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PubMed2007

NAD+ and NADH in brain functions, brain diseases and brain aging.

Numerous studies have suggested that NAD+ and NADH mediate multiple major biological processes, including calcium homeostasis, energy metabolism, mitochondrial functions, cell death and aging. In particular, NAD+ and NADH have emerged as novel, fundamental regulators of calcium homeostasis. It appears that most of the components in the metabolic pathways of NAD+ and NADH, including poly(ADP-ribose), ADP-ribose, cyclic ADP-ribose, O-acetyl-ADP-ribose, nicotinamide and kynurenine, can produce significant biological effects. This exquisiteness of NAD+ and NADH metabolism could epitomize the exquisiteness of life, through which we may grasp the intrinsic harmony life has evolved to produce. The exquisiteness also suggests a central regulatory role of NAD+ and NADH in life. It is tempted to propose that NAD+ and NADH, together with ATP and Ca2+, constitute a Central Regulatory Network of life. Increasing evidence has also suggested that NAD+ and NADH play important roles in multiple biological processes in brains, such as neurotransmission and learning and memory. NAD+ and NADH may also mediate brain aging and the tissue damage in various brain illnesses. Our latest studies have suggested that NADH can be transported across the plasma membranes of astrocytes, and that NAD+ administration can markedly decrease ischemic brain injury. Based on this information, it is proposed that NAD+ and NADH are fundamental mediators of brain functions, brain senescence and multiple brain diseases. Because numerous properties of NAD+ and NADH remain unclear, future studies regarding NAD+ and NADH may expose some fundamental mechanisms underlying brain functions, brain pathologies and brain aging.

Aging↗
PubMed1987

Brain 12-HETE formation in different species, brain regions, and in brain microvessels.

We used gas chromatography/mass spectrometry to measure brain 12-HETE (12-Hydroxy-5,8,10,14-eicosatetraenoic acid) formation from endogenous arachidonic acid in different species and different brain regions and in isolated brain microvessels. When blood-free brain slices were incubated for 20 minutes we found that the rabbit and cat brain incubates contained little 12-HETE when compared to rat and mouse brain incubates. Further in vitro studies of various rat brain regions showed a generally even distribution of 12-HETE. When isolated rat or rabbit microvessels were incubated and analyzed, we found 1 and 0.25 micrograms, respectively, of 12-HETE/mg of microvessel protein. Also, rabbit brain had limited or no capacity to actively metabolize tritiated 12-HETE. In summary, these studies show substantial species variation with respect to brain formation of 12-HETE and indicate that the vasculature is a potentially significant contributor to the 12-HETE found in whole brain tissue.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1998

Continuous osmotic minipump infusion of alcohol into brain decreases brain [Mg2+] and brain bioenergetics and enhances susceptibility to hemorrhagic stroke: an in vivo 31P-NMR study.

31P-NMR spectroscopic studies were performed in vivo on brains of rats chronically infused for 7 and 14 days with 30% ethanol (in the third cerebral ventricle). Peripheral blood alcohol concentration (BAC) rose to between 16.5-30.5 mg/dl. Brain intracellular free Mg2+ ([Mg2+]i) fell 33-39%, brain mitochondrial cytosolic phosphorylation potential (CPP) fell 31-48%, and brain phosphocreatine (PCr) fell approximately 15%; however, neither brain intracellular free hydrogen ion concentration (pHi) nor brain intracellular inorganic phosphate (Pi) were affected significantly by the chronic release of ethanol from the brain implants. Correlations were found between [Mg2+]i and [PCr] and between [Mg2+]i and CPP. Although brain free [MgADP] was not affected, [MgATP] fell by almost 20% accompanied by a 35-40% rise in free [ADP]. Interestingly, 14-day surgical implantation of 0.9% sterile saline into the third cerebral ventricle was associated with a 20% fall in brain [Mg2+]i and a 35% fall in CPP; however, PCr, ATP, or pHi was not significantly altered. Systemic administration of 4 g/kg ethanol into the 7- and 14-day chronic ethanol animals resulted in a 9- and 12-fold increase in hemorrhagic stroke mortality compared to naive, control rats. Eating habits, grooming, gait and arterial blood pressure were not affected by the chronic brain implantation of ethanol. These data lend support to the notion, primarily based on epidemiologic evidence, that chronic exposure to alcohol can pose a high risk for hemorrhagic stroke. Our alcohol pump-implanted rats also might provide a new model of slow, moderate alcohol intoxication.

Adenosine Triphosphate↗
PubMed1980

N-isopropyl-[123I] p-iodoamphetamine: single-pass brain uptake and washout; binding to brain synaptosomes; and localization in dog and monkey brain.

The kinetics of N-isopropyl-p-[123I]iodoamphetamine in rat brains were determined by serial measurements of brain uptake index (BUI) after intracarotid injection; also studied were its effects on amine uptake and release in rat's brain cortical synaptosomes; and its in vivo distribution in the dog and monkey. Serial BUI correspond to a first-pass extraction efficiency of 100% and a washout half-time of approximately 318 sec. The S-(+)-isomer inhibited norepinephrine uptake in synaptosomes as strongly as D-amphetamine, but was more potent in inhibiting synaptosomal uptake of serotonin. Both isomers were comparable to D-amphetamine in causing release of serotonin from synaptosomes, but the S-(+)-isomer promoted release of dopamine, whereas D-amphetamine did not. No specific localization in brain nuclei of the dog was seen, but there was progressive accumulation in the eyes. Rapid initial brain uptake in the ketamine-sedated monkey was noted, and further slow brain uptake occurred during the next 20 min but without retinal localization. High levels of brain activity were maintained for several hours. The quantitative initial single-pass clearance of the agent in the brain suggests its use in evaluation of regional brain perfusion. Its interaction with brain amine-binding sites suggests its possible application in studies of cerebral amine metabolism.

Amphetamines↗
PubMed1993

[Neurological problems in the diagnosis of brain death--observation of spinally-mediated movements in brain-dead patients and proposal of a "brain death judging doctor" system].

We report two cases in which neurological examination met the Second Tentative Criteria for Brain Death of Chiba University Medical School, except for spontaneous contractions of the rectus abdominis muscle during apnea testing. In Case 1, a 54-year-old man with brainstem infarction, judgement of brain death was suspended initially, but was ultimately declared after the contractions were deemed to be spinal in origin. MRI findings after declaration and autopsy were compatible with brain death. In Case 2, a 27-year-old man with fulminant hepatitis and subsequent severe brain edema, judgement was postponed due to detection of the contractions at the second testing, and was ceased with family intent. Several cases of abnormal gross and fine movements in brain-dead patients have been reported. These paradoxical phenomena may confuse an inexperienced examiner and delay the declaration of brain death. Whether brain death should be considered real death of the person or not, neurologists should be aware of the occasional presence of neurological problems in the diagnosis of brain death, such as spinally-mediated movements. Since the major opposition to brain death is the distrust of medical doctors, we propose a pilot system of a "brain death judging doctor".

Adult↗
PubMed2000

Neuroprotective effects of citicoline on brain edema and blood-brain barrier breakdown after traumatic brain injury.

OBJECT: Cytidine 5'-diphosphocholine (CDPC), or citicoline, is a naturally occurring endogenous compound that has been reported to provide neuroprotective effects after experimental cerebral ischemia. However, in no study has such protection been shown after traumatic brain injury (TBI). In this study the authors examined the effect of CDPC on secondary injury factors, brain edema and blood-brain barrier (BBB) breakdown, after TBI. METHODS: After anesthesia had been induced in Sprague-Dawley rats by using 1.5% halothane, an experimental TBI was created using a controlled cortical impact (CCI) device with a velocity of 3 m/second, resulting in a 2-mm deformation. Four sham-operated control animals used for brain edema and BBB breakdown studies underwent the same surgical procedure, but received no injury. Brain edema was evaluated using the wet-dry method 24 hours postinjury, and BBB breakdown was evaluated by measuring Evans blue dye (EBD) extravasation with fluorescein 6 hours after TBI. The animals received intraperitoneal injections of CDPC (50, 100, or 400 mg/kg two times after TBI [eight-10 animals in each group]) or saline (eight animals) after TBI. Traumatic brain injury induced an increase in the percentage of water content and in EBD extravasation in the injured cortex and the ipsilateral hippocampus. No significant benefit from CDPC treatment was observed at a dose of 50 mg/kg. Cytidine 5'-diphosphocholine at a dose of 100 mg/kg attenuated EBD extravasation in both regions, although it reduced brain edema only in the injured cortex. In both regions, 400 mg/ kg of CDPC significantly decreased brain edema and BBB breakdown. CONCLUSIONS: This is the first report in which dose-dependent neuroprotective effects of CDPC have been demonstrated in the injured cortex as well as in the hippocampus, a brain region known to be vulnerable to injury, after experimental TBI. The results of this study suggest that CDPC is an effective neuroprotective agent on secondary injuries that appear following TBI.

Animals↗
PubMed2006

Brain bank of the Brazilian aging brain study group - a milestone reached and more than 1,600 collected brains.

INTRODUCTION: Brain banking remains a necessity for the study of aging brain processes and related neurodegenerative diseases. In the present paper, we report the methods applied at and the first results of the Brain Bank of the Brazilian Aging Brain Study Group (BBBABSG) which has two main aims: (1) To collect a large number of brains of elderly comprising non-demented subjects and a large spectrum of pathologies related to aging brain processes, (2) To provide quality material to a multidisciplinar research network unraveling multiple aspects of aging brain processes and related neurodegenerative diseases. METHODS: The subjects are selected from the Sao Paulo Autopsy Service. Brain parts are frozen and fixated. CSF, carotids, kidney, heart and blood are also collected and DNA is extracted. The neuropathological examinations are carried out based on accepted criteria, using immunohistochemistry. Functional status are assessed through a collateral source based on a clinical protocol. Protocols are approved by the local ethics committee and a written informed consent form is obtained. RESULTS: During the first 21 months, 1,602 samples were collected and were classified by Clinical Dementia Rating as CDR0: 65.7%; CDR0.5:12.6%, CDR1:8.2%, CDR2:5.4%, and CDR3:8.1%. On average, the cost for the processing each case stood at 400 US dollars. To date, 14 laboratories have been benefited by the BBBABSG. CONCLUSION: The high percentage of non- demented subjects and the ethnic diversity of this series may be significantly contributive toward aging brain processes and related neurodegenerative diseases understanding since BBBABSG outcomes may provide investigators the answers to some additional questions.

Aging↗
PubMed2005

In vivo evidence for the efflux transport of pentazocine from the brain across the blood-brain barrier using the brain efflux index method.

The efflux transport of pentazocine (PTZ) from the brain across the blood-brain barrier (BBB) was investigated using the Brain Efflux Index method. PTZ was eliminated with the apparent elimination half-life of 13.0 min after microinjection into the parietal cortex area 2 region of the rat brain. The apparent efflux clearance of PTZ across the BBB was 137 microl/min/g brain, which was calculated from the elimination rate constant (5.35 x 10(-2) min(-1) and the distribution volume in the brain (2.56 ml/g brain). The efflux transport of PTZ was decreased in the presence of unlabeled PTZ, suggesting that PTZ is eliminated by a carrier-mediated transport system across the BBB. To characterize the efflux transport of PTZ from the brain in vivo, the effects of several compounds on the efflux transport of PTZ were investigated. P-glycoprotein (P-gp) inhibitors (verapamil and quinidine) reduced the PTZ efflux transport. In addition, the efflux transport of PTZ was inhibited by organic cations such as l-carnitine and tetraethylammonium (TEA), whereas organic anions such as p-aminohippuric acid, probenecid and taurocholate did not affect the PTZ efflux transport. The present results suggest that PTZ is transported from the brain across the BBB via l-carnitine/TEA-sensitive carrier-mediated efflux transport system(s) in addition to P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Selective brain to blood efflux transport of para-aminohippuric acid across the blood-brain barrier: in vivo evidence by use of the brain efflux index method.

Efflux transport of para-aminohippuric acid (PAH) across the blood-brain barrier (BBB) has been demonstrated by use of the brain efflux index (BEI) method. PAH was eliminated from the ipsilateral cerebrum extensively with an apparent efflux rate constant of 0.0587 (min-1) after microinjection into a cerebral cortex region termed Par2. This efflux transport showed a saturation with the Michaelis constant of approximately 400 microM. No more than 3% dose of PAH and carboxyl-inulin, used as a reference compound showing limited permeability at the BBB, were found in the contralateral cerebrum, cerebellum or cerebrospinal fluid up to 20 min after administration. Under saturated conditions for carrier-mediated efflux of PAH via the blood-cerebrospinal fluid barrier, the BEI value of PAH did not change significantly, which suggested that blood-cerebrospinal fluid barrier was not responsible for the elimination of PAH from the brain after microinjection. No significant metabolism of PAH was demonstrated in the brain for at least 20 min after microinjection, and most of the radioactivity in the ipsilateral and contralateral carotid veins was as the intact form. With the distribution volume of PAH, 0.800 ml/g brain, obtained from the brain slice uptake experiment, the apparent efflux clearance was calculated as 46.9 microl/min/g brain. In addition, the influx clearance of PAH across the BBB determined by the in vivo brain uptake index method was much smaller than the efflux clearance, which demonstrates that BBB transports PAH selectively from the brain to the circulating blood.

Animals↗
PubMedDate not supplied

Effects of ethanolamine (Etn) administration on Etn and choline (Ch) levels in plasma, brain extracellular fluid (ECF) and brain tissue, and on brain phospholipid levels in rats: an in vivo study.

The sources and fates of brain ethanolamine (Etn) are poorly known and the effects of its administration have not been investigated, even though cortical levels are known to be reduced in certain neurodegenerative diseases. We studied the effect of different Etn doses (10(-3), 5 x 10(-3) and 10(-2) mol/kg, i. p.) on its and choline's (Ch) levels in arterial plasma and brain extracellular fluid (ECF) of awake rats. We also studied its effects on brain levels of Etn, Ch, and their respective major phospholipids. Etn administration caused dose dependent increases in Etn levels within both plasma and brain ECF. For the 10(-2) mol/kg dose, Etn levels were significantly (p<0.01) greater than pre-injection values in both the plasma and ECF. Whole brain Etn and phosphatidylethanolamine were also significantly (p<0.05) increased by 10(-2) mol/kg Etn. Exogenous Etn significantly (p<0.05) increased Ch levels in plasma and whole brain; Etn also increased brain ECF Ch levels. Our data show for the first time that circulating Etn can act as a source of brain Ch. Metabolic pathways that might mediate the increases in Etn and Ch are discussed, as are possible mechanisms of the decreases in brain Eth seen in Alzheimer's disease.

Alzheimer Disease↗
PubMed1992

Brain cytochrome P450 and testosterone metabolism by rat brain subcellular fractions: presence of cytochrome P450 3A immunoreactive protein in rat brain mitochondria.

The hydroxylation of testosterone by rat brain subcellular fractions has been studied using an HPLC method with an enhanced resolution for the separation of testosterone and its monohydroxy derivatives. Although the analysis time is longer than that reported for earlier methods, a baseline separation was obtained between all hydroxytestosterones, excepting 6 alpha-hydroxytestosterone and 15 beta-hydroxytestosterone, which were separated using a second chromatography system. This separation was important as rat brain microsomes metabolized testosterone to 15 alpha-, 6 beta-, 15 beta-, 16 beta-, 2 beta-, 1 beta-hydroxytestosterone and androstenedione. Testosterone metabolism was found to be linear with time and protein concentration. The rat brain mitochondrial fraction metabolized testosterone to androstenedione. Small amounts of immunoreactive bands comigrating with purified cytochromes P450j, P450b, and P450p were detected by Western blot analysis in rat brain microsomes, while only an immunoreactive protein related to cytochrome P450p was found in the mitochondrial fractions. Immunoinhibition studies showed that BEA33, a monoclonal antibody to cytochrome P450b and simultaneously recognizing cytochromes P450e and P450a, was able to inhibit the metabolism of testosterone to the 1 beta-, 15 alpha-, 2 beta-, and 6 alpha-hydroxylated metabolites, whereas polyclonal anti-cytochrome P450p did not inhibit the formation of the 6 beta-hydroxytestosterone by rat brain microsomes. The metabolism of testosterone by rat brain microsomal or mitochondrial fractions was refractory to induction by 3-methylcholanthrene or pregnenolone-16 alpha-carbonitrile. Thus, in the brain multiple isozymes of cytochrome P450 are constitutively expressed in different subcellular fractions, which suggests that brain cytochrome P450 may play an important role in the metabolism of endogenous compounds. The significance and role of cytochrome P450p-related protein in the rat brain mitochondrial fraction are yet to be determined.

Animals↗
PubMed2004

Randomized controlled trial of effects of the airflow through the upper respiratory tract of intubated brain-injured patients on brain temperature and selective brain cooling.

BACKGROUND: Pyrexia is common after brain injury; it is generally believed to affect outcome adversely and the usual clinical methods of reducing temperature are not effective. The normal physiological mechanisms of brain cooling are heat loss from the upper airways and through the skull, and these can produce selective brain cooling. METHODS: Air at room temperature and humidity was continuously administered to 15 brain-injured, intubated and mechanically ventilated patients via a sponge-tipped oxygen catheter in each nostril at a combined rate of 115 ml kg(-1) min(-1). Brain temperature was measured using a pressure-temperature Camino catheter which is designed to site the thermistor 1 cm into the parenchyma in the frontal lobe. Oesophageal temperature was measured using an oesophageal stethoscope with a thermistor. After establishing baseline for 30 min, patients were randomized to receive airflow or no airflow for 6 h and then crossed over for a further 6 h. RESULTS: Airflow replicating normal resting minute volume did not produce clinically relevant or statistically significant reductions in brain temperature [0.13 (SD 0.55) degrees C; 95% CI, 0.43-0.17 degrees C]. However, we serendipitously found some evidence of selective brain cooling via the skull, but this needs further substantiation. CONCLUSIONS: A flow of humidified air at room temperature through the upper respiratory tracts of intubated brain-injured patients did not produce clinically relevant or statistically significant reductions in brain temperature measured in the frontal lobe.

Adolescent↗
PubMed1987

Brain spectrin(240/235) and brain spectrin(240/235E): differential expression during mouse brain development.

Mouse brain contains at least 2 distinct spectrin subtypes: brain spectrin(240/235) and brain spectrin(240/235E) (Riederer et al., 1986). In this study, we demonstrate that these subtypes are differentially expressed during mouse brain development. Brain spectrin(240/235) can be detected in fetal tissue and increases 2-fold during brain development. This subtype is enriched in the cortical cytoplasm of germinative neural cells and is also found in fibers resembling axons as early as fetal life. Brain spectrin(240/235E), which is specifically detected with antibodies to red blood cell spectrin, is below the limits of detection in fetal and neonatal brain but rapidly increases in concentration during the second postnatal week. Brain spectrin(240/235E) is confined to the cell body and dendrites of differentiating neurons and to glial cells but is not expressed in mitotic cells. This subtype is most prominent in granule cells of the cerebellum and dentate gyrus in the hippocampus.

Animals↗
PubMed2004

Expression of brain-specific angiogenesis inhibitor 3 (BAI3) in normal brain and implications for BAI3 in ischemia-induced brain angiogenesis and malignant glioma.

Murine brain-specific angiogenesis inhibitor 1 and 2 (mBAI1, mBAI2) are involved in angiogenesis after cerebral ischemia. In this study, mBAI3 was cloned and characterized. Northern and Western blot analyses demonstrated a unique developmental expression pattern in the brain. The level of mBAI3 in brain peaked 1 day after birth, unlike mBAI1 and mBAI2, which peaked 10 days after birth. In situ hybridization analyses of the brain showed the same localization of BAI3 as BAI1 and BAI2, which includes most neurons of cerebral cortex and hippocampus. In the in vivo focal cerebral ischemia model, BAI3 expression decreased from 0.5 h after hypoxia until 8 h, but returned to control level after 24 h. The expression of vascular endothelial growth factor following ischemia showed an inverse pattern. The decreased expressions of BAIs in high-grade gliomas were observed, but BAI3 expression was generally lower in malignant gliomas than in normal brain. Our results indicate that the expression and distribution of BAI3 in normal brain, but not its developmental expression, are very similar to those of BAI1 and BAI2, and that BAI3 may participate in the early phases of ischemia-induced brain angiogenesis and in brain tumor progression.

Amino Acid Sequence↗
PubMed2001

Neuroprotection in transient focal brain ischemia after delayed intravenous administration of brain-derived neurotrophic factor conjugated to a blood-brain barrier drug targeting system.

BACKGROUND AND PURPOSE: Neuroprotection with brain-derived neurotrophic factor (BDNF) requires direct injection into the brain owing to poor transport of the neurotrophin through the blood-brain barrier (BBB) in vivo. The present studies investigate whether BDNF alone or conjugated to a BBB drug targeting system is neuroprotective in focal, reversible brain ischemia after delayed intravenous administration at 60 or 120 minutes after middle cerebral arterial occlusion. METHODS: BDNF was conjugated to the OX26 murine monoclonal antibody to the rat transferrin receptor, which undergoes transport into brain from blood via the BBB transferrin receptor transcytosis system. After a 1-hour occlusion of the middle cerebral artery in nitrous oxide- ventilated animals with normal blood sugar, the brain was reperfused, and either BDNF or the BDNF/OX26 conjugate was administered as a single intravenous injection at a dose of 50 microg per rat. RESULTS: After the intravenous administration of unconjugated BDNF, there was no neuroprotection on the basis of analysis of brain at either 24 hours or 7 days after a 1-hour middle cerebral arterial occlusion. In contrast, there was a 68% and 70% reduction in cortical stroke volume at 24 hours and 7 days, respectively, after intravenous administration of 50 microg per rat of the BDNF conjugate (P<0.01). No effects on subcortical stroke volume were observed. CONCLUSIONS: These studies demonstrate marked neuroprotection in focal, transient brain ischemia with a single, delayed intravenous injection of BDNF if the neurotrophin is conjugated to a BBB drug targeting system. The neuroprotection is long lasting and persists for at least 7 days after a 1-hour middle cerebral artery occlusion.

Animals↗
PubMed2002

Expression of brain-specific angiogenesis inhibitor 2 (BAI2) in normal and ischemic brain: involvement of BAI2 in the ischemia-induced brain angiogenesis.

Previously, the authors cloned and characterized murine brain-specific angiogenesis inhibitor 1 (mBAI1). In this study, the authors cloned mBAI2 and analyzed its functional characteristics. Northern and Western blot analyses demonstrated a unique developmental expression pattern of mBAI2 in the brain. The expression level of mBAI2 appeared to increase as the development of the brain progressed. Reverse transcription-polymerase chain reaction (RT-PCR) analyses demonstrated the existence of alternative splice variants of mBAI2, which were defective in parts of type I repeat of thrombospondin or the third cytoplasmic loop of the seven-span transmembrane domain that were considered essential to the functions of mBAI2. The expressions of spliced variants in the brain were differently regulated compared with wild-type mBAI2 during development and ischemic conditions. In situ hybridization analyses of the brain showed the same localization of BAI2 as BAI1, such as in most neurons of cerebral cortex. In the in vivo focal cerebral ischemia model and the in vitro hypoxic cell culture model with cobalt, BAI2 expression decreased after hypoxia and preceded the increased expression of vascular endothelial growth factor (VEGF). RT-PCR analysis of antisense BAI2 cDNA-transfected SHSY5Y cells showed an increased VEGF expression as well as a decreased BAI2 expression. Immunohistochemical study of focal ischemic cortex showed that the regional localization of decreased BAI2 was related to the formation of new vessels. These results suggest that the brain-specific developmental expression pattern of angiostatic BAI2 is correlated with the decreased neovascularization in the adult brain, and that angiostatic BAI2 participates in the ischemia-induced brain angiogenesis in concert with angiogenic VEGF.

Amino Acid Sequence↗
PubMed2001

Clinical cerebral microdialysis: brain metabolism and brain tissue oxygenation after acute brain injury.

While continuous monitoring of brain tissue oxygenation (P(ti)O2) is known as a practicable, safe and reliable monitoring technology supplementing traditional ICP-CPP-monitoring, the impact of cerebral microdialysis, now available bedside, is not proven extensively. Therefore our studies focused on the practicability, complications and clinical impact of microdialysis during long term monitoring after acute brain injury, especially the analysis of the correlation between changes of local brain oxygenation and metabolism. Advanced neuromonitoring including ICP-CPP-p(ti)O2 was performed in 20 patients suffering from acute brain injury. Analysis of the extracellular fluid metabolites (glucose, lactate, pyruvate, glutamate) were performed bedside hourly. No catheter associated complications, like infection and bleeding, occurred. However, longterm monitoring was limited in 5 out of 20 patients caused by obliteration of the microdialysis catheter after 3-4 days. In the individual patients partly a correlation between increased lactate levels as well as lactate pyruvate ratios and hypoxic brain tissue oxygenation could be found. Analysing the data sets of all patients only a low correlation was detected indicating physiological and increased lactate and lactate/pyruvate ratio during sufficient brain oxygenation. Additionally, concentrations of excitatory amino acid glutamate were found in normal and elevated range during periods of hypoxic oxygenation (P(ti)O2 < 10 mmHg) and intracranial hypertension. Our data strongly suggest partly evidence of correlation between hypoxic oxygenation and metabolic disturbances after brain injury. On the other hand brain metabolism is altered without changes of cerebral oxygenation. Further studies are indicated to improve our pathophysiological knowledge before microdialysis is routinely useful in neurointensive care.

Adolescent↗
PubMed1999

4-methylcatechol increases brain-derived neurotrophic factor content and mRNA expression in cultured brain cells and in rat brain in vivo.

Practical use of brain-derived neurotrophic factor (BDNF) as therapy is limited by two serious problems, i.e., its inability to cross the blood-brain barrier and its instability in the bloodstream. In the present study, we investigated the effects of 4-methylcatechol (4-MC), which stimulates nerve growth factor synthesis and protects against peripheral neuropathies in rats, on BDNF content and mRNA expression in cultured brain cells and in vivo in the rat brain. 4-MC elevated BDNF content in culture media of both rat astrocytes and neurons with different dose-response relations. The increase in BDNF mRNA level was correlated with the increase in BDNF content, demonstrating that 4-MC can stimulate BDNF synthesis of both neurons and astrocytes. Then we examined the in vivo effects of 4-MC. First, we found that ventricularly administered 4-MC facilitated an increase in the BDNF content in the cerebral cortex and hippocampus in association with its diffusion into the brain parenchyma. Second, i.p. administration of 4-MC enhanced BDNF mRNA expression in the infant rat brain, in which the blood-brain has not yet fully been established. These results demonstrate that 4-MC, once delivered into the brain, can stimulate BDNF synthesis.

Animals↗