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Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, 12, 323-332
323
VIP in Neurological Diseases: More Than A Neuropeptide
María Morell, Luciana Souza-Moreira and Elena González-Rey*
Instituto de Parasitología y Biomedicina "López-Neyra", Consejo Superior De Investigaciones Cientificas, Granada
18100, Spain
Abstract: A hallmark in most neurological disorders is a massive neuronal cell death, in which uncontrolled immune
response is usually involved, leading to neurodegeneration. The vasoactive intestinal peptide (VIP) is a pleiotropic peptide
that combines neuroprotective and immunomodulatory actions. Alterations on VIP/VIP receptors in patients with
neurodenegerative diseases, together with its involvement in the development of embryonic nervous tissue, and findings
found in VIP-deficient mutant mice, have showed the relevance of this endogenous peptide in normal physiology and in
pathologic states of the central nervous system (CNS). In this review, we will summarize the role of VIP in normal CNS
and in neurological disorders. The studies carried out with this peptide have demonstrated its therapeutic effect and render
it as an attractive candidate to be considered in several neurological disorders linked to neuroinflammation or abnormal
neural development.
Keywords: Neuroimmunology, neuroinflammatory diseases, neurological disorders, neuropeptides, VIP.
TISSUE EXPRESSION AND ACTIONS OF VIP AND
ITS RECEPTORS
VIP is a 28-amino acid peptide originally described in
lung and small intestine as a vasodilator [1]. VIP was later
identified in the central and peripheral nervous systems,
and recognized as a widely distributed neuropeptide
acting as a neurotransmitter/neuromodulator in numerous
organs, including heart, lung, thyroid gland, kidney,
pancreas, immune system, urinary tract and genital
organs [2]. According to its wide distribution, VIP plays a
role in numerous biological processes including systemic
vasodilatation, increased cardiac output, bronchodilatation,
hyperglycemia, smooth muscle relaxation, hormonal
regulation, analgesia, neurotrophic effects, learning and
behavior, bone metabolism, and gastric motility [3].
Recently, this pleiotropic neuropeptide was identified as a
key player in the immune system, involved in the
maintenance of neuroendocrine–immune communication
[4]. VIP is detected in the thymus, spleen, and lymph
nodes, where is released from nerve terminals and immune
cells, showing a therapeutic potential for a variety of
immune disorders [5]. It acts as a potent immunomodulatory
factor, regulating the balance between anti-and proinflammatory mediators, and restoring immune tolerance by
inducing regulatory T cells with suppressive activity against
autorreactive responses [6]. VIP exerts its broad range of
biological functions through specific membrane receptors,
VPAC1, VPAC2 and PAC1, belonging to class II G protein
–coupled receptor family. VIP-receptors are widely
distributed throughout the entire body, with special presence
in endocrine organs, immune tissues, and blood vessels
[7]. The binding of VIP to its receptors mainly triggers
the cAMP/protein kinaseA pathway that is considered
*Address correspondence to this author at the Instituto de Parasitología y
Biomedicina, Consejo Superior de Investigaciones Científicas. Avd/
Conocimiento. PT Ciencias de La Salud, Granada, 18100 Spain;
Tel: 34 958 181670; Fax: 34 958 181632; E-mail: [email protected]
2212-3873/12 $58.00+.00
an immunosuppressive signalling pathway, although binding
to PAC1 also involves intracellular calcium increase,
phospholipase D, and protein kinase C signalling [8-10].
VIP IN NORMAL ADULT BRAIN PHYSIOLOGY
VIP and its receptors are widely expressed in numerous
brain regions [3] (Fig. 1), suggesting an important role for
this neuropeptide in CNS. The neurotransmitter and
neuromodulatory activities of VIP include diverse actions as
rhythm generation in the suprachiasmatic nucleus [11, 12]
the regulation of neuroendocrine secretions in the
hypothalamus [13] and energy metabolism of glial cells [14].
Likewise, VIP modulates the hypothalamic-pituitary axis and
influences immune function through central VIPergic
neurons that interact with the CNS circuitry regulating
neural-immune interactions [15]. In addition, VIP influences
embryonic development of the nervous system [14],
glycogen metabolism in the cerebral cortex, and promotes
neuronal survival, mitosis, neurite sprouting of neuroblasts,
and glial cell proliferation, maturation or survival [15].
Moreover, VIP- containing neurons, transiently present,
serve as guideposts for thalamocortical axons coming in to
innervate specific cortical areas (reviewed in [15]). Indirect
effects of VIP on CNS include the expression and secretion
of neurotrophic factors, cytokines and chemokines from glial
cells [16-19]. VIP enhances the secretion of the astrocytederived protease nexin I (PNI), the activity-dependent
neurotrophic factor (ADNF), and the activity-dependent
neuroprotective protein (ADNP), by astrocytes [20, 21]. All
these factors mediate VIP-induced neuroprotection. PNI is a
known promoter of neurite outgrowth in cell culture and a
potent inhibitor of serine proteases that also enhances
neuronal cell survival [22]. The VIP-ADNF-neurotrophin 3
neuronal-glial pathway regulates glutamate responses from
an early stage in the synaptic development of excitatory
neurons and may also contribute to the known effects of VIP
on learning and behaviour in the adult nervous system [23].
Insulin-like growth factor 1 (IGF-1), nerve growth factor
© 2012 Bentham Science Publishers
324 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 4
(NGF), and brain-derived neurtrophic factor (BDNF) [24,
25] are also among factors regulated by VIP that contributes
to growth regulation and to the VIP-protective role following
neuronal injury.
Regarding VIP-receptors, different studies have suggested
a role for VPAC1 in learning and memory processes, while
VPAC2 seems to be involved in generating normal circadian
rhythms, clock gene expression, and behaviour, effects that
are also share by PAC1 [26-28] (Fig. 1). Recently, it has
been demonstrated that VPAC2 is up-regulated in reactive
astrocytes and that the VIP/VPAC2 system induces the upregulation of functional glutamate transporters limiting
excitotoxicity in neurological disorders and playing a key
role in neuroprotection [29]. Importantly, VIP receptors
are present in blood-brain barrier (BBB), where VIP
transmembranely diffused into the brain parenchyma [30].
Noteworthy is the presence of VIP receptors in CNS small
blood vessels surrounding perivascular compartments known
as Virchow-Robin spaces where VIP seems to be involved in
functional integrity of the BBB, affecting permeability,
coordination of neuroregulatory pathways, and protection
against neuronal apoptosis. A recent hypothesis suggests that
a potential autoimmunity against VIP or its receptors may
affect BBB function and alter CNS homeostasis promoting
the aetiology of some neurodegenerative processes [31].
ROLE OF VIP
DISORDERS
Morell et al.
IN
NEURODEVELOPMENTAL
VIP regulates different developmentally important events
in early postimplantation embriogenesis when the major
events are neural tube formation, neurogenesis and
expansion of the vascular system [reviewed in [32]].
Receptors for VIP appear during these events and exhibit
changing localization patterns throughout the development
of the brain. The administration of a VIP antagonist
during a critical period of neurogenesis (E9-11) resulted in
microcephaly, with a disproportionately greater inhibition of
brain growth compared to the rest of the body, while the
administration of the same antagonist later in gestation had
no detectable effect on embryonic growth [33]. Likewise,
VIP-antagonist administration during development has been
proved to affect the behaviours of the male adult animals that
exhibited reduced sociability and deficits in cognitive
function [34]. In humans, VIP expression has also been
detected in fetus and new born infant spinal cord [35]. These
results suggest that dysregulation of VIP during these
processes may have major and permanent consequences in
neuroanatomy, neurochemistry and behaviour and may be a
participating factor in disorders of neurodevelopment. In this
sense, VIP has been linked to autism, Down syndrome and
foetal alcohol syndrome.
Fig. (1). Brain distribution of VIP and VIP receptors. The figure shows the colocalization between VIP and its receptors in different brain
areas. VIP is expressed in cerebral cortex, limbic forebrain structures (septum, amygdala, hippocampus), thalamus, and hypothalamic areas.
VPAC1 mainly appears in cerebral cortex and hippocampus. VPAC2 is specially localized in the thalamus and suprachiasmatic nucleus, and
in lower levels in the hippocampus, cerebral cortex, periventricular nucleus, hypothalamus, spinal cord and dorsal root ganglia. PAC1 is
found in olfactory bulb, thalamus, hypothalamus, hyppocampal dentate gyrus, and granule cells of the cerebellum. Specific functions related
with each brain area are illustrated in the figure. Interaction between VIP and the receptors influences these functions. Binding of
VIP/VPAC1 induces neuroprotection. VIP/VPAC2 interaction normalizes circadian rhythm, contributes to insulin sensitivity, and regulates
production of proinflammatory cytokines. VIP/PAC1 mediates light-induced behaviour and gene expression, facilitates glucose homeostasis,
and also regulates inflammatory mediators. ANS: autonomic nervous system.
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325
VIP in Autism
VIP IN NEUROINFLAMMATORY DISEASES
Autism is a neurodevelopmental disorder in which
multiple genes interactions can be modified by
environmental factors [36]. It is characterized by impairment
of social behaviour, language, repetitive behaviours and
narrowly focused interests. Secondary symptoms include
mental retardation, cognitive dysfunction, gastric immunopathology [37], sleep disorders [38], and an increased
inflammatory response [39].
Besides of the crucial role of VIP during development of
the CNS, alterations on VIP levels in nervous tissues of
adults seem to be crucial in the onset and progression of
different neurodegenerative diseases such as multiple
sclerosis (MS), Parkinson’s and Alzheimer´s disease (PD
and AD, respectively). Conversely, neurological disorders
also induce important imbalances in VIP levels. Recent
evidences have demonstrated the implication of an
inflammatory component associated with neurodegeneration
in these neurological diseases, skipping the traditional
consideration regarding brain as an immune-privileged
organ. Today we know that under injury, trauma or infection,
CNS can develop an immune response, limited by the BBB
(which difficult the entry of immune cells, pathogens and
macromolecules), and regulated by the activation of
astrocytes and microglia. Under normal conditions, microglia,
which are ontogenetic representatives of peripheral
macrophages, are involved in immune defence against
infectious agents secreting cytotoxic factors and immune
modulators that protect the CNS, repair brain tissue, and
eliminate pathogens and cell debris [52]. Pathological
activation of microglia and astrocytes leads to persistent
inflammation causing neuronal death and contributes to the
progressive damage in neurological disorders (Fig. 2). In
acute CNS injury (ischaemic, brain trauma, and epilepsy),
proinflammatory cytokines and prostaglandins have showed
a direct involvement in neurodegeneration [53]. In chronic
CNS diseases, environmental factors, genetic background,
and ageing contribute to immune system activation, leading
to development/progression of MS, PD, and AD (reviewed
in [54]). Current treatments of these disorders using
some immunosuppressive drugs have been proven to delay
disease onset and reduce the relapse rate, although fail in
suppressing progressive clinical disability, supporting the
multifactorial component of these disorders. The neuroprotective and immunomodulatory role of VIP/VIP
receptors, clarified through findings with mutant mice, have
supported the potential role of VIP to be considered as an
important therapeutic strategy in these neuroinflammatory
diseases.
Evidences of VIP relationship with autism development
include: higher concentrations of VIP found in the blood
samples of newborn babies that subsequently develop autism
[40], the fact that VIP regulates the period of neural tube
closure that in humans is related with initiation of autism
[41], the immunomodulatory effect of VIP that might control
the increased production of proinflammatory cytokines
reported in autism [39], and the effect of VIP on sleep-wake
cycles that are dysregulated in autism [38]. In addition,
polymorphisms in the upstream region of the VPAC2
receptor gene suggest a potential link between this gene and
the gastrointestinal and stereotypical behaviours in autistic
persons [42].
VIP in Down Syndrome
Down syndrome is due to an additional copy of
chromosome 21 in humans and is the most common known
genetic cause of mental retardation. Some of the main
characteristics of this disorder such as growth restriction,
developmental delays, cognitive dysfunction, as well as
dystrophic neurons and dendritic spines [43], are found in
mice that have experienced blockage of VIP during
embryogenesis or neonatal development. Also, learning and
memory are disturbed in adult rats treated with
intracerebroventricular administration of a VIP antagonist
[44]. In addition, recent studies have shown that VIP
biochemistry is altered in the brains of segmental trisomy
mice showing more VIP binding sites, VIP mRNA and VIPimmunopositive cells [45].
VIP in Fetal Alcohol Syndrome
Maternal alcohol consumption is the most commonly
identified nongenetic cause of mental retardation [46]
in which children born with microcephaly, growth restriction
and central nervous system damage. There are important
known links between VIP and alcohol. During embriogenesis, alcohol exposure in the mouse caused a reduction in
VIP and VIP mRNA in the uterus (decidua, membranes
and embryo) and in the suprachiasmatic nucleus [47].
This results in growth abnormalities which are prevented
when ADNF and ADNP, both regulated by VIP, are used.
Alcohol also inhibits alpha adrenergic potentiation of VIPregulated cAMP and cGMP responses [48]. Additionally,
VIP binding is altered with alcohol administration [49]. As
blockage of VIP during mouse embryogenesis also results in
microcephaly, growth restriction and developmental delays
[50, 51], neurological deficits in fetal alcohol syndrome may
be related to an alcohol-induced imbalance of VIP during
early embryogenesis.
VIP in Ischemic Injury and Brain Trauma
Alterations in VIP levels could be observed in different
neural injuries, suggesting a neuroprotective role of VIP.
Following complete cerebral ischemia and posterior
reperfusion in rabbits, a progressive decrease in neurons
correlates with diminution of VIP levels [55]. Although
VIPergic neurons decrease in frontoparietal cortex and
hippocampus after transient forebrain ischemia, the number
of VIP+ neurons completely recovered 40 days after
reperfusion in cortex but not in hippocampus, suggesting a
specific neuropeptide distribution [56]. Decreased VIP levels
were also found in restorative processes following brain
lesions in rats [57]. In contrast, in other model systems of
neuronal injury, VIP expression is increased, probably as a
compensatory mechanism [58]. Likewise, administration of
VIP in a rat model of focal cerebral ischemia has shown to
enhance angiogenesis, increasing the levels of vascular
326 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 4
Morell et al.
Fig. (2). Neuroimmune interactions in pathological states of the CNS. In the healthy central nervous system (CNS), an immune
quiescent-like situation is showed, in which immune participation is related with neuron survival and brain protection. After CNS injury,
important differences could be observed in localization, distribution, size and composition of the lesions depending on their acute or chronic
properties. In acute CNS injury, such as brain trauma or ischemia, there is extensive haemorrhage, microglia activation, release of
proinflammatory cytokines and prostaglandins that contribute to the wound-healing response and debris elimination. However, continuous
presence of these mediators involves gliosis and neuronal cell death. In chronic CNS damage, as in multiple sclerosis, Alzheimer´s disease or
Parkinson´s disease, specific areas of the brain are affected by the activation of inflammatory and autorreactive cells. The exacerbated
immune responses can be developed by resident glia but also by infiltrating activated cells that reach the focal areas of the lesions through
the compromised brain vasculature. The unbalance in the different cells and molecular mediators leads to the neuronal damage, loss of
synaptic connections, and degeneration that, depending on the brain area that is affected, will result in loss of memory, changes in behaviour
or mechanical defects. BBB: blood-brain barrier.
endothelial growth factor and its receptors. VIP has shown to
increase PN1 expression in Schwann cells, regulating neural
survival and neurite outgrowth [59] and to elevate laminin
release, improving basement membrane assembly and axonal
function of Schwann cells. A clear example of the potential
of VIP in regeneration after trauma is the effect on
myelinization process. After transection of the sciatic nerve,
local administration of VIP elongates the axons increasing
the amount of myelin produced and accelerating the
regeneration process [60].
VIP in Neuroinflammation
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 4
VIP has been used in a mouse model of excitotoxic white
matter lesions which mimics perinatal brain injury [61]. This
problem is linked to prenatal hypoxia or ischemia, maternal
infection, genetic factors or dysregulation of growth factors
or proinflammatory cytokines, and currently there are few
therapies to treat perinatal injury. Intracerebroventricular
treatment with VIP simultaneously with damage induction
prevents excitotoxic cortical damage [61]. Inflammation is a
common feature in any kind of trauma in the CNS (Fig. 3). A
recent report indicated that VIP administration in a murine
model of stab wound brain trauma decreased many of the
pathological hallmarks that follow brain injury, i.e., dramatic
neurodegeneration, recruitment of mononuclear phagocytes,
a significant increase in activated microglia, and increased
production of TNF- and IL-1 [62]. These results showed
that administration of VIP is beneficial, at least in certain
327
regions of the brain, preventing neuronal cell loss in tissues
surrounding the lesion.
VIP in Multiple Sclerosis
Multiple sclerosis (MS) is a disabling inflammatory,
autoimmune demyelinating disease of the central nervous
system, in which reactive Th1 cells, specific to components
of the myelin sheath, infiltrate the CNS parenchyma, and
promote macrophage infiltration and activation. The
subsequent production of inflammatory mediators plays a
critical role in demyelination, oligodendrocyte loss, and
degenerative axonal pathology [63]. Interestingly, patients
with MS showed lower levels of VIP in cerebrospinal fluid
compared with healthy controls [64] and altered expression
of VIP receptors associated with aberrant Th1 immunity has
Fig. (3). Mechanisms of action of VIP on CNS during pathological conditions. Traumatic, ischemic, infections, and degenerative diseases
have in common the activation of the resident microglia that induces the secretion of inflammatory mediators, such as cytokines, free radicals
(i.e., nitric oxide, NO) and chemokines (CK), which contribute to the pathophysiological changes associated with these neuroimmunologic
disorders. Microglia-derived chemokines recruit immune cells that maintain the inflammatory response. Presentation of antigens by
microglia to patrolling or infiltrating T cells, contributes to further activation of glial cells. All these factors destroy invading pathogens but
also a prominent proinflammatory response in the CNS activates autorreactive cell populations that in turn will damage and kill neighboring
cells, such as neurons. In this context, VIP released by healthy neurons, coming from the blood through the compromised BBB vasculature,
or secreted by activated Th2-type immune cells can limit the inflammatory process. VIP downregulates the production of cytotoxic mediators
by microglia and decreases cell recruitment. It also deactivates effector Th1/Th17 responses diminishing the autoimmune component of these
diseases. VIP has an inhibitory direct effect over massive proliferation of astrocytes and decreases neuronal cell death. The neuroprotective
effects of VIP by inducing the production of neurotrophic factors by glia cells contribute to survival and regeneration. With this scenario,
VIP may be considered an attractive candidate with therapeutic potential on brain trauma and neurodegenerative disorders.
328 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 4
also been reported [65]. These data suggest a potential
involvement of VIP in the progression of this disease and
that the endogenous peptide might normally provide
protection against such pathology. Animal models of
experimental autoimmune encephalomyelitis (EAE), that
mimics human MS, have showed the therapeutic potential of
VIP against this disease. Administration of VIP ameliorated
the clinical and pathological manifestations of EAE.
The mechanisms of action include the regulation of
a wide spectrum of inflammatory mediators, blocking
encephalitogenic T-cell reactivity, and the induction of
regulatory T cells (Fig. 3). Importantly, VIP treatment was
therapeutically effective in established EAE and prevented
the recurrence of the disease [66]. Paradoxically, VIP KO
mice were almost completely resistant to EAE, with delayed
onset and mild or absent clinical profile. These mice
exhibited Th1/Th17 populations with encephalitogenic
potential as show by the analysis of phenotypic markers,
following antigenic-specific proliferation and cytokine
responses. However, histological analyses indicated that
VIP-deficient mice seem to have impaired parenchymal
infiltration [67]. These results may have important
therapeutic relevance and also indicate the complexity of the
role of VIP in this autoimmune neuroinflammatory disease.
VIP in Parkinson´s Disease
Parkinson's disease (PD) is a progressive neurodegenerative disease pathologically characterized by protein
aggregates found in intracellular inclusions in the substantia
nigra pars compacta (SNpc). This leads to progressive
deterioration of dopaminergic neurons in the SNpc and
subsequent loss of nerve projections in the striatum.
Consequently, the main clinical signs of PD are related with
mobility, stiffness, tremor, cognitive dysfunction, and mental
confusion. Genetic factors, environmental toxins, ageing, the
inflammatory process and oxidative damage are involved
[68]. During development, loss of the orphan nuclear
receptor Nurr1 function results in diminished VIP mRNA
and protein levels within the developing midbrain. Nurr1 is
required for the development of the ventral mesencephalic
dopaminergic neurons, the maturation of progenitors into
fully post-mitotic dopaminergic neurons, and their survival.
This suggests that VIP is a dopaminergic neuronal trophic
factor which is regulated by Nurr1 [69]. Likewise, different
groups have showed that VIP-containing neurons are not
affected in Parkinsonian patients, suggesting that VIP
neuronal systems are not involved in the course of dementing
process in Parkinson's disease [70]. However, levels of VIP
were significantly lower in Parkinsonian adrenal medullae
compared to levels predicted from the control group [71].
Other studies have demonstrated that VIP could protect
dopaminergic cells of mouse embryonic neurons from
inflammation induced by bacterial endotoxin LPS or the
neurotoxic agent MPTP by deactivating microglia and the
production of inflammatory cytotoxic factors (Fig. 3) [72].
VIP was also found to protect neurons against dopamine and
6-hydroxydopamine (6-OHDA) toxicity raising cellular
resistance against oxidative stress [73]. Systemically
administration of VIP was effective at reversing the motor
deficits in a rat model of Parkinson's disease, and decreasing
neuronal cell death, and myelin sheet loss, although did not
Morell et al.
restore the low dopamine levels. In addition, VIP attenuates
neuronal cell death by possibly inducing the release
of neuroprotective agents from brain mast cells, such as
nerve growth factor (NGF) [74, 75]. In a mouse model of
PD, VIP treatment significantly decreases MPTP-induced
dopaminergic neuronal loss in SNpc and nigrostriatal
nerve-fiber loss [72]. Recently, VIP has been used as an
adjuvant together with nitrated alpha synuclein (the main
protein found in intracellular aggregates in dopaminergic
neurons) for immunization in the MPTP murine model of
PD. In contrast to the exacerbated neuroinflammatory and
nigrostriatal degeneration elicited by immunization using
only nitrated alpha synuclein, VIP induced regulatory T cells
that affect positively to neural repair and protection reducing
dopaminergic degeneration [76]. In this study VIP-induced
Tregs were able to overcome the toxicities of effector T cells
that mediate nigrostriatal degeneration.
VIP in Alzheimer´s Disease
Alzheimer's disease (AD) is a progressive and
irreversible neurodegenerative disorder that affects the brain
and leads to dementia, with clinical onset usually occurring
in individuals over 65 years. The disease is characterized
by extracellular deposits of amyloid fibrils into senile
plaques and intracellular neurofibrillary deposition of tau
protein (microtubule-associated protein). The plaques
activate microglia and astrocytes that subsequently release
inflammatory mediators which cause oxidative damage, and
lead to neuronal death and mitochondrial dysfunction [77].
This neurodegeneration functionally involves the loss of
neurons and synapses in the cerebral cortex and certain
subcortical regions (hippocampus), resulting in cognitive
impairment and behavioural disorders. Initial studies using
post-mortem brains of patients with AD showed no
significant changes of VIP levels in different regions such as
the hippocampus, amygdale, thalamus, hypothalamus or
striatum [78]. In contrast, brain samples of patients with
Alzheimer -type dementia (ATD), showed a significant
reduction in vasoactive like inmunoreactivites [79]. The
differences in these studies could be related with the quality
of the sample, the stage of the disease, and the technical
procedure used to detect the neuropeptide. Other studies
have also shown that there is an altered processing of VIP
precursor in senile dementia of the Alzheimer type, and that
these alterations might have a significant role in the
pathogenesis of this disease [80]. Likewise, it has been
observed a basal activity of adenylate cyclase significantly
elevated in hippocampus and a higher sensibility of the
enzyme to VIP in samples from patients with Alzheimer’s
disease (AD) [81]. More recently, it has been shown that VIP
may have a therapeutic role in AD based on its immunomodulatory and neuroprotective actions. In vitro, VIP is able
to limit the release of neurotoxins produced by the betaamyloid induced microglia activation and, subsequently, to
decrease the neuronal cell death that leads to AD pathology
in the brain [82]. VIP binds to VPAC1 receptor blocking p38
MAPK and p42/p44 ERK, and initiating the cAMP/PKA
signalling pathway [82]. This pathway stimulates the
production of neuroprotective glial proteins, such as activitydependent neurotrophic factor ADNF that induces neuronal
survival [83]. Although more research in this field will help
VIP in Neuroinflammation
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 4
to understand the endogenous role of VIP, the results suggest
the potential therapeutic use of this peptide for the treatment
of this neurodegenerative disease.
VIP-RELATED THERAPEUTIC STRATEGIES IN
NEUROLOGICAL DISORDERS
The potential usefulness of VIP as a therapeutic agent in
treatment of neurological disorders is based on the important
role of VIP during development and the discovery of
anomalous VIP in human disorders of this kind. The main
advantage of using VIP is related with the wide spectrum of
action of this endogenous mediator versus agents directed
only against one component of these diseases. In addition,
VIP has been administered to humans for the treatment of
pulmonary hypertension or sarcoidosis without complications
or side effects [84, 85]. However, the use of VIP as a drug is
limited by its susceptibility to endopeptidases and its poor
passage across biological membranes. In this sense, VIP
analogues have been developed including cyclic molecules,
such as RO-25-1553, and fatty molecules, such as stearylnorleucine-VIP (SNV). These molecules have been
shown important therapeutic properties in CNS. RO-25-1553
stimulates in vivo neocortical astrocytogenesis [86], and
SNV promotes survival of cultured neurons and prevents in
vivo neuronal degeneration associated with beta-amyloid
toxicity [87]. The prevention of Alzheimer-like symptoms in
these mice indicated that VIP and VIP agonists might prove
useful in preventing the learning and memory deficits found
in many developmental disorders. To note, systemicallyinjected VIP analogues effectively protect the developing
white matter against excitotoxicity lesions in a mouse model
mimicking brain damage, even when VIP analogues were
given several hours after the insult [88]. VIP and SNV have
also been shown to protect PC12 cells and neuroblastoma
cells from the oxidative stress induced by 6-OHDA, proving
their possibilities in protecting dopaminergic neurons in
disorders such as PD [73]. Another issue to take into account
is the nature of VIP as a peptide that involves a short halflife which difficult crossing the blood brain barrier or the
placenta, and makes VIP a potential poor candidate for
neurological disorders in adults or during development.
However, intracerebroventricularly administered VIP is not
transported out of the brains suggesting that VIP released
from cephalic neurons is likely to remain in the brain.
More interesting, VIP transmembranely diffused into
the brain parenchyma with limited enzymatic degradation
after peripheral infusion [23]. In addition, both VIP and
VIP agonists can reach embryonic and fetal tissues
after intraperitoneal administration to pregnant mice [89],
demonstrating that prenatal application of these peptides can
act upon in utero developing tissues. Also, the peri- and
postnatal treatment with VIP and VIP analogs in animal
models also indicates that these peptides could be useful in
the treatment of newborns at risk for neurodevelopmental
disorder [32]. Recently, important progress has been made in
order to increase VIP half-life, and improve its targeted
tissue delivery. Aminoacid modifications or substitutions
have been proposed as a general strategy to increase
stability. Following this strategy, various VIP derivatives
were generated, which showed efficacy as an inhalable
powder formulation in a model of asthma/COPD [90, 91],
329
and they have tremendous promise for the clinic. The
development of metabolically stable VIP analogs might
represent a desirable approach for translational applications.
Understanding the structure/function relationship between
VIP and its receptors in physiological and pathological
situations is important to develop novel pharmacologic
agents. One possibility is the development of nonpeptide
receptor agonists. However, in the case of receptors for VIP
which belong to the type 2 GPCRs family, the industry has
failed so far in generating effective nonpeptide agonists [92].
By other hand, formulations based on micelles or liposomes
were also shown to continuously release neuropeptides in
vitro and in vivo [93]. However, the size of VIP-liposome
formulations could compromise their access to the target
organ. To avoid this problem, a recent study described a
formulation of silver-protected VIP nanoparticles which
functioned similar to naïve VIP deactivating microglia [94].
This study is an important approach as nanoparticlemediated drug delivery represents one promising strategy to
successfully increase the CNS penetration of several
therapeutic agents [95]. An additional problem for using VIP
is that this neuropeptide has widespread actions in the body
and increases or blockage of the peptide might result in
undesirable side effects. Major progressions have been made
in this sense and various groups have tried to implement
some of the tools used for gene therapy in other diseases as
an alternative to improve delivery of VIP to target tissues.
Recently, it was evaluated the efficacy of lentiviral vectors
expressing VIP in a model of autoimmune arthritis [96].
However, these vectors integrate in almost all cells when
administered systemically. A potential improvement could
be the use of combined gene-cell therapy, in which the
neuropeptide-containing vector is integrated in a certain cell
ex vivo before inoculation. Following this strategy, it was
demonstrated recently that dendritic cells transduced with
lenti-VIP vectors during differentiation have a therapeutic
effect on EAE [97]. The DCs migrate to the inflamed/injured
site and peripheral lymphoid organs and secrete continuously
VIP. This strategy not only increases the efficacy of
the treatment but also addresses the selectivity/safety
issue. Other strategies include the use of the downstream
activators of VIP, ADNF and ADNP, or NAP, an active
motif of ADNP, which is neuroprotective in abroad range of
neurodegenerative disorders [98].
CONCLUSION
Neurodevelopmental disorders that include an imbalance
of VIP during embryogenesis highlight the potential of
VIP as a therapeutic agent in CNS disorders. In addition,
immunomodulatory and neurotrophic properties of VIP
highly support its therapeutic use on neuroinflammatory
disorders. However, delivery of VIP to the CNS for the
treatment of neurodegenerative disorders is restricted due to
the limitations posed by the BBB as well as due to
degradation by plasma proteins in the systemic circulation
and potential peripheral side effects. To overcome these
disadvantages, therapeutic strategies using new agonists,
research about new administration routes for the peptide/
agonists or peptide derivatives, or improving tools for
protection and delivery are currently on development.
Coming years will therefore elucidate whether, or not, the
330 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 4
promising beneficial effects of VIP in animal models of
neuropathological disorders will be translated into clinical.
[17]
[18]
CONFLICT OF INTEREST
[19]
The author(s) confirm that this article content has no
conflict of interest.
[20]
ACKNOWLEDGEMENTS
We thank the many researchers and laboratories that have
contributed to our current understanding of the fundamental
role that Vasoactive Intestinal Peptide play in neurological
diseases. This work was supported by grant from the Spanish
Ministry of Science and Innovation.
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Received: 24 March, 2011
Accepted: 29 March, 2012
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