR downregulation prevents neurodegeneration and ß-amyloid production in a thiamine-deficient model.

Brain thiamine homeostasis has an important role in energy metabolism and displays reduced activity in Alzheimer's disease (AD). Thiamine deficiency (TD) induces regionally specific neuronal death in the animal and human brains associated with a mild chronic impairment of oxidative metabolism. These features make the TD model amenable to investigate the cellular mechanisms of neurodegeneration. Once activated by various cellular stresses, including oxidative stress, PKR acts as a pro-apoptotic kinase and negatively controls the protein translation leading to an increase of BACE1 translation. In this study, we used a mouse TD model to assess the involvement of PKR in neuronal death and the molecular mechanisms of AD. Our results showed that the TD model activates the PKR-eIF2α pathway, increases the BACE1 expression levels of Aß in specific thalamus nuclei and induces motor deficits and neurodegeneration. These effects are reversed by PKR downregulation (using a specific inhibitor or in PKR knockout mice).

Epidermal growth factor receptors in isolated adult mouse intestinal cells: studies in vivo and in organ culture.

In isolated intestinal cells from adult fed mouse, the binding of [125I]epidermal growth factor (EGF) was time and temperature dependent. Maximum binding was obtained after 30 min of incubation at 20 C. For a concentration of 5 X 10(-11)M [125I]EGF (180 microCi/micrograms), specific binding for isolated cells from duodenum, jejunum, and ileum was closely similar, with means of 9.4 +/- 0.9, 13.3 +/- 0.8, and 9.3 +/- 2.0%/mg protein, respectively. The binding increases along the crypt-villus axis. Inhibition dose-response analysis indicated high affinity binding with 50% inhibition at 3 X 10(-10) M unlabeled EGF. The specific binding decreased by 19% after 48 h of fasting. In the P1 fraction (microsome and lateral membranes) from scrapings or isolated cells of the jejunal mucosa, specific binding was 2.4 +/- 0.8 and 6.5 +/- 0.7%/mg protein, respectively. In the P2 fraction (brush border), specific binding was 6.9 +/- 1.6% and 16.3 +/- 0.7%/mg protein. After 24 h of organ culture, specific binding is not modified in duodenal explants. Moreover, in the presence of EGF (500 ng/ml) in the culture medium, the binding is decreased by 72%. These results show that isolated intestinal cells from adult mice possess a high concentration of EGF receptors that exhibit kinetic properties identical to those of other EGF target cells. Unlike insulin receptors, EGF receptors are numerous on the intestinal brush border and in intestinal crypts and decrease by fasting.

Insulin receptors in isolated adult mouse intestinal cells: studies in vivo and in organ culture.

Isolated intestinal cells from adult mice possess a high concentration of insulin receptors. The binding capacity and the number of binding sites are higher in duodenum than in jejunum or ileum and in the upper part of the villus than in the crypts. The specific binding is, respectively, 11.8 +/- 1.0%, 9.1 +/- 4.0%, and 5.5 +/- 0.3%/mg . protein for duodenum, jejunum, and ileum. The number of high affinity sites per cell is, respectively, 11.0 X 10(3), 3 X 10(3), and 2.5 X 10(3). The number of low affinity sites per cell is, respectively, 11.0 X 10(4), 4.1 X 10(3), and 3.9 X 10(3). This specific binding increases to 15.9 +/- 0.9% after 24 h of fasting and to 24.5 +/- 2.2% mg protein after 48 h of fasting. This increase is due not only to an increment in the number of sites but also to alterations in affinity constants (K1, control, 0.380, 48-h fasting, 0.044 X 10(9) M-1; K2, control, 1.20, 48-h fasting; 2.61 X 10(7) M-1). The receptors are mainly located on the basolateral and internal membranes (P1, 9.4 +/- 0.7%/mg protein), but are also present on brush border membranes (P2, 2.6 +/- 1.1%/mg protein, P less than 0.01). After 24 h of organ culture, the specific binding is not modified in duodenal explants. Moreover, in the presence of insulin in the culture medium, the binding is decreased by 59%.

Increased hypoxic tolerance by chemical inhibition of oxidative phosphorylation: "chemical preconditioning".

A short ischemic episode preceding sustained ischemia is known to increase tolerance against ischemic cell death. We report early-onset long-lasting neuroprotection against in vitro hypoxia by preceding selective chemical inhibition of oxidative phosphorylation: "chemical preconditioning." The amplitude of CA1 population spikes (psap) in hippocampal slices prepared from control animals (control slices) was 31 +/- 27% (mean +/- SD) upon 45-min recovery from 15-min in vitro hypoxia. In slices prepared from animals treated in vivo with 20 mg/kg 3-nitropropionate (3-np) 1-24 h prior to slice preparation (preconditioned slices), psap improved to 90 +/- 15% (p < 0.01). Posthypoxic oxygen free radicals were reduced to 65 +/- 10% (mean +/- SD) of control in preconditioned slices (p < 0.05). Posthypoxic neuronal density improved from 52 +/- 15% (mean +/- SD) in control slices to 97 +/- 23% in preconditioned slices (p < 0.001). Glibenclamide, an antagonist at KATP-channels, partly reversed increased hypoxic tolerance. We conclude that chemical preconditioning induces early-onset long-lasting tolerance against in vitro hypoxia. Ultimately, this strategy may be applicable as a neuroprotective strategy in humans.