Enhance Brain Function Research Articles

The Rhizomes of Acorus gramineus and the Constituents Inhibit Allergic Response In vitro and In vivo

The rhizomes of Acorus gramineus have frequently been used in traditional medicine mainly for sedation as well as enhancing brain function. In this study, the anti-allergic activity of A. gramineus was investigated. The 70% ethanol extract of the rhizomes of A. gramineus was found to inhibit the allergic response against 5-lipoxygenase (5-LOX)-catalyzed leukotriene (LT) production from rat basophilic leukemia (RBL)-1 cells and β-hexosaminidase release from RBL-2H3 cells with IC50’s of 48.9 and >200 μg/ml, respectively. Among the 9 major constituents isolated, β-asarone, (2R,3R,4S,5S)-2,4-dimethyl-1,3-bis (2',4',5'-trimethoxyphenyl)tetrahydrofuran (AF) and 2,3-dihydro-4,5,7-trimethoxy-1-ethyl-2-methyl-3-(2,4,5-trimethoxyphenyl)indene (AI) strongly inhibited 5-LOX-catalyzed LT production in A23187-treated RBL-1 cells, AI being the most potent (IC50=6.7 μM). Against β-hexosaminidase release by antigen-stimulated RBL-2H3 cells, only AI exhibited strong inhibition (IC50=7.3 μM) while β-asarone and AF showed 26.0% and 39.9% inhibition at 50 μM, respectively. In addition, the ethanol extract of A. gramineus showed significant inhibitory action against the hapten-induced delayed hypersensitivity reaction in mice by oral administration at 200 mg/kg. Therefore, it is suggested that A. gramineus possesses anti-allergic activity and the constituents including β-asarone and AI certainly contribute to the anti-allergic activity of the rhizomes of A. gramineus.

Acute moderate exercise enhances compensatory brain activation in older adults

A growing number of reports state that regular exercise enhances brain function in older adults. Recently a functional near-infrared spectroscopy (fNIRS) study revealed that an acute bout of moderate exercise enhanced activation of the left dorsolateral prefrontal cortex (L-DLPFC) associated with Stroop interference in young adults. Whether this acute effect is also applicable to older adults was examined. Sixteen older adults performed a color-word matching Stroop task before and after 10 minutes of exercise on a cycle ergometer at a moderate intensity. Cortical hemodynamics of the prefrontal area was monitored with a fNIRS during the Stroop task. We analyzed Stroop interference (incongruent-neutral) as Stroop performance. Though activation for Stroop interference was found in the bilateral prefrontal area before the acute bout of exercise, activation of the right frontopolar area (R-FPA) was enhanced after exercise. In the majority of participants, this coincided with improved performance reflected in Stroop interference results. Thus, an acute bout of moderate exercise improved Stroop performance in older adults, and this was associated with contralateral compensatory activation.

Reconstructing brains: A biological impossibility?

The reconstruction of damaged brain tissue is desirable because brain damage constitutes a major area of unmet medical need. In the view of some advocates, the cell therapy approaches that will lead to the reconstruction of damaged brain tissue will also enhance brain function in normal people. Although the meeting of unmet medical need appears laudable, human enhancement is viewed by some as a threat, but is brain reconstruction achievable whether desirable or not? This article argues that the prospects for true regenerative medicine in the brain are considerably exaggerated. Although current studies may lead to clinical advancement, progress on true reconstruction is very limited. I argue that brain reconstruction might prove to be an example of genuine biological impossibility.

The influence of naturalistic experience on plasticity markers in somatosensory cortex and hippocampus: Effects of whisker use

We have previously demonstrated that exposure of adult rat to a type of enriched environment, known as ‘naturalistic habitat’ (NH), induces extensive functional plasticity in the whiskers’ representations within the primary somatosensory cortex. Here we have investigated the molecular basis for such functional plasticity involved in this model. Based on the role of BDNF on synaptic plasticity and neuronal growth, the focus of this study is on BDNF and its downstream effectors CREB, synapsin I, and GAP-43. In particular, we determined the effects of natural whisker use during 2, 7 or 28days exposure to a NH on barrel cortex and hippocampus, as compared to standard cage controls. Naturalistic whisker use resulted in increased levels of mRNAs and proteins for BDNF and its downstream effectors. Level changes for these markers were already detected after 2days in the naturalistic habitat and grew larger over longer exposures (7 and 28days). The cerebral cortex was found to be sensitive to the naturalistic habitat exposure at all time points, and more sensitive than the hippocampus to the trimming of the whiskers. Trimming of the whiskers decreased the level of most of the markers under study, suggesting that whiskers exert a tonic influence on plasticity markers that can be further enhanced by naturalistic use. These results implicate BDNF and its downstream effectors in the plasticity induced by the naturalistic habitat. The critical action of experience on molecular substrates of plasticity seems to provide molecular basis for the design of experienced-based rehabilitative strategies to enhance brain function.

Effect of occlusal support by implant prostheses on brain function

The present study was carried out to identify how gum chewing with and without occlusal support by implant prostheses affects brain function as well as chewing function. Twenty-four subjects rehabilitated with implant-supported fixed prostheses were evaluated. An electroencephalograph (EEG) (ESA-Pro) and mandibular kinesiograph (Bio PAK(®)) wear used to measure brain function and chewing function, respectively, before and after gum chewing with and without an implant superstructure. Based on brain function estimated by the Dα values derived from measurement data, the subjects were divided into the normal region group (including the sub-normal region group) (n=15; Dα≥0.952) and the impaired region group (n=9; Dα<0.952). All the data were statistically analyzed using the Wilcoxon test (α=0.05). Brain function in the normal region group showed no change after gum chewing, whether or not an implant superstructure was in place (p>0.05). However, brain function in the impaired region group showed significant improvement after gum chewing (p<0.05). Seven of 9 subjects using an implant superstructure in impaired region group indicated an increase or no change in brain function compared to the results without an implant superstructure. In the impaired region group, there was a high positive correlation between brain function and masticatory movement (γ=0.75). Subjects in the impaired region group revealed a strong positive correlation between brain function and masticatory movement, indicating that occlusal support by implant-supported fixed prostheses has the potential to enhance brain function.

Moderate exercise changes synaptic and cytoskeletal proteins in motor regions of the rat brain

Physical exercise is known to enhance brain function in several aspects. We evaluated the acute effects of a moderate forced exercise protocol on synaptic proteins, namely synapsin I (SYN) and synaptophysin (SYP), and structural proteins (neurofilaments, NFs) in rat brain regions related to motor function and often affected by neurodegenerative disorders. Immunohistochemistry, Western blotting and real-time PCR were used to analyze the expression of those proteins after 3, 7 and 15 days of exercise (EX3, EX7 and EX15). In the cerebellum, increase of SYN was observed at EX7 and EX15 and of NF68 at EX3. In the substantia nigra, increases of protein levels were observed for NF68 and NF160 at EX3. In the striatum, there was an increase of SYN at EX3 and EX7, of SYP at EX7 and of NF68 at EX3. In the cortex, decreased levels of NF68 and NF160 were observed at EX3, followed by an increase of NF68 at EX15. In the reticular formation, all NF proteins were increased at EX15. The mRNA data for each time-point and region also revealed significant exercise-related changes of SYN, SYP and NF expression. These results suggest that moderate physical exercise modulates synaptic and structural proteins in motor brain areas, which may play an important role in the exercise-dependent brain plasticity.

Dietary restriction and brain health

The benefits of dietary restriction (DR) on health and aging prevention have been well recognized. Recent studies suggest that DR may enhance brain functions including learning and memory, synaptic plasticity, and neurogenesis, all of which are associated with brain health. Under the stress stimulated by DR, a favorable environment is established for facilitating neuronal plasticity, enhancing cognitive function, stimulating neurogenesis and regulating inflammatory response. DR-induced expressions of factors such as heat shock proteins (HSPs), neurotrophic factors, and Sirtuin1 (SIRT1) are responsible for the effect of DR on the brain. Due to the difficulty in practising long-term DR in human, the potential mimics of DR are also discussed.

EXERCISE‐INDUCED PLASTICITY IN THE RAT HIPPOCAMPUS, MOTOR CORTEX AND BRAIN STEM

Increasing evidence shows that physical exercise is neuroprotective and enhances brain function by improving memory, cognitive functions, neuroplasticity, and learning. The aim of this study was to observe the plastic effects physical exercise has on regions of the CNS related to cognitive and motor functions by evaluating the expression of structural proteins. A group of 40 adult male Wistar rats were subjected to an exercise protocol on an adapted treadmill. Following a 2 day adaptation period, the exercised group ran for 40 min/day, at 0.6km/h for 3 (3D), 7 (7D) or 15 (15D) days. At the end of the exercise protocol, brains were subjected to immunoblotting analysis to evaluate the expression of neurofilaments (NF) in the hippocampus, motor cortex and brain stem. In the hippocampus, immunoblot analysis showed increased expression of NF68 (p&lt;0.005) following 3D exercise. In the motor cortex, however, the levels of both NF68 and NF160 decreased (p&lt;0.05) after 3D exercised and increased at 15D for NF68 (p&lt;0.05). The brain stem showed increased expression of all NFs at 15D (p&lt;0.05). These results suggest that physical exercise alters the expression of structural neuronal proteins in brain regions associated with motor control, cognition, memory and learning. Our current ongoing studies focuses on the functional role astrocytes have on exercise‐induced structural neuronal changes.Support: FAPESP, CNPq, CAPES

Gut, Fat, Iron, and Brain: Where Are We?

As new knowledge on nutrition during pregnancy and infancy evolves it becomes increasingly necessary to periodically review and update our approach on how to translate the emerging science to practice. This cycle can be shortened if we have close collaboration and dialogue between researchers and those charged with transforming nutritional science into consumer products. The occasion of the 3rd World Congress of Pediatric Gastroenterology, Hepatology and Nutrition in Iguassu, Brazil, provides a unique opportunity to congregate members of the Danone International Institutes as well as selected guest participants to discuss new knowledge on how essential fatty acids and iron affect brain development before and after birth and what we can do to support fetal, infant, and child brain development by providing optimal nutrition to mothers and children during these critical periods. The program addressed the emerging area of crosstalk between the gastrointestinal tract and the brain starting from the programming of smell and taste preferences in early life to the role of nutrients in establishing hormonal and metabolic patterns that affect brain circuitry and contribute to the regulation of energy balance. The implications of enhancing brain function for educational performance and economic productivity in later life are critical elements for national development especially in regions of the world that are undergoing rapid transitions and modernization. The symposium focused on two critical nutrients for brain development (omega-3 fatty acids and iron) that have major influences on brain structural and functional development. Dr Sheila Innis from Canada covered “Omega-3, PUFA and brain development to two years of age: do we know enough for dietary recommendations?” and Dr Bert Koletzko from Germany addressed the question “Are omega-3 PUFA needed for brain function in school aged children?” Dr Patricio Peirano from Chile presented his research work on “Neurofunctional development and iron deficiency: what are the main functions sensitive to iron deficiency and supplementation, what are the markers to monitor the effects, what are the dietary recommendations in different regions of the world.” Considering that nutrients enter the body through the gut and that absorption is the first regulatory step for nutrients as they enter the body Dr Esteban Carmuega from Argentina addressed “Gut and iron: bioavailability for gut flora and absorption -what are the markers to monitor the effects?” Specific updates on bioavailability of iron in dairy products from a physiological point of view have been presented considering the need to have specific information on infant or toddlers and how far can adult data be extrapolated to infants. The specific role of diet and metabolic hormones in perinatal programming of brain circuits regulating energy homeostasis have been presented by Dr Sebastien Bouret from France, whereas taste and flavour programming of taste and smell preferences in early life have been addressed by Dr Gary Beauchamp from the United States. Dr Bruce Holub, Prof Bert Koletzko, Dr Dennis Bier, and Dr Stanley Zlotkin, contributed as discussants and moderators. Dr Virginia Stallings, Children's Hospital of Philadelphia, USA and Dr Ricardo Uauy, University of Chile, served as cochairs for the program. Through this initiative, Danone Institute International intends to nurture discussions and debates on emerging topics in prenatal and postnatal nutrition, in order to support the practical applications of this knowledge and benefit the health and well-being of populations with a global perspective.

Monomeric IgG Is Neuroprotective via Enhancing Microglial Recycling Endocytosis and TNF-α

In brain, monomeric immunoglobin G (IgG) is regarded as quiescent and only poised to initiate potentially injurious inflammatory reactions via immune complex formation associated with phagocytosis and tumor necrosis factor alpha (TNF-alpha) production in response to disease. Using rat hippocampal slice and microglial cultures, here we show instead that physiological levels (i.e., 0.2-20 microg/ml) of monomeric IgG unassociated with disease triggered benign low-level proinflammatory signaling that was neuroprotective against CA1 area excitotoxicity and followed a U-shaped or hormetic dose-response. The data indicate that physiological IgG levels activated microglia by enhancing recycling endocytosis plus TNF-alpha release from these cells to produce the neuroprotection. Minocycline, known for its anti-inflammatory and neuroprotective effects when given after disease onset, abrogated IgG-mediated neuroprotection and related microglial effects when given before injury. In contrast, E-prostanoid receptor subtype 2 (EP2) activation, which served as an exemplary paracrine stimulus like the one expected from neuronal activity, amplified IgG-mediated increased microglial recycling endocytosis and TNF-alpha production. Furthermore, like monomeric IgG these EP2 related effects took days to be effective, suggesting both were adaptive anabolic effects consistent with those seen from other long-term preconditioning stimuli requiring de novo protein synthesis. The data provide the first evidence that brain monomeric IgG at physiological levels can have signaling function via enhanced recycling endocytosis/TNF-alpha production from microglia unassociated with disease and that these IgG-mediated changes may be a means by which paracrine signaling from neuronal activity influences microglia to evoke neuroprotection. The data provide further support that low-level proinflammatory neural immune signaling unassociated with disease enhances brain function.

The neuroprotective potential of flavonoids: a multiplicity of effects

Flavonoids exert a multiplicity of neuroprotective actions within the brain, including a potential to protect neurons against injury induced by neurotoxins, an ability to suppress neuroinflammation, and the potential to promote memory, learning and cognitive function. These effects appear to be underpinned by two common processes. Firstly, they interact with critical protein and lipid kinase signalling cascades in the brain leading to an inhibition of apoptosis triggered by neurotoxic species and to a promotion of neuronal survival and synaptic plasticity. Secondly, they induce beneficial effects on the vascular system leading to changes in cerebrovascular blood flow capable of causing angiogenesis, neurogenesis and changes in neuronal morphology. Through these mechanisms, the consumption of flavonoid-rich foods throughout life holds the potential to limit neurodegeneration and to prevent or reverse age-dependent loses in cognitive performance. The intense interest in the development of drugs capable of enhancing brain function means that flavonoids may represent important precursor molecules in the quest to develop of a new generation of brain enhancing drugs.

Protective effects of ginkgo biloba leaves extract on peroxide-induced oxidative stress damage in PC12 cells

Background Extracts of ginkgo biloba leaves (EGB) and its metabolites have been reported to enhance brain function and nerve behavior. It has also been hypothesized that they can protect neurons from oxidative stress. Objective To investigate protective effects of EGB on peroxide (H 2O 2)-induced oxidative stress damage in PC12 cells. Design Observational contrast study. Setting Department of Pathophysiology, Guangdong Pharmacological College. Materials EGB was provided by Xi'an Fujie Biotechnological Development Company; 1640 culture medium, methylthiazolyl tetrazolium (MTT), trypsin and dimathyl sulfoxide (DMSO) by Sigma Company; PC12 cell strain by Cell Center of Medical College of Zhongshan University; calf serum by Hangzhou Sijiqing Bioengineering Company; lactate dehydrogenase (LDH) kit by Nanjing Jiancheng Bioengineering Research Institute. Methods The experiment was carried out in Department of Cell Biology of Guangdong Pharmacological College from June to December 2005. ▪ Cell culture PC12 cells were cultured in 1640 medium containing 200 g/L fetal calf serum. The cells were diluted to 1×10 7 L −1 and washed every two days. Those cells were used to experiment until they grew in logarithm on solid wall. ▪ Grouping and intervention: PC12 cells (1×10 8 L −1) were plated in 96-well plates with the density of 200 μL/hole and divided into three groups: normal control group (routinely adding media), H 2O 2 group (treating with media and H 2O 2 for 20 hours) and EGB group (adding media, 100 μmol/L EGB and 100 μmol/L H 2O 2). ▪ MTT assay: PC12 cells (1× 10 8 L −1) were plated in 96-well plates and divided into three groups with 8 holes for each group. Under sterile condition, cells were added with 5 g/L MTT (100 μL) and cultured for 4 hours. And then, 200 μL DMSO fluid was added and shaken for 30 minutes until blue crystal products formed were dissolved soundly. ▪ Experimental evaluation: Absorbance ( A) at 630 nm was measured and LDH activity was measured at the same time. Main Outcome Measures Results of MTT assay and LDH activity. Results ▪Results of MTT assay A value was lower in the H 2O 2 group than that in the normal control group ( P < 0.01), while A value was higher in the EGB group than that in the H 2O 2 group ( P < 0.01). ▪ LDH activity: LDH activity was higher in the H 2O 2 group than that in the normal control group ( P < 0.01), while LDH activity was lower in the EGB group than that in the H 2O 2 group ( P < 0.01). Conclusion EGB can inhibit H 2O 2-induced oxidative stress damage in PC12 cells possibly by preventing damage to the cell membrane.

Effect of Dietary Docosahexaenoic Acid and Catechins on Maze Behavior in Mice

Background/Aims: Docosahexaenoic acid (DHA; 22:6 n–3) and catechins are food components that play an important role in maintaining human health. However, the effect of a simultaneous intake of DHA and catechins on brain function is unknown. The purpose of this study was to investigate the effect of DHA and catechins on maze behavior in mice. Method: Adult (5 months old) and old (15 months old) male mice were fed 5% lard diets containing 0 or 1.5% DHA ethyl ester (DHA-EE), either with or without 0.5% catechins, for 3.5 months. Maze behavior was assessed 3 months after the start of the feeding experiment. The time required and distance traveled to reach the maze exit, and the number of times that a mouse strayed into blind alleys in the maze were measured. The fatty acid compositions of plasma and brain lipids were measured after the maze behavior experiment. Results: Adult mice in the catechin, DHA-EE, and DHA-EE + catechin diet groups required less time and traveled a shorter distance to reach the maze exit, and strayed into blind alleys fewer times than those in the corresponding lard groups. Among old mice, the DHA-EE + catechin diet group showed an improvement in maze behavior. No marked differences in the brain fatty acid composition between lard and catechin diet groups were observed; in the DHA-EE intake groups, the brain DHA percentage was raised. Conclusion: These results suggest that a simultaneous intake of DHA and catechins may certainly enhance brain function in both adult and old mice.

Effects of physical fatigue in mice on learning performance in a water maze.

We investigated the effects of physical fatigue produced by swimming exercise on learning the Morris water maze in BALB/c mice. We measured the escape latency in the maze immediately after the swimming exercise. The control group was soaked in the water but not fatigued. For easier tasks, like one with an obvious cue flag, the escape latency was not changed by exercise fatigue. However, escape latency was increased after exercise fatigue for more difficult tasks of spatial learning. These results appear to suggest that physical fatigue impaired learning performance. The effects of swimming exercise fatigue on learning efficiency were then investigated. Mice were continuously fatigued during the spatial learning period. This increased escape latency between the first and third sessions. The results suggest that learning efficiency was impaired by exercise fatigue. This system may be useful for screening new foods used to enhance brain function during exercise.

Enhancing brain and cognitive function of older adults through fitness training.

The present article provides a brief review of the human and animal literature that has investigated the relationship between fitness training and brain and cognitive function. The animal research clearly suggests that improvements in fitness can lead to both morphological and functional changes in the brains of older animals. Results of a recent meta-analysis suggest that fitness training can also have beneficial effects on human cognition, particularly on tasks requiring executive control processing. These effects are also moderated by a number of factors, including the proportion of men and women in the intervention studies, the length of training sessions, the age of the participants, and the combination of fitness training regimes. The article also discusses preliminary results that link, for the first time, fitness training and differences in human brain structure and function. Finally, we discuss the important issue of participant adherence to fitness training programs and the factors that influence fitness participation.

Chapter 3 Activity-dependent regulation of neuronal plasticity and self repair

Plasticity is an essential characteristic of the brain: it is part of how the brain functions and is continuous while the brain interacts with the outer world. The state of activation and the level of activity of the entire organism affect the brain's plastic response. Brain plasticity has many substrates, ranging from synapses to neurites and entire cells. The production of new neurons is part of plasticity even in the adult and old brain, but under normal conditions neurogenesis only occurs in two privileged regions of the adult brain: hippocampus and olfactory system. At least in the hippocampus, physical activity stimulates neurogenesis by acting on the proliferation of neuronal stem cells. More specific functions such as learning may be able to recruit new neurons from the pool of cells with neurogenic potential. In a broader context neuronal stem cells can likely be found throughout the brain. Therefore, novel approaches to neuroregeneration will, when most effective, make use of the activity-related effects on neuronal stem cells in the adult brain to activate these stem cells in a targeted manner to enhance brain function.

Paedomorphosis and Simplification in the Nervous System of Salamanders; pp. 153–161

Comparative neuroanatomists since Herrick [1914] have been aware of the paradox that the brain of amphibians, especially salamanders, is less complex than one would expect based on their phylogenetic position among the Tetrapoda. Many features of the brain are less differentiated in salamanders than in tetrapod outgroups, including chondrichthyans and bony fishes, and for some brain characters, the salamander brain is even more simple than that of the agnathans. Here, we perform a cladistic analysis on 23 characters of four sensory systems (visual, auditory, lateral line and olfactory) and the brain. Our taxa include myxinoids, lampreys, chondrichthyans, actinopterygians, Latimeria, Neoceratodus and the Iepidosirenid lungfishes, amniotes, frogs, caecilians, salamanders and bolitoglossine salamanders. Of the 23 characters we examined, 19 are most parsimoniously interpreted as secondarily simplified in salamanders from a more complex ancestral state, two characters are equally parsimonious under both hypotheses, one character (well developed ipsilateral retinotectal projections) is more complex in bolitoglossine salamanders than in vertebrates generally, and only one character (migration of neurons in the medial pallium) is most parsimoniously interpreted as retention of the plesiomorphically simple condition. Secondary simplification of the salamander brain appears to result from paedomorphosis, or retention of juvenile or embryonic morphology into adulthood. Paedomorphosis is correlated with an increase in genome size, which in turn is positively correlated with cell size, but negatively correlated with cell proliferation and differentiation rates. Available data suggest that, although increasing genome size and paedomorphosis tend to compromise the function of the salamander brain, compensating mechanisms have evolved that may restore or even enhance brain function.

Paedomorphosis and Simplification in the Nervous System of Salamanders; pp. 162–170

Comparative neuroanatomists since Herrick [1914] have been aware of the paradox that the brain of amphibians, especially salamanders, is less complex than one would expect based on their phylogenetic position among the Tetrapoda. Many features of the brain are less differentiated in salamanders than in tetrapod outgroups, including chondrichthyans and bony fishes, and for some brain characters, the salamander brain is even more simple than that of the agnathans. Here, we perform a cladistic analysis on 23 characters of four sensory systems (visual, auditory, lateral line and olfactory) and the brain. Our taxa include myxinoids, lampreys, chondrichthyans, actinopterygians, Latimeria, Neoceratodus and the Iepidosirenid lungfishes, amniotes, frogs, caecilians, salamanders and bolitoglossine salamanders. Of the 23 characters we examined, 19 are most parsimoniously interpreted as secondarily simplified in salamanders from a more complex ancestral state, two characters are equally parsimonious under both hypotheses, one character (well developed ipsilateral retinotectal projections) is more complex in bolitoglossine salamanders than in vertebrates generally, and only one character (migration of neurons in the medial pallium) is most parsimoniously interpreted as retention of the plesiomorphically simple condition. Secondary simplification of the salamander brain appears to result from paedomorphosis, or retention of juvenile or embryonic morphology into adulthood. Paedomorphosis is correlated with an increase in genome size, which in turn is positively correlated with cell size, but negatively correlated with cell proliferation and differentiation rates. Available data suggest that, although increasing genome size and paedomorphosis tend to compromise the function of the salamander brain, compensating mechanisms have evolved that may restore or even enhance brain function.

Verapamil enhances brain function tolerance against severe hypoxia without enhancing cerebral blood flow in the rat.

In spontaneously breathing, lightly anesthetized rats with chronically implanted epicortical electrodes, tolerance times were measured from onset of progressive hypoxia, anoxia or decapitation, until ultimate apnea and subsequent cessation of brain electrical activities. Arterial and cerebrovenous blood was collected initially and during progressive hypoxia, starting 5 min after intravenous verapamil or NaCl (controls). Verapamil induced significant hyperpnea, arterial alkalosis, slight bradycardia and brain venous acidosis. During progressive hypoxia, hyperpnea persisted and heart rate remained stable for a longer period than in controls. Tolerance times were significantly prolonged. Time courses of arterial PO2 and PCO2 and of cerebrovenous PO2 were hardly influenced. However, arterial alkalosis and brain venous acidosis became highly significant versus control courses. This raised the O2 saturation in arterial and O2 extraction in cerebral venous blood. Sinus sagittalis puncture needle outflow (as a measure of CBF) tended to be below the control rat courses throughout. This led to a higher O2 supply to the brain in verapamil rats only during severe hypoxia. Verapamil did not prolong tolerance times in anoxia or ischemia. It is concluded that the verapamil-induced increase of tolerance to hypoxia is primarily due to the acid-base (Bohr) effects observed in response to hyperpnea and prolonged cerebral metabolic activity.