Current Pharmaceutical Design - Volume 17, Issue 10, 2011

In 1970 and 1972, Sami Said and Victor Mutt identified and isolated “vasoactive intestinal polypeptide” (VIP) from porcine intestine based on its ability to increase peripheral blood flow and decrease arterial blood pressure in dogs [1,2]. In 1989 Akira Arimura and his colleagues isolated pituitary adenylate cyclase-activating polypeptide (PACAP) based on its ability to stimulate the production of cyclic AMP in rat pituitary cells [3]. VIP and PACAP serve as hormones, transmitters, modulators, and tropic factors, which act in both the central (CNS) and the peripheral nervous systems (PNS) through specific high-affinity receptors. Their actions are versatile and diverged within an organism as pleiotropic neuropeptides. In 1999, the laboratory of Illana Gozes in collaboration with the laboratory of Douglas Brenneman discovered the VIP-regulated activity-dependent neuroprotective protein (ADNP) and identified an ADNP derived peptide NAP (NAPVISPQ) [4]. NAP (davunetide) is now being developed as a drug candidate in progressive supreanuclear palsy, a rare fatal disease often misdiagnosed as Parkinson disease [5]. The various VIP and PACAP receptors are differentially expressed in discrete areas in the CNS and PNS as well as other peripheral organs and tissues. VIP and PACAP receptors have been identified in numerous tissues, and three different types are discerned. Two of these (VPAC1 and VPAC2) bind PACAP and VIP with similar high affinity. The third type, PAC1 is a PACAP specific receptor. PAC1 binds PACAP with high affinity and usually interacts with VIP only at high VIP concentration. PAC1 is also unique because it exists in at least thirteen different forms derived forms derived by alternate mRNA splicing. These different splice variants regulate receptor ligand affinity and specificity, and coupling to adenylte cylase and phosopholipase C pathways [6]. PAC1, VPAC1 and VPAC2 have been identified not only in the nervous system but in endocrine glands such as the pituitary, the thyroid, the gonads and the adrenal, as well as in the gastrointestinal tract, liver, pancreas, respiratory system, cardiovascular system, immune system, bones and tumor cells. Although a very large number of functions are described, it is likely that new roles for PACAP and VIP will be discovered followed by therapeutic applications. PACAP, VIP and its related peptides are shown to play very important roles in controlling homeostasis throughout the animal kingdom from sea squirt to humans. Both VIP and PACAP appear to play important, but distinct roles in circadian rhythms, nerve injury, ischemia and excitotoxicity, pain, epilepsy, schizophrenia, Alzheimer's disease, emotional and psychomotor behavior, neurodevelopment and immune response [6, 7, 8, 9, 10, 11, 12, 13, 14). In this special issue, leading international experts discuss most relevant topics on novel potential targets for VIP, PACAP and NAP. The special issue will strongly contribute to progress not only in basic research in this field but also in translational research and it may encourage moving forward toward human translational research. Finally, we would like to thank all the contributors to this special issue for their excellent participation.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic and multifunctional peptide exerting its effects via 3 main receptors (PAC1, VPAC1 and VPAC2). PACAP is now considered to be a potent neurotrophic and neuroprotective peptide. It plays an important role during the embryonic development of the nervous system. PACAP also protects neurons against various toxic insults in neuronal cultures of diverse origins. In vivo, PACAP shows neuroprotection in models of ischemic and traumatic brain injuries, and those of neurodegenerative diseases. The present review summarizes the findings on the neuroprotective potential of PACAP in models of neurodegenerative diseases, with special focus on in vitro and in vivo models of Parkinson's disease, Huntington chorea and Alzheimer's disease. Based on these observations, both endogenous and exogenously administered PACAP or its novel analogs, fragments offer a novel therapeutic approach in the treatment of neurodegenerative diseases.

After central nervous system (CNS) injury, reactive astrocytes display opposing functions, inducing neural repair and axonal regeneration via the release of growth factors, or forming a glial scar which acts as a barrier to axonal regeneration. Endogenous neural stem/progenitor cells have also recently been identified at the site of CNS injury, where they have been shown to differentiate into mature neurons in an animal model of ischemia. However, the pathophysiological mechanisms underpinning the contribution of reactive astrocytes and neural stem/progenitor cells to neural repair are still to be fully elucidated. Pituitary adenylate cyclase activating polypeptide (PACAP) is widely expressed in the CNS, where it has been shown to exert numerous biological effects. This review will summarize the current state of knowledge regarding the expression of PACAP and its receptors during neural development, as well as the involvement of PACAP in astrocytes and neural stem/progenitor cell biology. In addition, we will also discuss emerging evidence that implicates PACAP in neurogenesis and neural repair in response to brain pathophysiology.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide that functions as a neurotransmitter, neuromodulator and neurotrophic factor. Accumulating evidence implicates PACAP as an important regulator of both central and/or peripheral components of the stress axes, particularly exposure to prolonged or traumatic stress. Indeed, PACAP and its cognate receptors are widely expressed in the brain regions and peripheral tissues that mediate stress-related responses. In the sympathoadrenomedullary system, PACAP is required for sustained epinephrine secretion during metabolic stress. It is likely that PACAP regulates autonomic function and contributes to peripheral homeostasis by maintaining a balance between sympathetic and parasympathetic activity, favoring stimulation of the sympathetic system. Furthermore, PACAP is thought to act centrally on the paraventricular nucleus of the hypothalamus to regulate both the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Intriguingly, PACAP is also active in brain structures that mediate anxiety- and fear-related behaviors, and the expression of PACAP and its receptors are dynamically altered under pathologic conditions. Thus PACAP may influence both hard-wired (genetically determined) stress responses and gene-environment interactions in stress-related psychopathology. This article aims to overview the molecular mechanisms and psychiatric implications of PACAP-dependent stress responses.

Major Depressive Disorder (MDD) is a psychiatric condition that represents an important public health concern in modern society. Current pharmacological antidepressant treatments improve depressive symptoms through complex mechanisms that are incompletely understood. There is a consensus that in the clinic they act through the modulation of monoaminergic neurotransmission, primarily involving the serotonin and norepinephrine systems. Recent studies have suggested that action of antidepressants on synaptic plasticity is mediated by their regulatory influence not only upon small-molecule neurotransmitters, but also via neuropeptides which may act both as neurotransmitters and as neuromodulators. Prominent among these neuropeptides is PACAP, whose signaling system is intensively studied for its pleiotropic involvement in various physiological and pathological conditions. This review outlines the current knowledge concerning the PACAP signaling system's involvement in depressive disorders.

In neurological insults, such as cerebral ischemia and traumatic brain injury, complex molecular mechanisms involving inflammation and apoptosis are known to cause severe neuronal cell loss, emphasizing the necessity of developing therapeutic strategies targeting simultaneously these two processes. Over the last decade, numerous in vitro and in vivo studies have demonstrated the unique therapeutical potential of pituitary adenylate cyclase-activating polypeptide (PACAP) for the treatment of neuronal disorders involving apoptotic cell death and neuroinflammation. The neuroprotective activity of PACAP is based on its capacity to reduce the production of deleterious cytokines from activated microglia, to stimulate the release of neuroprotective agents from astrocytes and to inhibit proapoptotic intracellular pathways. However, the use of PACAP as a clinically applicable drug is hindered by its peptidic nature. As most natural peptides, native PACAP shows poor metabolic stability, low bioavailability, inadequate distribution and rapid blood clearance. Moreover, injection of PACAP to human can induce peripheral adverse side effects. Therefore, targeted chemical modifications and/or conjugation of PACAP to different macromolecules are required to improve the pharmacokinetic and pharmacological properties of PACAP. This review presents the chemical, biochemical and pharmacological strategies that are currently under development to convert PACAP from a hypophysiotropic neurohormone into a clinically relevant neuroprotective drug.

Multiple sclerosis (MS) is a progressive neurodegenerative disease affecting myelin and axons, which is perpetuated by autoreactive lymphocytes and other inflammatory cell types. Because of the multifactorial nature of this disease, therapies targeting a single process may not be sufficient to halt its progression. VIP and PACAP are two neuropeptides shown to regulate multiple aspects of innate and adaptive immunity, and can also act independently on neural cells to promote their survival and regeneration. Animal studies have proven the efficacy of these peptides for the treatment of several models of neural inflammatory disorders, including those which, like MS, have major Th1/Th17 components. In this review, the immunomodulatory actions of VIP and PACAP will be discussed, with particular emphasis on their potential significance in MS.

Excitotoxicity is a key molecular mechanism of perinatal brain damage and is associated with cerebral palsy and long term cognitive deficits. VIP induces a potent neuroprotection against perinatal excitotoxic white matter damage. VIP does not prevent the initial appearance of white matter lesion but promotes a secondary repair with axonal regrowth. This plasticity mechanism involves an atypical VPAC2 receptor and BDNF production. Stable VIP agonists mimic VIP effects when given systemically and exhibit a large therapeutic window. Unraveling cellular and molecular targets of VIP effects against perinatal white matter lesions could provide a more general rationale to understand the neuroprotection of the developing white matter against excitotoxic insults.

NAP (davunetide) is an eight amino acid peptide (NAPVSIPQ) that has been shown to provide potent neuroprotection, in vitro and in vivo. In human clinical trials, NAP has been shown to increase memory scores in patients suffering from amnestic mild cognitive impairment, a precursor to Alzheimer's disease and to enhance functional daily behaviors in schizophrenia patients. NAP is derived from activity-dependent neuroprotective protein (ADNP) a molecule that is essential for brain formation, interacting with the chromatin associated protein alpha and the chromatin remodeling complex SWI/SNF and regulating >400 genes during embryonic development. Partial loss in ADNP results in cognitive deficits and pathology of the microtubule associated protein tau (tauopathy) that is ameliorated in part by NAP replacement therapy. Recent studies increased the scope of NAP neuroprotection and provided further insights into the NAP mechanisms of action. Thus, it has been hypothesized that the presence of tau on axonal microtubules renders them notably less sensitive to the microtubule-severing protein katanin, and NAP was shown to protect microtubules from katanin disruption in the face of reduced tau expression. Parallel studies showed that NAP reduced the number of apoptotic neurons through activation of PI-3K/Akt pathway in the cortical plate or both PI-3K/Akt and MAPK/MEK1 kinases in the white matter. The interaction of these disparate yet complementary pathways is the subject of future studies towards human brain neuroprotection in the clinical scenario.