# Postulated Role of Vasoactive Neuropeptide-Related Immunopathology of the Blood Brain Barrier and Virchow-Robin Spaces in the Aetiology of Neurological-Related Conditions

Authors: D. R. Staines; E. W. Brenu; S. Marshall-Gradisnik
Journal: Mediators of Inflammation
 (2008)

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## Abstract

Vasoactive neuropeptides (VNs) such as pituitary
adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide
(VIP) have critical roles as neurotransmitters, vasodilators including perfusion
and hypoxia regulators, as well as immune and nociception modulators.
They have key roles in blood vessels in the central nervous system (CNS)
including maintaining functional integrity of the blood brain barrier (BBB)
and blood spinal barrier (BSB). VNs are potent activators of adenylate cyclase and thus
also have a key role in cyclic AMP production affecting regulatory T cell and
other immune functions. Virchow-Robin spaces (VRSs) are perivascular compartments
surrounding small vessels within the CNS and contain VNs.
Autoimmunity of VNs or VN receptors may affect BBB and VRS function and,
therefore, may contribute to the aetiology of neurological-related conditions
including multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis.
VN autoimmunity will likely affect CNS and immunological homeostasis.
Various pharmacological and immunological treatments including phosphodiesterase inhibitors
and plasmapheresis may be indicated.


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## Body

## 1. Introduction

Vasoactive neuropeptides (VNs) (e.g., pituitary adenylate
cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP)) are widely distributed in the central nervous
system (CNS) and peripheral nervous system (PNS) including autonomic nervous
system (ANS) and peripheral tissues including heart, lung, pancreas, adrenal gland,
gonads, and gastrointestinal tract as well as immune cells and lymphatic
system [1].VNs have critical roles and functions as neurotransmitters and
neuroregulators, neurotrophic stimulators, hormonal regulators, vasodilators (including
perfusion and hypoxia regulators), as well as immune and nociception
modulators. They have key roles in blood vessel function in the CNSand contribute to high-level neurological
functions including memory and learning [2].
They have a well-described neuroprotective role [3] and act as
inflammatory mediators in microglial activation [4].VNs exert potent effects in metabolism as they have a vital role in
cyclic adenosine monophosphate (cAMP) production and regulation through
adenylate cyclase (AC) activation. Immunological dysregulation of vital
biochemical and/or epigenetic mechanisms affecting VNs resulting in down-regulation
of cAMP are possible pathways by which disease entities become manifest. Their
role along with other neurotrophic factors [5] in maintaining cAMP levels [6]
may be of vital importance for the integrity of blood brain barrier (BBB) and blood
spinal barrier (BSB).BBB and BSB have
traditionally been regarded as the main barriers between the brain and spinal
cord parenchyma and the intravascular compartment and are, therefore, important
in keeping immune cells and macromolecules from interfering with brain and
spinal neurological processes. However, disruption of BBB and BSBis well known in certain pathological states
suggesting that they function more as a “sieve” rather than an absolute
barrier.Virchow-Robin
spaces (VRSs) are compartments surrounding small vessels within the CNS
which contain interstitial fluid and, whilesome functional contact with
subarachnoid spaces may occur for solute exchange, they may not contain CSF as
commonly thought [7]. VRSs have important connections with lymphatic
drainage of the head and neck [8], having
intricate pial relations and providing a surface for
activity of neuropeptides, hormones, and cytokines. Pial cells may have a role in protecting the brain from exogenous
catecholamines [9], and VRS may have a complex role in leukocyte recruitment
across the BBB [10].VNs are known to have neuroprotective effects through hypoxia
protection on passage through the BBB [11] via a transport mechanism which enables
the intact peptides to enter the parenchymal space of the brain [12].
Additionally, VNs have protective effects on neurons and glial cells [13]. VNs may
have a significant role in blood BBB/BSB function and likely assist in immune regulation of VRS in the brain and spinal
cord. The present paper asserts that in view of the many vital roles of VNs in CNS neuroregulatory and immunological function
including BBB function, autoimmunity to VNs or VN receptors will have
significant effects on homeostasis resulting in disease states.


## 2. Vasoactive Neuropeptides in  Immunological Control

VNs exert influence over inflammatory control mechanisms including influencing
Th1 to Th2 shift, and the suppression of TNF alpha [14] has been established in
cAMP participation in vascular dysfunction involving endothelial cells [15].
The VRS has been identified as a location for immunoreactive lymphocytes in
penetration of neuronal parenchyma [16]. Also, VIP has been identified in connection with neuronal function and VRS suggesting that
VIP may have a regulatory function
associated with vasodilatation [17]. We assert that important immunoregulation
occurs in VRS and that this may involve VN regulation. Many regulatory
functions are dependent on IL-10 and IL-4, these may be compromised in VN
failure. Moreover, leakiness in BBB and BSB functions may encourage development or relapses in neurological conditions,
such as multiple sclerosis (MS) [18].Regulatory T cells (Tregs) function to control autoreactive T cells
in the periphery [19]. Moreover, Treg function is substantially influenced by
VNs [20] and may also have influence over Th17 direction [21]. Loss of Treg
function in VRS will, therefore, have significant implications for inflammatory
control. Moreover, Th17 development occurs under IL-6 and TGF beta influence [22],
and this may be a key switching point from a protective Treg to an autoimmune
Th17 phenotype. Certainly, Th1 and Th17 ratios are important in brain and spinal
inflammation regulation [23].Interestingly, a number of seemingly unrelated disorders may be
implicated in this postulated pathology. For example, Crohn's disease (CD) and MS
are inflammatory disorders with known Th1-directed cytokines and loss of Foxp3
Treg function [24, 25].As VRS have important roles in controlling macrophage and perivascular
infiltrates in MS [26], their immunological function in relation to VNs becomes
of considerable interest. Complement-fixing myelinolytic antigens have been
identified in the VRS in early MS [27], indicating the possible involvement of
VRS in immune activity.


## 3. Postulated Vasoactive Neuropeptide  Autoimmunity and the Blood Brain Barrier

VN autoimmunity has been postulated as a contributing cause for some
fatigue-related conditions [28]. The
present paper explores the possible role VN immune dysregulation may have on
VRS function and CNS activity as
this anatomical pathway may have a significant bearing on disease aetiology.Because VNs are widely distributed in the CNS,
neurovascular, and immune systems, they exert extraordinary influence on
neurological, vascular, and immunological functions. Significantly, VNs exert
mostly anti-inflammatory activities and loss of their function, for example,
through autoimmune compromise, could become manifest as unmodulated activation
of immune responses. Autoimmunity directed at VN guanine protein-coupled
receptors (GPCRs) is currently unproven and loss-of-function autoimmunity to
GPCRs generally is not widely documented. However, parallels exist with other
conditions such as Sjogren's syndrome which has T cell and/or B cell antibody
targeting of acetylcholine GPCRs [29]. The role of VNs in linking the innate
and acquired immune systems [30] suggests that there would be significant effects
on homeostasis if compromised.Pain, fatigue, and dysregulation of nociception may be prominent
features in these syndromes as a result of VN compromise in the CNS. Pain and nociception are mediated through
spinal and cerebral pathways particularly via spinothalamic, spinoreticular,
and spinomesencephalic structures. The periaqueductal grey (PAG) region surrounding the third ventricle and
cerebral aqueduct is a key area for regulation of noxious stimuli. This area
has high-density VN presence and may be a prominent target for VN autoimmune
compromise. Similarly, VRS have a critical role in maintaining the interstitial
fluid immunological milieu and may be a vulnerable area for VN compromise.It is likely that BBB, BSB, and VRS play an important role in
immunological maintenance and homeostasis within the CNS.
Macrophages in VRS express MHC class II antigens and interact with lymphocytes from the blood in initiating
and promoting immune responses to foreign antigens in the brain. Immunological
activity within VRS may have a role in a number of neurological conditions. Moreover,
sites deficient in BBB include the subarachnoid space and pial surface, and circumventricular
organs may be more prone to macromolecule penetration of CSF, and this may have
implications regarding autoimmune dysfunction within the CNS [31]. Collections
of macrophages may occur in VRS following trauma in a proinflammatory context  [32] and pathological dilatation of VRS may
occur from a variety of causes including ischaemia [33].VRS distribution in anatomically specific locations reflects the
functional attributes of these locations. For example, VRS in the nucleus
tractus solitarius in the dorsal medulla oblongata suggests they may have a
role in viscerosensory and autonomic functions [34]. Capillary diversity within the subfornical organ (SFO) and area
postrema (AP) may function as low-resistance pathways for the rapid dispersion
of blood-borne hormones inside their organ boundaries and this may have a role
in the regulation of blood pressure and body fluids [35]. Hence, these
functions linked to VRS microanatomy may be particularly susceptible to VN
compromise.


## 4. Postulated Cerebrovascular and CNS  Effects of VN Failure

Vascular compromise within the CNS possibly as a result of VN compromise may give rise to features consistent with
certain forms of dementia. Fronto-temporal dementia (FTD) is a
neurodegenerative disease in which a vascular component is suggested and
immunoreactivity of Bax, a proapoptotic protein regulated in part by VNs in
astrocytes, suggests a role for autoimmunity in the pathology of FTD [36]. Astrogliosis in FTD corresponds with
SPECT hypoperfusion, suggesting that astrocyte disruption may be related to disturbances
of cerebral perfusion in FTD [37]. Cognitive dysfunction is associated with
reduced cerebral blood flow in different types of dementia [38]. Moreover, VRS
dilatation associated with microvessel abnormality may contribute to the diagnosis
of vascular dementias [39]. Changes
in social behaviour occur in cerebrovascular comprise and may result from an
FTD-like syndrome [40]. Similarly, reduction in cortical blood flow has been
identified in CFS patients [41, 42];
however, these findings were not replicated in a study of twins with CFS [43].Astroglial water channel aquaporin (AQP4) is essential for the
maintenance of blood-brain barrier integrity [44]. Antibodies to AQP4 have a
highly specific role in neuromyelitis optica (NMO) and characteristically bind
to cerebral microvessels, pia mater, and VRSs [45]. Secretin is important for
other aquaporin expression via vasopressin. Secretin receptor-null mice, for
example, have reduced renal expression of AQP2 and AQP4 [46]. Interestingly, VIP, which is related to secretin, also has a
relationship with aquaporin distribution and function. An association with VRS
has been identified supporting the view that cortical nerve cells release VIP in the perivascular space during periods of
activity and thus contribute to local vasodilatation associated with neuronal
function. There is an important relationship whereby ATP over expression has a
down-regulatory impact on AQP4 expression [47]. Adenylate cyclase compromise could have an impact on ATP levels by
failure to convert to cAMP, arguably maintaining high levels of ATP with
adverse consequences for AQP4 function. Thus, VN failure may present with
dementia-like signs and symptoms.


## 5. Conclusions

Neurological conditions often present with fatigue and other
symptoms including memory and concentration loss, emotional lability, and
confusion. Multisystem involvement including cerebrospinal effects of these
conditions may be explained in part through VN compromise. In particular, cerebrovascular
and spinovascular compromise acting at the ultra-microscopic level involving
BBB and BSB may contribute to these
disorders. Compromise of VN receptors critical to BBB and BSB functioning may have a role in these disorders
and should be the subject of further research.This paper asserts that CNS vascular compromise including immunological dysfunction of the VRS may be
linked to postulated VN autoimmunity. Evidence for compromise of VN receptors
at different levels including VN receptor mRNA, protein transcription, cellular
migration and trafficking, cell membrane localisation, as well as possible
antibody or T cell targeting will be required to support this hypothesis.There are significant treatment implications from this hypothesis. VNs,
such as PACAP and VIP, exert potent effects in metabolism as they have a vital
role in cAMP production and regulation through AC activation. Phosphodiesterase
(PDE) enzymes metabolise cAMP as a
means of feedback regulation of cAMP levels. VN compromise will result in
impaired AC activation and hence impaired cAMP production. Thus,
phosphodiesterase inhibitors (PDEIs), novel therapeutic substances used to
promote cAMP levels, may have a role in treatment of VN autoimmune conditions.Proof of this hypothesis will require demonstration of pathological
antibodies or T cells specific to VN immunological pathology. Alternatively,
antagonistic variants of VNs themselves may exist.



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*Source: 792428-2009-02-16.xml*