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Characteristics of ethacrynic acid highly sensitive Mg2+-ATPase in microsomal fractions of the rat brain: functional molecular size, inhibition by SITS and stimulation by Cl-.

Studies were performed to characterize ethacrynic acid (EA) highly sensitive Mg2+-ATPase isolated from microsomal fractions of the rat brain. The functional molecular sizes of the EA highly sensitive and EA less sensitive Mg2+-ATPases, estimated by a radiation inactivation method, were 480 and 80 kDa, respectively. An anion transport inhibitor, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS) inhibited the EA highly sensitive Mg2+-ATPase activity. The type of inhibition was uncompetitive with respect to ATP, and the inhibition was suppressed by anions such as Cl-, Br- and I-. Chloride ions stimulated enzyme activity with an increase in Vmax, but not in Km, for ATP. Anions tested also increased the enzyme activity in the following order of decreasing potency: Cl- greater than Br- greater than CH3COO- = I- greater than SO4(2-) = HCO3- greater than SO3(2-). These results suggest that EA highly sensitive Mg2+-ATPase is a relatively large molecule with anion-sensitive sites that affect the ATP hydrolyzing activity and the SITS binding capacity through anions, with Cl- being the most potent.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo

Activation of brain function by S-135, a benzodiazepine receptor inverse agonist.

1. S-135, 2-(5-methylthien-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinoline-3- one, bind binds to benzodiazepine receptors with a high affinity and shows pharmacological actions opposite to those of conventional benzodiazepine drugs. 2. S-135 induced no convulsion in mice by itself, but selectively potentiated the effect of subconvulsive dose of pentylenetetrazole. 3. S-135 potentiated rat crossed extensor reflex and Ro 15-1788 completely antagonized this potentiation. 4. S-135 antagonized pentobarbital-induced anesthesia, tetrabenazine-induced ptosis and reserpine-induced hypoactivity and shortened immobilization time in the despair test in mice, indicating that this compound possesses antidepressive properties. 5. S-135 antagonized amnesia in mice and rats in passive avoidance tasks. 6. Glucose utilization in brain areas relating to memory and arousal functions was enhanced following S-135 treatment. 7. These results indicate that S-135 can be a useful drug for activating depressed brain function.

Animals

Magnetoencephalography: a tool for functional brain imaging.

At present, one of the most promising windows to the functional organization of the human brain is magnetoencephalography (MEG). By mapping the magnetic field distribution outside the head the sites of neural events can be located with an accuracy of a few millimeters and the temporal evolution of the activation can be traced with a millisecond resolution. This paper reviews some forward field calculation approaches suitable for the interpretation of the brain's electromagnetic signals. Inverse modelling with multiple dipoles is described in detail. An example of the analysis of the somatosensory evoked-responses illustrates the potential of multiple signal classification (MUSIC) algorithm in finding optimal dipole positions.

Algorithms

Magnetic resonance imaging mapping of brain function. Human visual cortex.

Magnetic resonance imaging (MRI) studies of human brain activity are described. Task-induced changes in brain cognitive state were measured using high-speed MRI techniques sensitive to changes in cerebral blood volume (CBV), blood flow (CBF), and blood oxygenation. These techniques were used to generate the first functional MRI maps of human task activation, by using a visual stimulus paradigm. The methodology of MRI brain mapping and results from the investigation of the functional organization and frequency response of human primary visual cortex (V1) are presented.

Brain Mapping

The effect of hypoxia on traumatic head injury in rats: alterations in neurologic function, brain edema, and cerebral blood flow.

We evaluated the effects of early posttraumatic hypoxia on neurologic function, magnetic resonance images (MRI), brain tissue specific gravities, and cerebral blood flow (CBF) in head-injured rats. By itself, an hypoxic insult (PaO2 40 mm Hg for 30 min) had little effect on any measure of cerebral function. After temporal fluid-percussion impact injury, however, hypoxia significantly increased morbidity. Of rats subjected to impact (4.9 +/- 0.3 atm) plus hypoxia, 71% had motor weakness contralateral to the impact side 24 h after injury, while only 29% of rats subjected to impact alone had demonstrable weakness (p less than 0.05). Lesions observed on MR images 24 h after injury were restricted to the impact site in rats with impact injury alone, but extensive areas with longer T1 relaxation times were observed throughout the ipsilateral cortex in rats with impact injury and hypoxic insult. Brain tissue specific gravity measurements indicated that much more widespread and severe edema developed in rats with impact injury and hypoxia. [14C]Iodoantipyrine autoradiography performed 24 h after injury showed that there was extensive hypoperfusion of the entire ipsilateral cortex in rats with impact injury and hypoxia. These results show that large areas of impact-injured brain are extremely vulnerable to secondary insults that can irreparably damage neural tissue, and provide experimental evidence for the observed adverse effects of hypoxia on outcome after human head injury.

Animals

Dependency on the brain function of arginine vasopressin system of the development to and recovery from analgesic tolerance to morphine.

Concomitant intracerebroventricular (i.c.v.) injection of anti-arginine vasopressin (AVP) antiserum dose-dependently suppressed the development of analgesic tolerance to daily morphine, 10 mg/kg, s.c., in mice. This suppressive effect of the antiserum was reduced by incubating the antiserum with AVP in vitro, before i.c.v. injection, suggesting that the antiserum inactivates brain AVP to result in the suppression of the development of tolerance in vivo. Similar to the antiserum, both AVP V1 and V2 antagonists given i.c.v., 10 ng and 20 ng/mouse, respectively, suppressed the development of morphine tolerance. Meanwhile, the administration of antiserum dose-dependently recovered morphine analgesia in morphine-tolerant mice and a complete recovery of analgesia was observed at the highest dose of antiserum following the second injection, and the effect of antiserum was maintained for 3 days after its withdrawal. Likewise, 10-100 ng/mouse of AVP V1 receptor antagonist given i.c.v. recovered morphine analgesia partially but significantly in a dose-dependent manner; however, AVP V2 receptor antagonist at the same doses partially recovered analgesic effect but the effect was neither significant nor dose-dependent. These findings suggest that the tolerance developed to morphine can be reversible when disturbing the function of brain AVP, but in addition to the different mechanisms of antiserum, V1 and V2 receptor antagonists, the V1 receptor-mediated mechanism may be more closely concerned in this phenomenon.

Angiotensin Receptor Antagonists

A brief history of the influence of trace elements on brain function.

From this brief review of history it is evident that lead, mercury, iodine, cobalt, iron, copper, manganese, and zinc have important influences on brain development and function. Identity of thresholds at which effects occur is needed for determination of safe and/or essential levels of these elements in diets. Such knowledge will help define human needs for essential elements, and the hazards of toxic elements.

Animals

[Effects of Ginkgo biloba extract on functional brain activity.. An assessment of clinical and experimental studies].

Electroencephalography is the only convenient method for functional exploration of the brain. The recent introduction of signal analysis techniques has given it a quantitative dimension and has resulted in pharmacological studies of electoencephalograms. In four studies of this kind the effects of Ginkgo biloba extract were investigated on three pathological animal models, in young healthy volunteers and in elderly people with dementia disorders. In man, the EEG tracings could be analyzed in relation to different psychometric tests. The results obtained confirm those of clinical trials, and notably the activity of Ginkgo biloba extract on alertness.

Adolescent

Two biological rhythms of perception distinguishing between intact and relatively damaged brain function in man.

A simple test of perception, the Critical Flicker Fusion threshold (CFF) was given successively for 20 mins. to 69 healthy subjects aged 7-63 and to 53 comparable neuropsychiatric patients. The latter could be divided into a functionally sick group and a group with brain damage. Auto-correlation analysis revealed significant sine-wave cycles of amplitude and ultradian frequency for the CFF mean scores and the CFF "Scatter* scores. Both cycles of recurrence showed frequencies which distinguished significantly between the total healthy subjects and the patients. Further analysis showed no difference between controls and emotionally sick patients (i.e. those with sociopathy, schizophrenia and manic depressive psychosis) but there was a highly significant difference between these three groups and patients with relatively damaged C.N.S. (i.e. those with mental deficiency, organic brain syndrome and organic dementia). Even among the control group a progressive increase in frequency of these perceptual cycles occurred with advancing age. These CFF results point to the existence of a cycle of perceptual acuity and another of vigilance in the organism. Both appear to relate to the neural integrity of the C.N.S.

Adolescent

Changes in brain functional connectivity in Alzheimer-type and multi-infarct dementia.

Clinical and neuropathological evaluation of elderly subjects with dementia has traditionally concentrated upon the focal distribution of brain disease, ignoring changes in the complex connections that link brain areas and that are crucial for cognition. We examined subjects with the two most common forms of dementia in the elderly (dementia of the Alzheimer type or DAT, and multi-infarct dementia or MID); and used electroencephalographic (EEG) coherence to examine the effects of these illnesses on the functional connections between brain areas. We studied coherence between brain areas known to be linked by two different types of connections: (i) dense narrow bands of long corticocortical fibres; (ii) broad complex networks of corticocortical and corticosubcortical fibres. Areas that were linked by dense narrow bands of long corticocortical fibres showed greatly diminished coherence in subjects with DAT; among MID subjects, this coherence was not significantly affected. Areas that were linked by broad connective networks showed the largest decreases in coherence among MID subjects. These findings are consistent with neuropathological evidence that Alzheimer's disease is a neocortical 'disconnection syndrome' in which there is a loss of structural and functional integrity of long corticocortical tracts. The findings further suggest that the vascular disease of MID most prominently affects broad fibre networks that may be more vulnerable to diffuse subcortical vascular damage. A ratio of coherence from complex corticocortical-corticosubcortical networks divided by coherence from long corticocortical tracts correctly classified 76% of subjects into DAT and MID categories. Overall, these results indicate that EEG coherence detects basic pathophysiological differences between subjects with DAT and MID, and that these differences may be clinically useful.

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