Lipopolysaccharide alters the blood-brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer's disease.

Alzheimer's disease (AD) brains are characterized by accumulation of amyloid beta protein (Abeta) and neuroinflammation. Increased blood-to-brain influx and decreased brain-to-blood efflux across the blood-brain barrier (BBB) have been proposed as mechanisms for Abeta accumulation. Epidemiological studies suggest that the nonsteroidal anti-inflammatory drug (NSAID) indomethacin slows the progression of AD. We hypothesized that inflammation alters BBB handling of Abeta. Mice treated with lipopolysaccharide (LPS) had increased brain influx and decreased brain efflux of Abeta, recapitulating the findings in AD. Neither influx nor efflux was mediated by LPS acting directly on BBB cells. Increased influx was mediated by a blood-borne factor, indomethacin-independent, blocked by the triglyceride triolein, and not related to expression of the blood-to-brain transporter of Abeta, RAGE. Serum levels of IL-6, IL-10, IL-13, and MCP-1 mirrored changes in Abeta influx. Decreased efflux was blocked by indomethacin and accompanied by decreased protein expression of the brain-to-blood transporter of Abeta, LRP-1. LPS paradoxically increased expression of neuronal LRP-1, a major source of Abeta. Thus, inflammation potentially increases brain levels of Abeta by three mechanisms: increased influx, decreased efflux, and increased neuronal production.

Endothelial-specific knockdown of interleukin-1 (IL-1) type 1 receptor differentially alters CNS responses to IL-1 depending on its route of administration.

Interleukin-1 (IL-1) has been implicated as a critical mediator of neuroimmune communication. In the brain, the functional receptor for IL-1, type 1 IL-1 receptor (IL-1R1), is localized primarily to the endothelial cells. In this study, we created an endothelial-specific IL-1R1 knockdown model to test the role of endothelial IL-1R1 in mediating the effects of IL-1. Neuronal activation in the hypothalamus was measured by c-fos expression in the paraventricular nucleus and the ventromedial preoptic area. In addition, two specific sickness symptoms, febrile response and reduction of locomotor activity, were studied. Intracerebroventricular injection of IL-1 induced leukocyte infiltration into the CNS, activation of hypothalamic neurons, fever, and reduced locomotor activity in normal mice. Endothelial-specific knockdown of IL-1R1 abrogated all these responses. Intraperitoneal injection of IL-1 also induced neuronal activation in the hypothalamus, fever, and reduced locomotor activity, without inducing leukocyte infiltration into the brain. Endothelial-specific knockdown of IL-1R1 suppressed intraperitoneal IL-1-induced fever, but not the induction of c-fos in hypothalamus. When IL-1 was given intravenously, endothelial knockdown of IL-1R1 abolished intravenous IL-1-induced CNS activation and the two monitored sickness symptoms. In addition, endothelial-specific knockdown of IL-1R1 blocked the induction of cyclooxygenase-2 expression induced by all three routes of IL-1 administration. These results show that the effects of intravenous and intracerebroventricular IL-1 are mediated by endothelial IL-1R1, whereas the effects of intraperitoneal IL-1 are partially dependent on endothelial IL-1R1.

Ghrelin controls hippocampal spine synapse density and memory performance.

The gut hormone and neuropeptide ghrelin affects energy balance and growth hormone release through hypothalamic action that involves synaptic plasticity in the melanocortin system. Ghrelin binding is also present in other brain areas, including the telencephalon, where its function remains elusive. Here we report that circulating ghrelin enters the hippocampus and binds to neurons of the hippocampal formation, where it promotes dendritic spine synapse formation and generation of long-term potentiation. These ghrelin-induced synaptic changes are paralleled by enhanced spatial learning and memory. Targeted disruption of the gene that encodes ghrelin resulted in decreased numbers of spine synapses in the CA1 region and impaired performance of mice in behavioral memory testing, both of which were rapidly reversed by ghrelin administration. Our observations reveal an endogenous function of ghrelin that links metabolic control with higher brain functions and suggest novel therapeutic strategies to enhance learning and memory processes.

Antagonists of growth hormone-releasing hormone cross the blood-brain barrier: a potential applicability to treatment of brain tumors.

Hypothalamic growth hormone (GH)-releasing hormone (GHRH) stimulates the synthesis and release of GH from the pituitary gland. GHRH and its mRNA are also found in human cancers of the breast, ovary, prostate, lung, and other tumors, suggesting that GHRH is also a tumor growth factor. Various studies show that GHRH antagonists have antiproliferative effects in many tumor models; however, glioblastomas were examined only recently. Previous studies have demonstrated that s.c. administration of GHRH antagonist (JV-1-36) inhibited growth of s.c. U-87MG human glioblastomas and increased survival of nude mice with orthotopic implants of glioblastomas. Although treatment with JV-1-36 reduced tumorigenicity, it is not known whether peripherally administered GHRH antagonists can cross the blood-brain barrier. Brain endothelial cells joined by tight junctions form the blood-brain barrier, a "barrier" between the general circulation and the CNS. In this study, we administered a GHRH antagonist (JV-1-42) and showed that, after i.v. injection, iodinated JV-1-42 (131I-JV-1-42) enters the brain intact at a rate of 0.8514 mocrol/g per min with a serum half-life of 12.2 min. A one-site binding hyperbolic model indicated that the maximal percent of i.v. dose taken up per gram of brain was 0.41%. Coinjection of unlabeled JV-1-42 indicated that the transport from blood to brain is not saturable; however, transport from brain to blood is saturable and involves P-glycoprotein. Taken together, these results demonstrate that i.v.-administered 131I-JV-1-42 readily crosses the blood-brain barrier and accumulates in the brain. This finding indicates that GHRH antagonists could provide a potential treatment for malignant glioblastomas.

Antisense therapeutics and the treatment of CNS disease.

Antisense oligonucleotides (ONs) have great therapeutic potential for conditions in which aberrant protein production results in pathology. This method of reducing the expression of a target gene is both precise and sequence-specific. Although there are many applications for antisense ONs as central nervous system (CNS) therapeutics, systemically administered antisense ONs must be capable of crossing the blood-brain barrier (BBB) in quantities effective enough to alter protein production in the CNS. Because antisense ONs are large, highly polar molecules, their rate of transport across the BBB is likely to be low. Recent studies have shown that antisense ONs are capable of crossing the BBB without the aid of a carrier system, however little is known about the molecular mechanisms which mediate this transport. This review will focus on nucleic acid chemistries suitable for in vivo research and their potential applications in the treatment of CNS disease.