Is Parkinson’s disease an autoimmune disorder of endogenous vasoactive neuropeptides?

Staines, Donald

doi:10.1016/j.mehy.2007.04.004

Cited by 8 publications

(6 citation statements)

References 26 publications

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“…In an animal model of septic shock systemic administration of PACAP decreases levels of TNF-α (Baranowska-Bik et al, 2006). In the brain, PACAP has been shown to exert neuroprotective effects in Parkinson’s disease models by inhibiting the production of inflammatory mediators (Staines, 2007). However, a direct effect on inflammatory protein release by neurons has not been demonstrated.…”

Section: Discussionmentioning

confidence: 99%

RANTES release contributes to the protective action of PACAP38 against sodium nitroprusside in cortical neurons

2009

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Pituitary adenylate cyclase activating polypeptide (PACAP), a promising neuroprotective peptide, plays an important role during development of the nervous system and in regeneration after injury. PACAP directly promotes survival via multiple signaling systems in neurons. This neuropeptide also has immuno-modulatory properties and can regulate the expression of various inflammatory mediators such as chemokines in nonneuronal cells. Chemokines and their G protein-coupled receptors are widely distributed in the brain, suggesting important functions for these inflammatory proteins in the CNS. The ability of brain endothelial cells and glia to release chemokines has been well documented, whether neurons are also a source for these mediators is unclear. The objective of this study is to determine whether PACAP38 affects expression of regulated on activation normal T expressed and secreted (RANTES) and macrophage inflammatory protein 1-alpha (MIP-1α) in cultured neurons and if these chemokines contribute to the neuroprotective effect of PACAP38. The data show that incubation of neuronal cultures with both PACAP38 and sodium nitroprusside (SNP) reduces the neuronal cell death evoked by SNP alone. PACAP38 dose-dependently increases immunodetectable levels of both RANTES and MIP-1α released in the media by cultured neurons. Co-treatment with a neutralizing antibody to RANTES decreases the PACAP38-mediated protection against SNP. Although RANTES treatment of neurons increased MIP-1α levels in the media and MIP-1α supports neuronal survival in unstressed cultures, MIP-1α does not protect neurons from SNP-induced toxicity. Furthermore, co-treatment with a MIP-1α neutralizing antibody did not affect PACAP38-induced protection against SNP. These results show that the protective effect of PACAP38 on cultured neurons is mediated, in part, by release of RANTES. The ability of PACAP to directly enhance neuronal survival through multiple intracellular signaling pathways as well as via the release of neuroprotective mediators such as RANTES highlights its utility as a potential therapeutic agent for the treatment of neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 99%

RANTES release contributes to the protective action of PACAP38 against sodium nitroprusside in cortical neurons

2009

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“…Similar to AD, PD is also classified as a protein deposition disorder; symptoms of PD include tremor and involuntary movements [16]. In PD, autoimmunity, including humoral immunity, has been found, and furthermore, through experimental autoimmune nigral damage, it has been found that this results in the degeneration of dopaminergic neurons, thus suggesting that PD is an autoimmune disease [17–20]. In PD, autoimmunity, including humoral immunity, has been found and furthermore, through experimental autoimmune nigral damage, it has been found that this results in the degeneration of dopaminergic neurons, thus suggesting that PD is an auto immune disease [17–20].…”

Section: Treatment Of Autoimmune Brain Diseasesmentioning

confidence: 99%

“…In PD, autoimmunity, including humoral immunity, has been found, and furthermore, through experimental autoimmune nigral damage, it has been found that this results in the degeneration of dopaminergic neurons, thus suggesting that PD is an autoimmune disease [17–20]. In PD, autoimmunity, including humoral immunity, has been found and furthermore, through experimental autoimmune nigral damage, it has been found that this results in the degeneration of dopaminergic neurons, thus suggesting that PD is an auto immune disease [17–20]. For the treatment of PD, Solomon presented a method through the use of an antibody on the bacteriophage that binds specifically with a pro-inflammatory cytokine in conjunction with a filamentous bacteriophage, resulting in a filamentous bacteriophage that lacks a mammalian cell internalization signal [107].…”

Section: Treatment Of Autoimmune Brain Diseasesmentioning

confidence: 99%

New Immunological Approaches in Treating and Diagnosing CNS Diseases

Guo

Janigro

2013

Pharm. Pat. Analyst

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The immune system evolved to launch effective and specific responses against pathogens. A key feature of this defense mechanism is its ability to differentiate between self and nonself. However, in autoimmune diseases, the host's immune system fails to discriminate self versus foreign. The CNS is further protected by the blood–brain barrier. In spite of its ‘immune privilege,’ the brain is not protected from autoimmunity; perhaps paradoxically xenoantibodies can be used to treat neurological diseases. We describe patents covering treatment methods for CNS diseases with suspected or demonstrated autoimmune etiology. These include multiple sclerosis and, Alzheimer's and Parkinson's disease. The goal is to less invasively, yet efficiently, treat neurological diseases. Although autoimmune responses are often detrimental, recent studies have begun to harness, boost and induce immune responses as a mechanism of treatment. The patents discussed herein highlight new treatments for Alzheimer's and Parkinson's disease, multiple sclerosis, and seizure disorders.

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“…These syndromes share common pathogenic features including inflammation, oxidative stress, and mitochondrial dysfunction. PACAP autoimmunity has also been postulated to play a role in Parkinson’s disease pathology due to observed pro-inflammatory responses consistent with apoptotic neurodegeneration (Staines, 2007). As PACAP has neuroprotective effects in Parkinson’s disease models, a defect in vasoactive neuropeptide function may act adversely on neurons to contribute to neurodegeneration.…”

Section: Pituitary Adenylate Cyclase Activating Peptide (Pacap)mentioning

confidence: 99%

Chemical modification of Class II G protein-coupled receptor ligands: Frontiers in the development of peptide analogs as neuroendocrine pharmacological therapies

Chapter

White

DeRidder

et al. 2010

Pharmacology & Therapeutics

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Recent research and clinical data have begun to demonstrate the huge potential therapeutic importance of ligands that modulate the activity of the secretin-like, Class II, G-protein coupled receptors (GPCRs). Ligands that can modulate the activity of these Class II GPCRs may have important clinical roles in the treatment of a wide variety of conditions such as osteoporosis, diabetes, amyotrophic lateral sclerosis and autism spectrum disorders. While these receptors present important new therapeutic targets, the large glycoprotein nature of their cognate ligands poses many problems with respect to therapeutic peptidergic drug design. These native peptides often exhibit poor bioavailability, metabolic instability, poor receptor selectivity and resultant low potencies in vivo. Recently, increased attention has been paid to the structural modification of these peptides to enhance their therapeutic efficacy. Successful modification strategies have included D-amino acid substitutions, selective truncation, and fatty acid acylation of the peptide. Through these and other processes, these novel peptide ligand analogs can demonstrate enhanced receptor subtype selectivity, directed signal transduction pathway activation, resistance to proteolytic degradation, and improved systemic bioavailability. In the future, it is likely, through additional modification strategies such as addition of circulation-stabilizing transferrin moieties, that the therapeutic pharmacopeia of drugs targeted towards Class II secretin-like receptors may rival that of the Class I rhodopsin-like receptors that currently provide the majority of clinically used GPCR-based therapeutics. Currently, Class IIbased drugs include synthesized analogues of vasoactive intestinal peptide for type 2 diabetes or parathyroid hormone for osteoporosis.

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Is Parkinson’s disease an autoimmune disorder of endogenous vasoactive neuropeptides?

Cited by 8 publications

References 26 publications

RANTES release contributes to the protective action of PACAP38 against sodium nitroprusside in cortical neurons

RANTES release contributes to the protective action of PACAP38 against sodium nitroprusside in cortical neurons

New Immunological Approaches in Treating and Diagnosing CNS Diseases

Chemical modification of Class II G protein-coupled receptor ligands: Frontiers in the development of peptide analogs as neuroendocrine pharmacological therapies

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