Alkylglycerol opening of the blood-brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries.

1. The blood-brain barrier (BBB) represents the major impediment to successful delivery of therapeutic agents to target tissue within the central nervous system. Intracarotid alkylglycerols have been shown to increase the transfer of chemotherapeutics across the BBB. 2. We investigated the spatial distribution of intracarotid fluorescein sodium and intravenous lissamine-rhodamine B200 (RB 200)-albumin in the brain of normal and C6 glioma-bearing rats after intracarotid co-administration of 1-O-pentylglycerol (200 mm). To elucidate the mechanisms involved in the alkylglycerol-mediated BBB opening, intraluminal accumulation of fluorescein isothiocyanate (FITC)-dextran 40,000 was studied in freshly isolated rat brain capillaries using confocal microscopy during incubation with different alkylglycerols. Furthermore, 1-O-pentylglycerol-induced increase in delivery of methotrexate (MTX) to the brain was evaluated in nude mice. 3. Microscopic evaluation showed a marked 1-O-pentylglycerol-induced extravasation of fluorescein and RB 200-albumin in the ipsilateral normal brain. In glioma-bearing rats, increased tissue fluorescence was found in both tumor tissue and brain surrounding tumor. Confocal microscopy revealed a time- and concentration-dependent accumulation of FITC-dextran 40,000 within the lumina of isolated rat brain capillaries during incubation with 1-O-pentylglycerol and 2-O-hexyldiglycerol, indicating enhanced paracellular transfer via tight junctions. Intracarotid co-administration of MTX and 1-O-pentylglycerol (200 mm) in nude mice resulted in a significant increase in MTX concentrations in the ipsilateral brain as compared to controls without 1-O-pentylglycerol (P<0.005). 4. In conclusion, 1-O-pentylglycerol increases delivery of small and large compounds to normal brain and brain tumors and this effect is mediated at least in part by enhanced permeability of tight junctions.

Anterograde projections of the motorcortical tongue area in the saddle-back tamarin (Saguinus fuscicollis).

In the New World monkey Saguinus fuscicollis, the anterograde projections of the motorcortical tongue area were studied. Three animals were analyzed. In two, biotin dextran amine was used as tracer; in the third, Phaseolus vulgaris leucoagglutinin was used. Identification of the tongue area was carried out by electrical brain stimulation. Intracortical projections were found into the neighboring primary motor cortex, ventral premotor cortex, frontoopercular cortex, and primary and secondary somatosensory cortex. Projections also ended in the ventrolateral prefrontal cortex, orbital cortex, supplementary motor area, anterior cingulate cortex and agranular as well as granular insula. In addition, weaker labeling was found in the inferior and dorsal parietal cortex, and perirhinal and inferotemporal cortex. Subcortically, there was a heavy projection into the ventral putamen, a moderate projection into the caudate nucleus and claustrum, and a weak projection into the anterior, central and lateral amygdala. In the thalamus, terminal labeling was found in the nuclei ventralis posterior medialis, ventralis lateralis, reticularis, centralis lateralis, medialis dorsalis, pulvinaris oralis, centrum medianum, reuniens and suprageniculatus in an order of intensity. Subthalamically, weak projections could be traced into the zona incerta and lateral hypothalamus. In the midbrain, labeling was found in the deep layers of the colliculus superior, area praetectalis, dorsal reticular formation and, very sparsely, in the periaqueductal gray. In the lower brainstem, fibers ended in the griseum pontis, medial and lateral parabrachial nuclei, lateral pontine and medullary reticular formation, paramedian and dorsal reticular nuclei, solitary tract nucleus and principal as well as spinal trigeminal nuclei. No terminals were found in the hypoglossal nucleus itself; there were, however, terminals in the immediately bordering reticular formation.