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Vascular endothelial growth factor in Alzheimer's disease and experimental cerebral ischemia

Several growth factors have been implicated in the pathogenesis of Alzheimers disease (AD). We considered whether the vascular endothelial growth factor (VEGF) is involved in the vascular pathology associated with most cases of AD. We observed enhanced VEGF immunoreactivity in clusters of reactive astrocytes in the neocortex of subjects with AD compared to elderly controls. VEGF reactivity was also noted in walls of many large intraparenchymal vessels and diffuse perivascular deposits. In addition, we established that astrocytic and perivascular VEGF reactivity was enhanced in cerebral cortex of rats subjected to cerebral ischemia and to chronic hypoxia; experimental conditions known to be associated with astrogliosis and angiogenesis. We suggest the increased VEGF reactivity, also observed in infarcted human brain tissue, implicates compensatory mechanisms to counter insufficient vascularity or reduced perfusion (oligemia) apparent in AD.

Lactate compartmentation in hippocampal slices: evidence for a transporter

Lactic acid accumulation has been implicated in the evolution of brain damage after ischemia. Since compartmentation of lactate may play a role in acid-base balance, lactate release from gerbil hippocampal slices was examined during a number of metabolic stresses including elevated [K+]e, ischemia, anoxia, and aglycemia. Slices were preincubated for 1 hr in artificial cerebrospinal fluid (ACSF) equilibrated with 95% O2/5% CO2 (pH 7.4 at 37°C) and then transferred to tubes containing 300μl of test medium. The rate of lactate release in control slices was 9.64 nmol/min/mg protein and increased 2.6- and 3.2-fold in the presence of 60 mM potassium and anoxia, whereas the rate of lactate release was decreased by 50 and 25% during ischemia and aglycemia. Lactate release was temperature dependent and was only minimally influenced by removing Ca2+ or by adding 5 mM d-lactate to the ACSF. In contrast, pyruvate inhibited lactate release with an apparent Ki of 2.4 mM. The results suggest that lactate can be released from cells via a saturable and stereospecific lactate transporter with an apparentKm of 10.7 mM andVmax of 43.7 nmol/mg protein/min. Such a relatively high-capacity transporter system can rapidly equilibrate brain lactate but is probably not involved in regulating intracellular acid-base balance.

A role forγ-aminobutyric acid (GABA) in the evolution of delayed neuronal death following ischemia

A series of putative neuroprotective agents was tested to determine their efficacy in preventing the loss of the CA 1 neurons of the hippocampus at 4 days following 5 min of bilateral ischemia in the gerbil. Agents associated with the GABAergic system were determined to be the most effective, but only when given prior to the ischemic episode, suggesting that there was aγ-aminobutyric acid (GABA)-related event during ischemia which triggers the delayed neuronal death of these cells. In this report, the unidirectional release of GABA and glutamate from gerbil hippocampal slices was determined under conditions mimicking anoxia and/or ischemia. Pentobarbital, the most effective of the GABAergic agents, had little or no effect on the time-dependent release of glutamate. In contrast, pentobarbital reduced in release of GABA in both anoxia and ischemia, but only after 25 to 30 min of incubation.

Adenosine Improves Cerebral Recovery in Rat after Cardiac Arrest and Resuscitation

Cardiac arrest and resuscitation produce global cerebral ischemia and reperfusion damage to the brain, which lead to high mortality and delayed neuronal death. Adenosine (ADO) has been suggested as an endogenous neuroprotective molecule, acting through multiple potential mechanisms (Sweeney, 1997). In this study we investigated the possible neuroprotective effects of adenosine on cerebral recovery following global ischemia induced by cardiac arrest and resuscitation.