Induce Blood-brain Barrier Breakdown Research Articles

Cytokine-induced acute inflammation in the brain and spinal cord.

Different compartments in the central nervous system mount distinct inflammatory responses. The meninges and choroid plexus respond to pro-inflammatory stimuli in a manner reminiscent of a peripheral inflammatory response, whereas the brain parenchyma is refractory. Trauma-induced lesions in brain and in spinal cord are associated with leukocyte infiltration, blood-brain barrier (BBB) breakdown, and secondary tissue destruction. Unexpectedly, these phenomena are generally more pronounced in the parenchyma of the spinal cord than in the parenchyma of the brain. To investigate whether these differences between brain and spinal cord can be attributed, at least in part, to differing sensitivities to proinflammatory cytokines, we stereotactically injected recombinant rat (rr) TNFalpha or rrIL-1beta into the striatum or the spinal cord of Wistar rats. In the brain, the injection of rrTNFalpha failed to evoke BBB breakdown or leukocyte recruitment, whereas in the spinal cord injection of TNFalpha resulted in marked BBB breakdown and leukocyte recruitment. Similarly, the injection of rrIL-1beta into the brain parenchyma failed to induce BBB breakdown and gave rise to only minimal neutrophil recruitment, whereas the injection of rrIL-1beta into the spinal cord induced significant BBB breakdown and recruitment of neutrophils and lymphocytes. Thus, using a minimally invasive injection technique, equivalent in both circumstances, we have shown that there are marked differences in the inflammatory response between the brain parenchyma and spinal cord parenchyma. This observation has important implications for the treatment of spinal cord injuries.

Immunohistochemical changes of the blood‐brain barrier in rat spinal cord after heavy‐ion irradiation

Changes in the blood‐brain barrier (BBB) of the rat spinal cord after irradiation with heavy ion were investigated ultrastructurally and immunohistochemically by using SMI 71, a monoclonal antibody against rat endothelial barrier antigen (EBA); anti‐ZO‐1, a polyclonal antibody against endothelial tight junctions, anti‐rat serum to extravasated serum, and anti‐vascular endothelial growth factor (VEGF). The lower thoracic and lumbar cord of male Wistar rats was singly irradiated with a carbon beam at a dose of 30 Gy. Rats were sacrificed before or after the onset of hind limb paralysis. Histologically, white‐matter vacuolization was observed from 13 weeks after irradiation, and white‐matter necrosis was first noted at 17 weeks. SMI 71 staining was decreased or lost 13 weeks after irradiation, just prior to the formation of white‐matter necrosis, and was almost completely lost in the center and periphery of the white‐matter necrosis. Although ZO‐1 expression and tight junctions in the ultrastructure were preserved at that time, serum leakage occurred almostly completely in parallel with the changes in EBA. Therefore, carbon‐ion irradiation at a dose of 30 Gy induces BBB breakdown 13 weeks after irradiation. The SMI 71‐negative blood vessels were sparsely distributed throughout the entire white and gray matter, and there was no evidence of preferential localization. Immunostaining of smooth muscle actin showed that most of the SMI 71‐negative blood vessels were veins or capillaries. These findings suggest that the hyper‐permeability of the veins and/or capillaries that occurs after a certain latent period is one of the important factors in the pathogenesis of delayed radiation injury by carbon ions, the same as by X‐rays. Radiation‐induced functional disturbances of the endothelium and involvement of cytokines such as VEGF are suspected of being the cause of such vascular hyper‐permeability.

Early white blood cell dynamics after traumatic brain injury: effects on the cerebral microcirculation.

Increasing clinical and experimental evidence suggests that traumatic brain injury (TBI) elicits an acute inflammatory response. In the present study we investigated whether white blood cells (WBC) are activated in the cerebral microcirculation early after TBI and whether WBC accumulation affects the posttraumatic cerebrovascular response. Twenty-four anesthetized rabbits had chronic cranial windows implanted 3 weeks before experimentation. Animals were divided into four experimental groups and were studied for 7 hours (groups I, IIa, and III) or 2 hours (group IIb). Intravital fluorescence videomicroscopy was used to visualize WBC (rhodamine 6G, intravenously), pial vessel diameters, and blood-brain barrier (BBB) integrity (Na+-fluorescein) at 6 hours (groups I, IIa, and III) or 1 hour (group IIb) after TBI. Group I (n = 5) consisted of sham-operated animals. Groups IIa (n = 7) and IIb (n = 5) received fluid-percussion injury at 1 hour. Group III (n = 7) received fluid-percussion injury and 1 mg/kg anti-adhesion monoclonal antibody (MoAb) "IB4" 5 minutes before injury. Venular WBC sticking, intracranial pressure (ICP), and arterial vessel diameters increased significantly for 6 hours after trauma. IB4 reduced WBC margination and prevented vasodilation. Intracranial pressure was not reduced by treatment with IB4. Blood-brain barrier damage occurred at 1 hour but not at 6 hours after TBI and was independent of WBC activation. This first report using intravital videomicroscopy to study the inflammatory response after TBI reveals upregulated interaction between WBC and cerebral endothelium that can be manipulated pharmacologically. White blood cell activation is associated with pial arteriolar vasodilation. White blood cells do not induce BBB breakdown less than 6 hours after TBI and do not contribute to posttraumatic ICP elevation. The role of WBC more than 6 hours after TBI should be investigated further.

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

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)