Jorge Cervós-Navarro

Increased blood-brain barrier permeability following acute short-term swimming exercise in conscious normotensive young rats

The status of the blood-brain barrier (BBB) was examined following short-term forced swimming (FS) exercise in younger rats (age 8-9 wks, 80-90 g). Subjection of animals to continuous FS for 30 min duration increased the permeability of the BBB to Evans blue albumin (EBA) and 131I-sodium in 5 and 8 brain regions, respectively. Extravasation of the tracers was markedly pronounced in the cerebellum followed by the cerebral cortex. EBA staining was confined mainly to the posterior cingulate cortex, parietal and occipital cortices, whole cerebellar vermis and the mediolateral cerebellar cortices as well as the dorsal surface of the hippocampus. In addition to the above brain regions. BBB permeability to 131I-sodium extended to the caudate nucleus, thalamus and hypothalamus. At this time period, the serotonin (5-hydroxytryptamine, 5-HT) content showed a profound increase in plasma and brain of about 150% and 250% respectively from the control value. Pretreatment with p-CPA (p-chlorophenylalanine, a serotonin synthesis inhibitor) prevented both the increased permeability of the BBB and the rise in plasma and brain 5-HT level. However, prior treatment with cyproheptadine (a 5-HT2 receptor antagonist) prevented the increased permeability alone. The 5-HT level continued to remain high. These results suggest that short-term FS increases BBB permeability in specific brain regions. This increased permeability appears to be mediated through serotonin via 5-HT2 receptors.

Traumatic brain injuries: structural changes

A host of complications and consequences may follow a contusion or other brain injury of any sort. An appreciation of the temporal evolution of the contusion from a microscopic standpoint is useful to a full understanding of the process by which physical force damages the brain and how the brain reacts to this damage. Some disruptions of the blood brain barrier quite early will result in extracellular edema. The microscopic appearance of an edematous area is usually spongy with numerous vacuoles. The neuropil may appear bubbly, and glial cells may be swollen. If edema has been long standing, the vacuoles may be larger and in fact a small cyst may appear in the white matter. If focal cerebral edema is not present for long periods of time and the underlying cause has been corrected, residual fluid and electrolytes are eventually removed, restoring the neuropil to a normal state, leaving no sign of its presence. However, in longer standing lesions, myelin pallor and some reactive gliosis may remain indefinitely. Neurons may show swelling very early and for a short period of time, which gives way to shrinkage, eosinophilia, and nuclear pyknosis. These changes may be observed at the periphery of lesions for as long as 5 or 6 months after the initial event. Before dissolution, nuclear pyknosis may remain in the tissue for many days and possibly longer, and may even become mineralized in situ (ferruginated neurons) to remain for years. In a traumatic lesion, swollen and ballooned axons may be found in and around the contusion but also at great distances from it (diffuse axonal injury). Axonal ballooning may be observed between 24 and 48 h postinjury and may persist wherever found for many years. Selective axonal calcification has been observed in humans as well as in experimental trauma. At about 7-10 days postinjury increased numbers of astroglia probably are present. Over the ensuing weeks and months, and probably years, astrocytes increase in number and in fibrillary appearance, eventually resulting in a glial scar in and about the injured area. It is thought that this reactive gliosis results in restoration of the blood-brain barrier in the damaged area.

Neuron-like physiological properties of cells from human oligodendroglial tumors

One of the most common symptoms of patients with oligodendrogliomas is the high frequency of epileptic seizures. We thus studied the physiological properties of cells in six human oligodendrogliomas and two oligoastrocytomas obtained from surgical material. The majority of tumor cells in living brain slices can generate action potentials as recorded with the patch-clamp technique indicating that this tissue is dominated by electrically excitable cells. In cultures from the same material, the action potential generating cells prevail within the first days and are subsequently replaced by electrically inexcitable cells. From histopathological and immunohistochemical data, the histogenesis of human oligodendroglial tumor is still uncertain. Our physiological study has not settled the debate on the origin of these tumors but revealed important findings with regard to this question. Since action potential generating glial cells have not been described in situ so far their occurrence in oligodendroglial tumors implies that oligodendroglial tumor cells may belong to the neuronal cell lineage.

NGF content in the cerebral cortex of non-demented patients with amyloid-plaques and in symptomatic Alzheimer's disease

There is increasing evidence that in Alzheimers disease nerve growth factor (NGF)protein and NGF mRNA content in post‐mortem cortex is not decreased, but may evenbe elevated although the NGF‐sensitive cholinergic basal forebrain neurons are preferentiallyaffected. However, only little is known about the early pathophysiological events leading toAlzheimers disease. We therefore measured the post‐mortem NGF concentrations intemporal and frontal cortex of Alzheimers disease patients, non‐demented controls withoutAlzheimers disease‐related pathology, as well as non‐demented patients with βA4plaques who might be classified as preclinical cases. In the Alzheimers disease group we found upto 43% increase in NGF concentrations in the frontal and temporal cortex as compared to the twoother groups. In a subgroup analysis of the non‐demented patients with plaques, NGFconcentrations were lower in the frontal cortex when βA4 plaques were present (46% ofthe control temporal area) than in patients without evidence of frontal plaques (81% of the controltemporal area). This NGF decrease was paralleled to a similar decrease of cholineacetyltransferase activity, which is regulated by NGF in the cholinergic basal forebrain. Thesefindings support the hypothesis of lower cortical NGF content at the onset of plaque formationand of elevated NGF levels in the clinically manifest and neuropathologically advanced stage ofthe disease.

Involvement of Nitric Oxide in the Pathophysiology of Acute Heat Stress in the Rat.: Influence of a New Antioxidant Compound H-290/51

Involvement of nitric oxide in the pathophysiology of acute heat stress inthe rat. Influence of a new antioxidant compound H-290/51.

Histamine modulates heat stress-induced changes in blood-brain barrier permeability, cerebral blood flow, brain oedema and serotonin levels: An experimental study in conscious young rats

The possibility that endogenous histamine plays an important role in modulating the pathophysiology of heat stress was examined in young rats using a pharmacological approach. Subjection of young animals (six to seven weeks old) to heat stress at 38 degrees C for 4 h in a biological oxygen demand incubator (relative humidity 47-50%, wind velocity 20-25 cm/s) resulted in a profound increase in blood-brain barrier permeability to Evans Blue albumin (whole brain 375%) and [131I]sodium (whole brain 478%) along with a significant reduction in the cerebral blood flow (mean 34%). The water content of the whole brain was elevated by 4.5% (about 19% volume swelling) from the control. At this time-period, the plasma and whole brain 5-hydroxytryptamine levels were elevated by 656% and 328%, respectively, from the control group. Pretreatment with cimetidine (a histamine H2 receptor antagonist) significantly thwarted the increases in the brain water content and the blood-brain barrier permeability. In cimetidine-pretreated animals, the cerebral blood flow was significantly elevated and the plasma and brain 5-hydroxytryptamine (serotonin) levels were slightly but significantly reduced as compared with the untreated stressed group. However, prior treatment with mepyramine (a histamine H1 receptor antagonist) neither attenuated the changes in water content and the blood-brain barrier permeability nor altered the cerebral blood flow and 5-hydroxytryptamine levels. In fact, there was a significantly higher permeation of the tracers across the cerebral vessels in these drug-treated animals along with a greater accumulation of the brain water content as compared with the untreated stressed group. The cerebral blood flow and 5-hydroxytryptamine levels showed only minor changes from the untreated stressed group. These results show, probably for the first time, that (i) the endogenous histamine plays an important role in the pathophysiology of heat stress, and (ii) this effect appears to be mediated via specific histamine H2 receptors.

Action potential-generating cells in human glioblastomas.

We studied the electrophysiological properties of cells from human glioblastomas obtained after surgery. The membrane currents were compared in cells of acute tissue slices and primary cultures using the whole cell mode of the patchclamp technique. Very strikingly, in about a third of the tumor cells in situ and in vitro, depolarizing voltage steps elicited large, tetrodotoxin-sensitive inward currents with a threshold of about −30 mV, indicating the presence of voltage-gated sodium channels. In addition, three types of potassium currents, a delayed rectifying, an A-type, and an inward rectifying, were observed. Such a set of voltage-gated channels is characteristic for neurons. Indeed, in these glioblastoma cells, depolarizing current pulses in the current clamp mode were able to generate action potentials with properties similar to those observed in neurons. We interpret this finding as the ability of glioblastoma cells to acquire neuronlike properties but retain some glial features, since they still express markers typical for astrocytes and their precursors. The role of sodium channels in glioblastoma cells is unclear at this moment and needs further investigation. Our findings, however, imply that the tumor tissue can be intrinsically excitable and that neoplastic glial cells themselves may be an etiologic factor for epileptic seizures.

Brain Oedema and Cellular Changes Induced by Acute Heat Stress in Young Rats

Exposure of young animals (70-80 g, Age 6-7 weeks) to heat stress (HS) at 38 degrees C for 4 h in a B.O.D. incubator (rel humid 50-55%, wind vel 28.6 cm/sec) resulted in a 4.41% increased brain water content from the control value. Morphological studies in parietal cerebral cortex at light microscopical level revealed chromatolysis and appearance of dark neurons. Electron microscopy of similar regions showed perivascular oedema, vacuolation and collapsed microvessels. The swelling of astrocytes and of postsynaptic membranes was frequent. A diffuse infiltration of lanthanum (La[NO3]3) in endothelial cell cytoplasm and in the vesicles was very common. Occasionally, the lanthanum was seen in the basement membrane but the tight junctions were mainly intact. At this time period, a significant increase in blood-brain barrier (BBB) permeability as well as 5-HT levels in brain and plasma were observed. Pretreatment with p-CPA (a 5-HT synthesis inhibitor) prevented the increase of brain water content. BBB permeability and 5-HT levels in brain and plasma. Cyproheptadine (a 5-HT2 receptor antagonist) treatment significantly reduced the occurrence of increased brain water content and the BBB permeability. The 5-HT level continued to remain high. These results point out a probable role of 5-HT in pathophysiology of HS via 5-HT2 receptors.

The basal nucleus of Meynert revised: the nerve cell number decreases with age

There is an age-dependent nerve cell loss in some areas of the brain, while other brain regions are stable with aging. The nucleus basalis of Meynert (NbM) is believed to be the source of cholinergic innervation of the cerebral cortex, and loss of its neurons seems to be followed by cognitive deficits. The normal age kinetics of the NbM are, therefore, of considerable importance. Sixteen autoptic human brains were examined, ages ranging from 35th week of gestation to 90 years of age. Blocks containing the NbM in its entirety were cut into 20-mu thick serial sections; every 25th section was cresyl-violet stained and underwent morphometric analysis. Nerve cell counts were slightly but significantly higher in the right hemisphere. The total number of neurons in the 9th decade was 23% below that in newborns. This decrease was statistically significant. We hypothesize that there is a threshold number of nerve cells below which cognitive failure is highly probable.

Early perifocal cell changes and edema in traumatic injury of the spinal cord are reduced by indomethacin, an inhibitor of prostaglandin synthesis

SummaryThe possibility that prostaglandins participate in the formation of perifocal edema and cell changes following a localized trauma to the spinal cord was investigated in a rat model. A laminectomy was performed in urethane-anesthetized animals at the thoracic T10–11 segment. Using a scalpel blade a unilateral lesion, about 2 mm deep and 5 mm long was made 1 mm to the right of the midline. The deepest part of the injury occupied Rexeds lamina VII of the dorsal horn. Animals were pretreated with the prostaglandin synthesis inhibitor, indomethacin (10 mg/kg, i.p. 30 min prior to trauma). Five hours after the injury the water content was determined and cell changes in and around the primary lesion were examined by light and electron microscopy. Normal and injured rats without indomethacin pretreatment served as controls. Untreated injured rats showed a profound increase of water content in the traumatized T10–11, the rostral (T9) and caudal (T12) segments compared with normal rats. These segments also exhibited marked cell changes in ipsilateral and contralateral dorsal and ventral horns. The gray matter had a spongy appearance and some nerve cells were condensed and distorted. The white matter contained many distorted fibers. Immunostaining for myelin basic protein showed a marked reduction of reaction product in the injured animals compared with normal rats. Ultrastructurally widened extracellular spaces, cytoplasmic vacuolation, swollen and condensed neurons, swollen astrocytes and vesiculation of myelin were frequent findings. Pretreatment of rats with indomethacin significantly reduced the accumulation of water in the traumatized and in the rostral and caudal segments. The structural changes were less pronounced particularly in the cranial and caudal segments. The results indicate that prostaglandins somehow are involved in the pathophysiology of perifocal spinal cord injury and influence both the fluid microenvironment and the early cell changes.