Inconsistent blood brain barrier disruption by intraarterial mannitol in rabbits: implications for chemotherapy

Abstract

The novel ability to quantify drug and tracer concentrations in vivo by optical means leads to the possibility of detecting and quantifying blood brain barrier (BBB) disruption in real-time by monitoring concentrations of chromophores such as Evan's Blue. In this study, experiments were conducted to assess the disruption of the BBB, by intraarterial injection of mannitol, in New Zealand white rabbits. Surgical preparation included: tracheotomy for mechanical ventilation, femoral and selective internal carotid artery (ICA) catheterizations, skull screws for monitoring electrocerebral activity, bilateral placement of laser Doppler probes and a small craniotomy for the placement of a fiber optic probe to determine tissue Evan's Blue dye concentrations. Evan's Blue (6.5 mg/kg) was injected intravenously (IV) just before BBB disruption with intracarotid mannitol (25%, 8 ml/40 s). Brain tissue concentrations of the dye in mannitol-treated and control animals were monitored using the method of optical pharmacokinetics (OP) during the subsequent 60 min. Hemo-dynamic parameters, heart rate, blood pressure, and EKG remained stable throughout the experiments in both the control and the mannitol-treated group. Brain tissue concentrations of Evan's Blue and the brain:plasma Evan's Blue partition coefficient progressively increased during the period of observation. A wide variation in brain tissue Evan's Blue concentrations was observed in the mannitol group. The experiments demonstrate the feasibility of measuring tissue concentrations of Evan's Blue without invading the brain parenchyma, and in real-time. The data suggest that there are significant variations in the degree and duration of BBB disruption induced with intraarterial mannitol. The ability to optically monitor the BBB disruption in real-time could provide a feedback control for hypertonic disruption and/or facilitate dosage control for chemotherapeutic drugs that require such disruption.

Noninvasive in vivo optical assessment of blood brain barrier permeability and brain tissue drug deposition in rabbits

“…7 In parallel studies, we had observed that BBBD in rabbits with IA mannitol was highly variable. 11,12 Similar variability in the degree of BBBD has also been reported in human subjects. 13 Such variability could have a very significant impact on the delivery of chemotherapeutic drugs that require BBBD.…”

Impact of Drug Size on Brain Tumor and Brain Parenchyma Delivery after a Blood–Brain Barrier Disruption

“…As the BBBD process can be highly variable between animals (for discussion on this topic, see Joshi et al 13 ), a large number of animals had to be included in each subgroup for this experiment. The data shown in Figure 2 represent the peak Gadomer concentration (mmol/L) in the treated hemisphere of animals injected at a specific delay after the BBBD procedure (Table 1).…”

“…10 One major weakness of this therapeutic strategy remains the intersubject variability in the BBB permeability; this is accompanied by an inherent difficulty in predicting and evaluating the extent of this permeability. 13 The extent of BBBD in preclinical studies has traditionally been studied with ex vivo brain samples using an Evan's blue staining technique, and consequently do not allow the follow-up of the animals. [13][14][15][16][17] Few studies have looked at the dynamic process of the BBBD, and the methodology used in these experiments typically required harvesting brain specimens at each time point, thereby preventing a longitudinal observation in a single subject.…”

“…13 The extent of BBBD in preclinical studies has traditionally been studied with ex vivo brain samples using an Evan's blue staining technique, and consequently do not allow the follow-up of the animals. [13][14][15][16][17] Few studies have looked at the dynamic process of the BBBD, and the methodology used in these experiments typically required harvesting brain specimens at each time point, thereby preventing a longitudinal observation in a single subject. 18,19 We have recently developed a new technique allowing the longitudinal in vivo study of the BBBD process by dynamic MRI.…”

Spatial mapping of drug delivery to brain tissue using hyperspectral spatial frequency-domain imaging

“…20,23,28,29 SFDI measurements could be introduced through a cranial window for the in vivo spatial mapping of brain pharmacokinetics. Data from spatially resolved pharmacokinetics could be used to develop multicompartment models for plasma and tissue concentrations in larger animal models where space is more appropriate for the limited resolution of the concentration maps.…”