CNS Delivery Via Adsorptive Transcytosis

Adsorptive-mediated transcytosis (AMT) provides a means for brain delivery of medicines across the blood-brain barrier (BBB). The BBB is readily equipped for the AMT process: it provides both the potential for binding and uptake of cationic molecules to the luminal surface of endothelial cells, and then for exocytosis at the abluminal surface. The transcytotic pathways present at the BBB and its morphological and enzymatic properties provide the means for movement of the molecules through the endothelial cytoplasm. AMT-based drug delivery to the brain was performed using cationic proteins and cell-penetrating peptides (CPPs). Protein cationization using either synthetic or natural polyamines is discussed and some examples of diamine/polyamine modified proteins that cross BBB are described. Two main families of CPPs belonging to the Tat-derived peptides and Syn-B vectors have been extensively used in CPP vector-mediated strategies allowing delivery of a large variety of small molecules as well as proteins across cell membranes in vitro and the BBB in vivo. CPP strategy suffers from several limitations such as toxicity and immunogenicity—like the cationization strategy—as well as the instability of peptide vectors in biological media. The review concludes by stressing the need to improve the understanding of AMT mechanisms at BBB and the effectiveness of cationized proteins and CPP-vectorized proteins as neurotherapeutics

Chronic Inflammatory Pain Leads to Increased Blood-Brain Barrier Permeability and Tight Junction Protein Alterations

The blood-brain barrier (BBB) maintains brain homeostasis by limiting entry of substances to the central nervous system through interaction of transmembrane and intracellular proteins that make up endothelial cell tight junctions (TJs). Recently it was shown that the BBB can be modulated by disease pathologies including inflammatory pain. This study examined the effects of chronic inflammatory pain on the functional and molecular integrity of the BBB. Inflammatory pain was induced by injection of complete Freund\u27s adjuvant (CFA) into the right plantar hindpaw in female Sprague-Dawley rats under halothane anesthesia; control animals were injected with saline. Edema and hyperalgesia were assessed by plethysmography and infrared pawwithdrawal latency. At 72 h postinjection, significant edema formation and hyperalgesia were noted in the CFA-treated rats. Examination of permeability of the BBB by in situ perfusion of [14C]sucrose while rats were under pentobarbital anesthesia demonstrated that CFA treatment significantly increased brain sucrose uptake. Western blot analysis of BBB TJ proteins showed no change in expression of zonula occludens-1 (an accessory protein) or actin (a cytoskeletal protein) with CFA treatment. Expression of the transmembrane TJ proteins occludin and claudin-3 and -5 significantly changed with CFA treatment with a 60% decrease in occludin, a 450% increase in claudin-3, and a 615% increase in claudin-5 expression. This study demonstrates that during chronic inflammatory pain, alterations in BBB function are associated with changes in specific transmembrane TJ proteins

Chronic inflammatory pain leads to increased blood-brain barrier permeability and tight junction protein alterations

South face of the Eighth Pylon, detail of the east lateral tableau that depicts the massacre of the prisoners; The largest precinct is that of Amun, which is surrounded by a rectangular enclosure wall, orientated to the four points of the compass. This wall, built by Nectanebo I (reigned 380-362 BCE), was 2.5 km in length, with four monumental and four secondary gates. Inside it there are the levelled remains of previous ramparts, which show that the sacred precincts had been extended. The Temple of Amun was built on a mound that symbolized the first land to emerge from the primordial swamp. The Amun complex incorporated a Sacred lake, which was supposed to represent the swamp in which the sun-god Re first manifested himself. The extensions along the north-south axis comprise a succession of four pylons (VII-X) and triumphal gates, which separate four courts, including the 'Cachette Court'. The jubilee temple of Amenophis II (reigned ca. 1426-ca. 1400 BCE) straddled the east wall of the fourth court (between pylons IX and X). Source: Grove Art Online; http://www.groveart.com/ (accessed 1/19/2008