Activation of the VIP/VPAC2 system induces reactive astrocytosis associated with increased expression of glutamate transporters

Nishimoto, Mika; Miyakawa, Hiroyoshi; Wada, Keiji; Furuta, Akiko

doi:10.1016/j.brainres.2011.01.082

Cited by 22 publications

(19 citation statements)

References 61 publications

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“…In a model of moderate traumatic injury to rat brain cortex, PACAP gene expression was found to be induced in the ipsilateral cortex, especially in the perifocal region, and also within the dentate gyrus of the hippocampus (Skoglosa et al, 1999). In a model of cortical focal cold injury, VPAC2 receptor immunoreactivity was up-regulated in reactive astrocytes, whereas VIP became expressed in microglia (Nishimoto et al, 2011). Finally, gene expression for both PACAP and PAC1 were induced in the spinal cord after moderate compression injury (Tsuchikawa et al, 2012).…”

Section: Up-regulation Of the Vip/pacap Ligand/receptor Signalling Symentioning

confidence: 97%

Section: The Role Of Vip and Pacap In The Regulation Of Systemic Inflmentioning

confidence: 99%

“…Finally, a bone marrow chimera approach was recently used to show that expression of VIP in radiosensitive haematopoietic cells was required to constrain Th polarization in a viral infection model (Li et al, 2011). Although Th polarization occurs mainly if not exclusively in the periphery, the latter finding raises the general possibility that VIP (or PACAP) produced in immune cells, including microglia (Nishimoto et al, 2011), are involved in modifying local inflammation or degeneration in the CNS Nearly all immune cell types express one or more VIP and PACAP receptor subtypes. VPAC 1 and VPAC2 receptors have been implicated in most of the immunomodulatory actions of PACAP and VIP (reviewed in Delgado et al, 2004a), although PAC1 receptors are expressed in MF, where they appear to have functional significance in innate , and perhaps adaptive immunity (Delgado et al, 1999b,c).…”

Section: The Role Of Vip and Pacap In The Regulation Of Systemic Inflmentioning

confidence: 99%

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VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair

Waschek

2013

British J Pharmacology

172

130

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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-a and IFN-g, 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. AbbreviationsAPE1, apurinic/apyrimidinic endonuclease; IL-1Ra, IL-1 receptor antagonist; IML, intermediolateral; KO, knockout; MOG35-55, myelin oligodendrocyte glycoprotein, amino acids 35-55; MS, multiple sclerosis; MF, macrophage; NA, noradrenaline; PACAP, pituitary adenylyl cyclase-activating peptide; PGC1a, peroxisome proliferator-activated receptor g co-activator 1a; SCG, superior cervical ganglia; SNS, sympathetic nervous system; Treg, regulatory T-cell; VIP, vasoactive intestinal peptide IntroductionThe brain was once thought to be excluded from immune surveillance and other inflammatory processes except under a few specific pathological conditions such as CNS infection and multiple sclerosis (MS). Indeed foreign antigens are quite limited in their ability to elicit robust T-cell or humoral responses in the CNS due to a relative lack of lymphoid drainage and limited expression of major histocompatibility complex molecules. Moreover, neither strong innate nor amplified adaptive inflammatory responses are generally observed in the brain due to the presence of tight endothelial junctions and astrocyte endfeet that provide a barrier against influx of infl...

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Section: Up-regulation Of the Vip/pacap Ligand/receptor Signalling Symentioning

confidence: 97%

Section: The Role Of Vip and Pacap In The Regulation Of Systemic Inflmentioning

confidence: 99%

Section: The Role Of Vip and Pacap In The Regulation Of Systemic Inflmentioning

confidence: 99%

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VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair

Waschek

2013

British J Pharmacology

172

130

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“…A direct effect of K + in stimulating gluconeogenesis and glycogen synthesis from glutamate but not from lactate has been demonstrated in amphibian retinal Muller glial cells (Goldman, 1988), where initiation of gluconeogenesis and blockade of glycolysis has been observed in response to vasoactive intestinal peptide (VIP) (Goldman, 1990). Interestingly, increased levels of VIP type-2 receptor is a features of reactive astrocytes (Nishimoto et al, 2011). VIP is known to induce glycogenolysis in cerebral cortical astrocytes (Magistretti, 1990).…”

Section: Excess Glutamate Affects the Metabolism Of Glycogen In Astromentioning

confidence: 99%

Does abnormal glycogen structure contribute to increased susceptibility to seizures in epilepsy?

et al. 2014

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Epilepsy is a family of brain disorders with a largely unknown etiology and high percentage of pharmacoresistance. The clinical manifestations of epilepsy are seizures, which originate from aberrant neuronal synchronization and hyperexcitability. Reactive astrocytosis, a hallmark of the epileptic tissue, develops into loss-of-function of glutamine synthetase, impairment of glutamate-glutamine cycle and increase in extracellular and astrocytic glutamate concentration. Here, we argue that chronically elevated intracellular glutamate level in astrocytes is instrumental to alterations in the metabolism of glycogen and leads to the synthesis of polyglucosans. Unaccessibility of glycogen-degrading enzymes to these insoluble molecules compromises the glycogenolysis-dependent reuptake of extracellular K+ by astrocytes, thereby leading to increased extracellular K+ and associated membrane depolarization. Based on current knowledge, we propose that the deterioration in structural homogeneity of glycogen particles is relevant to disruption of brain K+ homeostasis and increased susceptibility to seizures in epilepsy.

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“…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].…”

Section: Vip In Normal Adult Brain Physiologymentioning

confidence: 99%

VIP in Neurological Diseases: More Than A Neuropeptide

Morell

Souza-Moreira²,

González‐Rey³

2012

EMIDDT

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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.

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Activation of the VIP/VPAC2 system induces reactive astrocytosis associated with increased expression of glutamate transporters

Cited by 22 publications

References 61 publications

VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair

VIP and PACAP: neuropeptide modulators of CNS inflammation, injury, and repair

Does abnormal glycogen structure contribute to increased susceptibility to seizures in epilepsy?

VIP in Neurological Diseases: More Than A Neuropeptide

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