The relationship between extravasation of proteins into extracellular spaces of brain parenchyma and the water content of such regions were evaluated in an experimental model. In this model, a temporary opening of the blood-brain barrier (BBB) to proteins was produced without significant injury to the cellular elements of brain tissue. Rabbits were subjected to bolus injection of their own blood under 360-400 mm Hg pressure via the internal carotid artery. The opening of the barrier and its duration were evaluated with Evans blue (EB), horseradish peroxidase (HRP), and sodium fluorescein (NaFl) tracers. The water content of brain tissue was assessed by specific gravity (SG) measurements in 1-mm-diameter tissue samples. Quantitative evaluation of protein penetration into brain tissue was carried out using 125I bovine serum albumin (BSA). The opening of the BBB to proteins persisted up to 9 h, whereas the barrier remained permeable to small molecular NaFl for 24 h. The SG measurements indicated in the areas of EB extravasation a progressive increment in water content up to 9 h, i.e., the duration of BBB opening to proteins. Following this, there was a progressive clearance of edema in spite of the BBB remaining open for NaFl for 24 h. Quantitative evaluations of 125I-BSA and SG in the same tissue samples, supported by statistical analysis, indicated approximately linear relationship analysis, indicated approximately linear relationship between albumin and water, implying a strong correlation between the development of vasogenic edema and extravasation of proteins into extracellular spaces.

We assessed the consequences of transitory global cerebral ischemia and the influence of monosialoganglioside inner ester (AGF 2) treatment on neurologic outcome, cerebral blood flow, and cerebral metabolic rate in monkeys over 48 hours. Global cerebral ischemia was produced by a cervical tourniquet and a lowering of blood pressure to 6.65 kPa; recirculation followed after 30 minutes. AGF 2 (30 mg/kg) was administered intravenously immediately after initiation of recirculation and intramuscularly twice a day for 48 hours. Our results show that treatment with AGF 2 significantly accelerated the rate of neurologic recovery. Improvement was evident 5 hours after ischemia; full neurologic recovery was observed in half of the monkeys 48 hours after ischemia. This recovery was associated with a less severe reduction in cerebral blood flow without a concomitant increase in the cerebral metabolic rate. (Stroke 1989; 20:652-656) G angliosides are sialic acid-containing glycosphingolipids with particular abundance in the outer membrane surface of neuronal cells.' Although their biologic function is still largely obscure, considerable evidence now indicates that systemically administered gangliosides are effective in improving the outcome following neuronal injury to adult rodents. In the initial work of Ceccarelli et al, 2 a mixture of bovine brain gangliosides enhanced recovery of the denervated cat nictitating membrane, an effect most probably associated with an enhanced rate of axonal regrowth.3 Subsequently, the monosialoganglioside GM 1 (nomenclature according to Svennerholm 4 ) alone was found to affect recovery following injury to the central nervous system (CNS). For example, following partial unilateral hemitransection of the nigrostriatal pathway, chronically administered GM 1 facilitated the recovery of dopaminergic synaptic function in the lesioned striatum.5 This effect was associated with both enhanced survival of nigral dopaminergic cell bodies and with the associated reduction of the imbalance in energy metabolism and blood flow between the striata of the lesioned and unlesioned sides. Received March 4, 1988; accepted October 18, 1988. GM 1 effects have also been detected during the acute phase following brain insults, including cerebral ischemia. GM 1 treatment has been shown to have beneficial effects following both transitory middle cerebral artery occlusion in cats and permanent unilateral ligation of the common carotid artery in gerbils. -9We describe the effects of AGF 2, the inner ester derivative of GM 1, following transitory global cerebral ischemia in monkeys. We used AGF 2 because of its reportedly greater ability to penetrate the blood-brain barrier. 10 Materials and MethodsWe used 27 cynomolgus monkeys {Macaca fascicularis) of either sex weighing 3-6 kg. Anesthesia was induced with 3 mg/kg i.m. ketamine hydrochloride followed by an intravenous perfusion of 25 mg/kg chloralose. The monkeys were intubated and then ventilated (Delhomme, Bird Mark 8, Paris, France) so as to maintain Pacc>2 at 5...

Rat transient incomplete forebrain ischemia was induced by 60 min of bilateral carotid artery occlusion associated with systemic hypotension. Intraperitoneal treatment with either GM-1 monosialoganglioside or its inner ester AGF-2 started 1 h after release of carotid clamps and was repeated twice a day. Ganglioside treatment was effective in reducing the increase of cerebral water content, nonetheless AGF-2 reduces significantly not only cerebral edema, but also potassium efflux and calcium overload. With respect to ischemic untreated rats, GM-1- and AGF-2-treated rats showed a higher incidence of conditioned response retention of a single training trial, associated with improvement in cerebral blood flow and electrocorticographic patterns. In addition, 4 weeks following ischemia, the extent of tissue necrosis was reduced, although not statistically significant, in both ganglioside-treated groups. However, all these improvements are more evident in the AGF-2-treated rats than in the GM-1-treated ones. In conclusion, these results suggest that, except in some cases with different potency, both monosialoganglioside GM-1 and its inner ester derivative, AGF-2, are able to improve outcome after brain ischemia.

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