Summary: Brain edema formation during the early stages of focal cerebral ischemia is associated with an increase in both sodium content and blood-brain barrier (BBB) sodium transport. The goals of this study were to deter mine whether chloride is the principal anion that accumu lates in ischemic brain, how the rate of BBB transport of chloride compares with its rate of accumulation, and whether the stimulation seen in BBB sodium transport is also seen with other cations. Focal ischemia was pro duced by occlusion of the middle cerebral artery (MCAO) in anesthetized rats. Over the first 6 h after MCAO, the amount of brain water in the center of the ischemic cortex increased progressively at a rate of 0.15 ± 0.02 (SE) gig dry wtlh. This was accompanied by a net increase in brain sodium (48 ± 12 j.Lmol/g dry wtlh) and a loss of potassium (34 ± 7 j.Lmol/g dry wt/h). The net rate of chloride accu mulation (16 ± 1 j.Lmol/g dry wt/h) approximated the net rate of increase of cations. Three hours after MCAO, the BBB permeability to three ions e2Na, 36CI, and 86Rb) and two passive permeability tracers WH]a-aminoisobutyric Numerous studies have emphasized the impor tance of cations in the development of brain edema during focal ischemia (Ito et aI., 1979;Schuier and Hossmann, 1980; Gotoh et aI., 1985; Young et aI., 1987; Betz et aI., 1989; Menzies et aI., 1993). For example, during the first 3-6 h of ischemia, water accumulation results from a net increase in brain sodium despite a significant loss of brain potassium (Gotoh et aI., 1985; Young et aI., 1987; Betz et aI., 1989; Menzies et aI., 1993). The rate at which soReceived November 9, 1992; final revision received July 13, 1993; accepted July 16, 1993.Address correspondence and reprint requests to Dr. A. L. Betz at D3227 Medical Professional Building, University of Michigan, Ann Arbor, MI 48109-0718, U. S.A.Abbreviations used: AlB, a-aminoisobutyric acid; BBB, blood-brain barrier; MeAO, middle cerebral artery occlusion. 29acid eH]AIB) and e4C]urea} was determined. Permeabil ity to either passive tracer was not increased, indicating that the BBB was intact. The rate of 36CI influx was 3 times greater and the rate of 22Na influx 1.8 times greater than their respective net rates of accumulation in isch emic brain. The BBB permeability to 22Na relative to that of eRJAIB was significantly increased in the ischemic cortex, the relative permeability to 86Rb was significantly decreased, and the relative permeability to 36CI was un changed. These results indicate that the stimulation in BBB sodium transport is specific for sodium. Further, chloride accumulates with sodium in brain during the early stages of ischemia; however, its rate of accumula tion is low compared with its rate of transport from blood to brain. Therefore, inhibition of BBB sodium transport is more likely to reduce edema formation than is inhibition of BBB chloride transport. Key Words: Brain edema Electrolyte transport-Middle cerebral artery occlu sion-Permeability-surface area product.

The release of endogenous dopamine (DA) from rat striatal tissue was studied in an in vitro superfusion system following hormonal manipulations in vivo. Progesterone treatment in estrogen-primed ovariectomized female rats potentiated DA release stimulated either by amphetamine or potassium (K+). In addition, the amount of striatal DA released in response to K+-stimulation was influenced by the light-dark cycle. We conclude that striatal DA release is modulated by ovarian hormones, and suggest that ovarian hormone modulation of presynaptic striatal DA activity may contribute to well-known estrous cycle dependent variations in some non-reproductive behaviors.

The results of 3 experiments examining the influence of estrogen on the nigrostriatal dopamine (DA) system are reported. In two experiments the influence of hormonal manipulations on amphetamine (AMPH)-induced rotational behavior was investigated using rats with unilateral 6-hydroxydopamine lesions of the substantia nigra. It was found that: (1) female rats in estrus make more rotations than ovariectomized (OVX) rats; and (2) estrogen treatment (5 micrograms estradiol benzoate, daily for 4 days) in OVX rats enhances AMPH-induced rotational behavior 4 h and 4 days after estrogen treatment. During the intervening period, at 24 h after cessation of estrogen treatment, control and hormone-treated animals did not differ. In a third experiment, the effect of estrogen treatment on the release of endogenous DA from striatal tissue slices in superfusion was examined. Estrogen enhanced AMPH-stimulated striatal DA release 4 h after the last treatment relative to OVX controls. However, 24 h and 4 days after estrogen treatment DA release had returned to control levels. It is suggested that estrogen has an immediate potentiating effect on striatal DA release, and this may be responsible for the increased behavioral response to AMPH 4 h after estrogen treatment. The previously demonstrated increase in postsynaptic striatal DA receptors may be responsible for the second increase in AMPH-induced rotational behavior, that occurs 4 days after estrogen treatment.

Summary: Oxygen free radicals have been implicated as mediators of tissue damage in ischemic brain . We previ ously demonstrated that the hydroxyl radical scavenger 1,3-dimethyl-2-thiourea (DMTU) reduces infarct size af ter middle cerebral artery occlusion (MCAO) in rats. The present study was undertaken to determine whether this protection results from a preservation of the CBP . Adult male Sprague-Dawley rats were treated with DMTU (750 mg/kg i. There is increasing evidence that oxygen free rad icals are important mediators of brain injury during cerebral ischemia (Yamamoto et aI., 1983; Asano et aI., 1984; Watson et aI., 1984; Abe et aI., 1988; Hall et aI., 1988; Patt et aI., 1988; Young et aI., 1988; Liu et aI., 1989; Martz et aI., 1989); however, the mech anisms by which these toxic compounds damage brain tissue are unknown. Some studies suggest that the microvasculature may be a major site of injury. Free radicals clearly cause increased vascu lar permeability in intestine (Parks and Granger, 1983), skeletal muscle (Korthuis et aI., 1985), and hamster cheek pouch (Del Maestro et aI., 1981). In brain, administration of exogenous free radicals produces increased cerebrovascular permeability (Chan et aI., 1984;Olesen, 1987) and brain edemaReceived May 29, 1989; revised October 16, 1989; accepted October 18, 1989. Address correspondence and reprint requests to Dr. A. L. Betz at D3227 Medical Professional Building, University of Michigan, Ann Arbor, MI 48109-0718, U. S. A.Abbreviations used: AIB, a-aminoiso-butyric acid; BBB, blood-brain barrier; DMTU, 1,3-dimethyl-2-thiourea; MeAO, middle cerebral artery occlusion. 352([3H]a-aminoisobutyric acid) . CBF was reduced in a graded fashion in the ischemic cortex: 0.169 ± 0.020, 0.261 ± 0.017, and 0.435 ± 0.023 mUg/min (mean ± SEM, n = 8) after 4 h in the central, intermediate, and outer zones, respectively . Brain edema was present in a similar pattern, while blood-brain barrier permeability remained normal . Treatment with DMTU significantly reduced brain edema in the central and intermediate zones at both 4 and 24 h. However, CBP in the DMTU-treated animals was identical to that of the vehicle-treated animals . These results suggest that hydroxyl radicals play a role in the development of ischemic brain edema, but the mecha nism does not appear to involve a direct effect on CBP .

1. The potassium permeability of the blood-brain barrier (BBB) was determined in anaesthetized rats aged between 21 days gestation and adult using 86Rb+ as a marker for potassium.2. The brain influx rate constant for 86RbV was high in fetal cortex at 21 days gestation (42-5 + 43 #1 g-1 min-') but had decreased markedly by just after birth (12-2 + 0-6 #1 g-' min-'). There was a further, gradual, postnatal decline to 7 0 + 0 3 sl g-' min-' by 50 days after birth. 3. Developmental changes in passive BBB permeability were examined over the same age range using 14[C]urea. These studies showed similar developmental changes in influx rate to those found for 86Rb+. Specifically, a marked perinatal decline followed by a more gradual postnatal fall. Thus, the changes in potassium permeability probably reflect a decrease in the BBB paracellular leak during development. 4. The changes in BBB permeability coincide with changes in the rate of brain growth and the associated rate of brain potassium accumulation. As the potassium permeability properties of the adult BBB would provide insufficient potassium influx to meet the requirement associated with fetal brain growth, it is suggested that need for potassium may be the reason for the greater BBB permeability early in development.