vasoactive-intestinal-peptide and Brain-Diseases

Inflammatory processes play both regenerative and destructive roles in multiple sclerosis, stroke, CNS trauma, amyotrophic lateral sclerosis and aging-related neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's. Endogenous defence mechanisms against these pathologies include those that are directly neuroprotective, and those that modulate the expression of inflammatory mediators in microglia, astrocytes, and invading inflammatory cells. While a number of mechanisms and molecules have been identified that can directly promote neuronal survival, less is known about how the brain protects itself from harmful inflammation, and further, how it co-opts the healing function of the immune system to promote CNS repair. The two closely related neuroprotective peptides, vasoactive intestinal peptide (VIP) and pituitary adenylyl cyclase-activating peptide (PACAP), which are up-regulated in neurons and immune cells after injury and/or inflammation, are known to protect neurons, but also exert powerful in vivo immunomodulatory actions, which are primarily anti-inflammatory. These peptide actions are mediated by high-affinity receptors expressed not only on neurons, but also astrocytes, microglia and peripheral inflammatory cells. Well-established immunomodulatory actions of these peptides are to inhibit macrophage and microglia production and release of inflammatory mediators such as TNF-α and IFN-γ, and polarization of T-cell responses away from Th1 and Th17, and towards a Th2 phenotype. More recent studies have revealed that these peptides can also promote the production of both natural and inducible subsets of regulatory T-cells. The neuroprotective and immunomodulatory actions of VIP and PACAP suggest that receptors for these peptides may be therapeutic targets for neurodegenerative and neuroinflammatory diseases and other forms of CNS injury.

Topics: Animals; Brain Diseases; Central Nervous System; Humans; Ligands; Models, Biological; Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Vasoactive Intestinal Peptide; Signal Transduction; Spinal Cord Diseases; Vasoactive Intestinal Peptide

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.

Topics: Animals; Aquaporin 4; Blood-Brain Barrier; Brain; Brain Diseases; Humans; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide

The suprachiasmatic nuclei of the hypothalamus (SCN) are the site of the master circadian clock in mammals. The SCN clock is mainly entrained by the light-dark cycle. Light information is conveyed from the retina to the SCN through direct, retinohypothalamic fibres. The SCN also receive other projections, like cholinergic fibres from basal forebrain. To test whether cholinergic afferents are involved in photic resetting, lesions of cholinergic projections were performed in rats with intracerebroventricular (i.c.v.) injections or intra-SCN microinjections of 192 IgG-saporin. When injected in the SCN, this immunotoxin destroys the cholinergic projections and retinohypothalamic afferents that express p75 low-affinity nerve growth factor (p75(NGF)) receptors. The extent of lesions in the basal forebrain and SCN was assessed by acetylcholinesterase histochemistry, p75(NGF) receptor, choline acetyl-transferase, calbindin-D28K and VIP immunocytochemistry. The intra-SCN treatment reduced light-induced phase advances by 30%, and induced a complete loss of forebrain and retinal afferents expressing p75(NGF) receptors within the SCN and a decrease of forebrain cholinergic neurons, most likely those projecting to the SCN. The i.c.v. treatment reduced light-induced phase advances by 40%, increased phase delays and led to extensive damage of forebrain p75(NGF)-expressing neurons, while sparing half of the fibres expressing p75(NGF) receptors (retinal afferents?) in the SCN. Because the integrity of forebrain p75(NGF)-expressing neurons appears to be critical in mediating the effects on light-induced phase advances, we therefore suggest that anterior cholinergic projections expressing p75(NGF) receptors modulate the sensitivity of the SCN clock to the phase advancing effects of light.

Topics: Acetylcholine; Acetylcholinesterase; Animals; Antibodies, Monoclonal; Body Temperature; Brain Diseases; Calbindin 1; Calbindins; Cell Count; Cholinergic Fibers; Circadian Rhythm; Denervation; Drug Administration Routes; Immunohistochemistry; Immunotoxins; Light; Male; Medial Forebrain Bundle; Motor Activity; N-Glycosyl Hydrolases; Prosencephalon; Psychomotor Performance; Rats; Rats, Long-Evans; Receptor, Nerve Growth Factor; Receptors, Nerve Growth Factor; Ribosome Inactivating Proteins, Type 1; S100 Calcium Binding Protein G; Saporins; Staining and Labeling; Suprachiasmatic Nucleus; Time Factors; Vasoactive Intestinal Peptide

Intracerebral administration of ibotenate produces, through activation of N-methyl-D-aspartate (NMDA) receptors, neuronal heterotopias in the newborn hamster neocortex: high doses of ibotenate induce periventricular and subcortical neuronal heterotopias, while low doses of ibotenate produce intracortical heterotopias and molecular layer ectopias. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are closely related peptides with neurotrophic properties. They share common VPAC1 and VPAC2 receptors, which use cAMP as a second messenger. Previous studies have shown that VIP prevents excitotoxic neuronal death and exacerbates glutamate-induced c-fos neuronal expression. In order to gain new insight into the molecular control of neuronal migration, the present study examined the effects of VIP and PACAP on ibotenate-induced heterotopias in the newborn hamster. Co-treatment with VIP and a high dose of ibotenate produced a pattern of neuronal heterotopias similar to the one observed in animals treated with low doses of ibotenate alone. Pups co-injected with a low dose of ibotenate and a VIP antagonist displayed cortical dysgeneses similar to those observed in animals treated with high doses of ibotenate alone. The modulating effects of VIP on excitotoxin-induced heterotopias were mimicked by forskolin, PACAP, and by a specific VPAC2 receptor agonist but not by a VPAC1 agonist, and were blocked by a protein kinase A (PKA) inhibitor. Taken together, these data suggest that VIP and PACAP can attenuate ibotenate-induced heterotopias in newborn hamster and that this effect is mediated by the VPAC2 receptor utilizing the cAMP-PKA pathway.

Topics: Animals; Animals, Newborn; Binding Sites; Brain Diseases; Choristoma; Cricetinae; Drug Synergism; Ibotenic Acid; Mesocricetus; Neocortex; Nerve Tissue; Neuropeptides; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide

Intracerebral administration of the excitotoxin ibotenate to newborn mice induces white matter lesions mimicking periventricular leukomalacia, the most frequent brain lesion occurring in premature human babies. In this model, coinjection of vasoactive intestinal peptide prevents white matter lesions. In the present study, coadministration of ibotenate, vasoactive intestinal peptide, and selective transduction inhibitors showed that protein kinase C and mitogen-associated protein kinase pathways were critical for neuroprotection. In vivo and in vitro immunocytochemistry revealed that vasoactive intestinal peptide activated protein kinase C in astrocytes and neurons, and mitogen-associated protein kinase in neurons. In vitro neuronal transduction activation was indirect and required medium conditioned by astrocytes in which protein kinase C had been activated by vasoactive intestinal peptide. Although vasoactive intestinal peptide did not prevent the initial in vivo appearance of white matter lesion, it promoted a secondary repair of this lesion with axonal regrowth. Through protein kinase C activation, vasoactive intestinal peptide also prevented ibotenate-induced white matter astrocyte death. These data support the following hypothetical model: Vasoactive intestinal peptide activates protein kinase C in astrocytes, which promotes astrocytic survival and release of soluble factors; these released factors activate neuronal mitogen-associated protein kinase and protein kinase C, which will permit axonal regrowth.

Topics: Animals; Animals, Newborn; Astrocytes; Axons; Brain; Brain Diseases; Calcium-Calmodulin-Dependent Protein Kinases; Cell Death; Cells, Cultured; Cerebral Cortex; Cysts; Excitatory Amino Acid Agonists; Ibotenic Acid; Immunohistochemistry; Mice; Neurons; Neuroprotective Agents; Neurotoxins; Protein Kinase C; Signal Transduction; Vasoactive Intestinal Peptide

Stearyl-Nle17-VIP (SNV) is a novel agonist of vasoactive intestinal peptide (VIP) exhibiting a 100-fold greater potency than the parent molecule and specificity for a receptor associated with neuronal survival. Here, mice deficient in apolipoprotein E (ApoE), a molecule associated with the etiology of Alzheimer's disease, served as a model to investigate the developmental and protective effects of SNV. In comparison to control animals, the deficient mice exhibited (a) reduced amounts of VIP messenger RNA; (b) decreased cholinergic activity (c) significant retardation in the acquisition of developmental milestones: forelimb placing behavior and cliff avoidance behavior; and (d) learning and memory impairments. Daily injections of SNV to ApoE-deficient newborn pups resulted in increased cholinergic activity and marked improvements in the time of acquisition of behavioral milestones, with peptide-treated animals developing as fast as control animals and exhibiting improved cognitive functions after cessation of peptide treatment. Specificity was demonstrated in that treatment with a related peptide (PACAP), pituitary adenylate cyclase-activating peptide, produced only limited amelioration. As certain genotypes of ApoE increase the probability of Alzheimer's disease, early counseling and preventive treatments may now offer an important route for therapeutics design.

Topics: Alzheimer Disease; Animals; Apolipoproteins E; Brain; Brain Diseases; Choline O-Acetyltransferase; Cholinergic Fibers; Learning; Memory Disorders; Mice; Mice, Knockout; Neuropeptides; Neuroprotective Agents; RNA, Messenger; Vasoactive Intestinal Peptide

Perivascular innervation in cerebral arteries of spontaneously hypertensive rats and of normotensive Wistar-Kyoto rats was studied. Adrenergic nerve fibers and neuropeptide Y-containing nerve fibers, indicative of vasoconstrictor nerves, were denser in all cerebral arteries of spontaneously hypertensive rats than those of Wistar-Kyoto rats. In contrast, cholinergic nerve fibers and vasoactive intestinal polypeptide, substance P-containing nerve fibers, indicative of vasodilator nerves, remained unchanged in all cerebral arteries of spontaneously hypertensive rats, as compared with findings in the Wistar-Kyoto rats. Thus, not only adrenergic nerve fibers but also neuropeptide Y-containing nerve fibers may play an important role in preventing the disruption of the blood-brain barrier and the development of hypertensive encephalopathy in spontaneously hypertensive rats.

Topics: Adrenergic Fibers; Animals; Brain Diseases; Cerebral Arteries; Cholinergic Fibers; Hypertension; Immunohistochemistry; Male; Neuropeptide Y; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Substance P; Vasoactive Intestinal Peptide; Vasoconstriction; Vasodilation

The effects of lesions of the suprachiasmatic (SCN) and paraventricular nuclei (PVN) of the hypothalamus on photoperiodic responses were examined in adult Siberian hamsters. SCN lesions reduced nocturnal water intake in long days, whereas PVN lesions increased body weight and food intake in both short and long days. SCN or PVN lesions blocked short-day-induced decreases in body, fat pad, and testes weights and in food intake. Serum prolactin (PRL), but not follicle-stimulating hormone, levels were increased. The distribution of immunostained neurons and fibers for gonadotropin-releasing hormone (GnRH), beta-endorphin, arginine vasopressin (AVP), and vasoactive intestinal polypeptide (VIP) resembled that of other rodent species. Short-day exposure reduced AVP staining in lateral septum, medial amygdala, and bed nucleus of the stria terminalis but not in the PVN of the thalamus or the SCN. Short-day-exposed hamsters had fewer beta-endorphin-positive arcuate nucleus cells and tended to have fewer GnRH-positive preoptic cells than long-day controls. VIP staining was unaffected by photoperiod. Most day length effects on immunostaining were eliminated by either lesion. These results establish the importance of the SCN and PVN in the photoperiodic control of several seasonal responses in Siberian hamsters.

Topics: Analysis of Variance; Animals; Arginine Vasopressin; beta-Endorphin; Body Weight; Brain Diseases; Circadian Rhythm; Cricetinae; Follicle Stimulating Hormone; Gonadotropin-Releasing Hormone; Immunohistochemistry; Luteinizing Hormone; Male; Melatonin; Neuropeptides; Paraventricular Hypothalamic Nucleus; Prolactin; Suprachiasmatic Nucleus; Testis; Vasoactive Intestinal Peptide

Topics: Adult; Aged; Atrophy; Brain Diseases; Female; Gastrointestinal Hormones; Humans; Intervertebral Disc Displacement; Male; Middle Aged; Multiple Sclerosis; Spondylitis; Vasoactive Intestinal Peptide