Passage of VIP / PACAP / Secretin Family Across the Blood-Brain Barrier: Therapeutic Effects

Abstract

In recent years, VIP/PACAP/secretin family has special interest. Family members are vasoactive intestinal peptide (VIP), pituitary adenylate cyclase-activating polypeptide (PACAP), secretin, glucagon, glucagon like peptide-1 (GLP(1)), GLP(2), gastric inhibitory peptide (GIP), growth hormone releasing hormone (GHRH or GRF), and peptide histidine methionine (PHM). Most of the family members present both in central nervous system (CNS) and in various peripheral tissues. The family members that are released into blood from periphery, especially gut, circulate the brain and they can cross the blood brain barrier. On the other hand, some of the members of this family that present in the brain, can cross from brain to blood and reach the peripheral targets. VIP, secretin, GLP(1), and PACAP 27 are transported into the brain by transmembrane diffusion, a non-saturable mechanism. However, uptake of PACAP 38 into the brain is saturable mechanism. While there is no report for the passage of GIP, GLP(2), and PHM, there is only one report that shows, glucagon and GHRH can cross the BBB. The passage of VIP/PACAP/secretin family members opens up new horizon for understanding of CNS effects of peripherally administrated peptides. There is much hope that those peptides may prove to be useful in the treatment of serious neurological diseases such as Alzheimer's disease, amyotropic lateral sclerosis, Parkinson's disease, AIDS related neuropathy, diabetic neuropathy, autism, stroke and nerve injury. Their benefits in various pathophysiologic conditions undoubtly motivate the development of a novel drug design for future therapeutics.

PACAP38 increases vesicular monoamine transporter 2 (VMAT2) expression and attenuates methamphetamine toxicity

“…However, most intriguing from the standpoint of neurological therapeutic development is that systemic administration of PACAP38 can have central nervous system effects by crossing the bloodbrain barrier (BBB) via a saturable transporter (Banks, et al 1993, Dogrukol-Ak, et al 2004). This transport efficiently allows systemic administration of PACAP to successfully prevent neuronal damage in models of stroke and ischemia (Uchida, et al 1996, Reglodi, et al 2002.…”

“…These properties make PACAP38 and its signaling pathways interesting therapeutic targets for the treatment and prevention of neurological disease. Most intriguing from the standpoint of neurological therapeutic development is that systemic administration of PACAP38 can have central nervous system effects by crossing the blood-brain barrier via a saturable transporter (Banks, et al 1993, Uchida, et al 1996, Dogrukol-Ak, et al 2004). …”

The Role of Insulin and Incretins in Neuroinflammation and Neurodegeneration

“…Passage of GLP-1 and GIP across the BBB occurs by simple diffusion [56,57] . The GIP receptor (GIPR) has been detected on neuronal cells, but is yet to be detected on microglia or astrocytes [58,59] .…”

Development of Simplified Vasoactive Intestinal Peptide Analogs with Receptor Selectivity and Stability for Human Vasoactive Intestinal Peptide/Pituitary Adenylate Cyclase-Activating Polypeptide Receptors

“…VIP is proposed to play a role in a number of disease states (Gozes and Furman, 2004), including a role in growth of cancer cells (Moody, 1996;Moody et al, 2003;Gozes and Furman, 2004), various central nervous system disorders (Gozes and Brenneman, 2000;Dogrukol-Ak et al, 2004;Gozes and Furman, 2004), various inflammatory disorders such as rheumatoid arthritis (Gozes and Brenneman, 2000), and various immunological disorders (Delgado et al, 2004), and a role has been proposed for VIP in treatment of asthma (Groneberg et al, 2001), impotence (Sandhu et al, 1999;Kalsi et al, 2002), and for treatment of septic shock (Kalsi et al, 2002;Delgado et al, 2004), central nervous system disorders (Gozes and Brenneman, 2000;Dogrukol-Ak et al, 2004), and diabetes (Yung et al, 2003).…”