Disruption of the blood‐brain barrier in hyperammonemic coma and the pharmacologic effects of dexamethasone and difluoromethyl ornithine

Abstract

Both hyperammonemia and blood-brain barrier (BBB) breakdown have been implicated in the evolution of hepatic encephalopathy. To define a possible relationship, Swiss Albino mice were subjected to sublethal encephalopathic doses of ammonium acetate; the integrity of the BBB was determined grossly with Evans blue and quantitatively with [14C]-alpha-aminoisobutyrate (AIB). Some animals were injected with a dose of ammonium acetate sufficient to maintain coma for 1 hr (AC group). One group, termed stuporous (AS), received only enough ammonium acetate to interfere with grooming and exploratory activity; this dosage was insufficient to completely block the righting response, which was absent in the AC group. When compared to that of controls (CON) receiving normal saline instead of ammonium acetate, cerebral tissue from the AC group was stained blue and contained nearly double the amount of AIB; AS group brain tissue was unstained and the AIB content did not differ significantly from normal. Some of the AC group were pretreated with drugs known to retard BBB breakdown; one set received dexamethasone (AC-DXMN), another the ornithine decarboxylase inhibitor difluoromethyl ornithine (AC-DFMO), and a third L-ornithine (AC-ORN). Brain tissue from the AC-ORN group stained blue and AIB content did not differ significantly from that of the untreated AC group. Cerebral tissue of the AC-DXMN pretreatment group stained light blue; AIB content was significantly lower than in the AC group and greater than the CON group. The AC-DFMO brains were unstained and AIB content was significantly lower than in the AC group but did not differ significantly from CON. These results indicate that hyperammonemia may induce BBB breakdown but that the disruption of barrier integrity is not antecedent to the development of coma, although it seems to coincide with coma in time.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of acute and repeated hyperammonemia on γ-glutamyl transpedtidase in homogenates and capillaries of various rat brain regions

“…All the animals in this group developed sublethal coma, in agreement with the original description of the model (Sears et al, 1985). In the "subchronic" group, both blood and brain ammonia were about 60% higher than in (9) 0.24 ± 0.04 (8) "Acute" 1500 t 50 (5) 1.35 ± 0.19 (9) "Subchronic" 160 ± 6 (5) 0.37 ± 0.03 (8) "Chronic" 219 ± 19 (6) 0.38 ± 0.02 (8) Results are mean ± SD, with number of experiments in parentheses.…”

“…control rats (Table 1). In its behavioral pattern, the group resembled the "stuporous" group described by Sears et al (1985); the animals showed a severe impairment, but not a complete block of the righting response. In "chronic" hyperammonemia, blood ammonia was two times higher than control, whereas brain ammonia showed a 60% increase.…”

“…One group was treated first with a 750 mg/kg dose, that was followed after 30 min by a 600 mg/kg dose, and tissue and blood were collected 10 min after the last injection. As originally described by Sears et al (1985), animals treated in this way were in a comatose state. This group will be further referred to as subjected to "acute hyperammonemia."…”

Polyamine metabolism in different pathological states of the brain

“…Several lines of evidence have been presented indicating that activation of polyamine synthesis may play a pivotal role in disturbances of the blood-brain barrier under different experimental conditions including cold lesion to the brain, hyperosmolal opening of the blood-brain barrier and disruption of the blood-brain barrier in hyperammonemic coma (Koenig et al, 1983a(Koenig et al, , 1989aSears et al, 1985;Trout et al, 1986). The first results indicating that blood-brain barrier breakdown may be triggered by an activation of polyamine synthesis were published by Koenig et al (1983a) using a cryogenic lesion of the rat cerebral cortex as model.…”

“…In a third series of experiments, ammonium acetate was used to study the effect of hyperammonemia as a model of hepathic encephalopathy on the integrity of the blood-brain barrier (Sears et al, 1985). When measured with Evans blue or [ 14 C]aminoisobutyrate, hyperammonemia produced marked disturbances of the blood-brain barrier, which were completely suppressed in animals pretreated with DFMO.…”