A substance P mediated pathway contributes to 6-hydroxydopamine induced cell death

Thornton, Emma; Tran, Tuyet T.B.; Vink, Robert

doi:10.1016/j.neulet.2010.06.057

Cited by 33 publications

(23 citation statements)

References 22 publications

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“…SP expression was shown to be elevated following 6-OHDA treatment of dopaminergic neurons in vitro 68 and, comparably, increased SP levels were found in the SN of the rat model 39 . This early increase of SP level was associated with augmented BBB permeability, microglial and astrocyte activation, increased dopaminergic cell death and profound motor deficit.…”

Section: Nk1r Antagonists and Neurodegenerative Diseasesmentioning

confidence: 85%

Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System

Martínez

Philipp

2016

J Neurol Neuromedicine

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This review addresses the role that substance P (SP) and its preferred receptor neurokinin-1 (NK1R) play in neuroinflammation associated with select bacterial, viral, parasitic, and neurodegenerative diseases of the central nervous system. The SP/NK1R complex is a key player in the interaction between the immune and nervous systems. A common effect of this interaction is inflammation. For this reason and because of the predominance in the human brain of the NK1R, its antagonists are attractive potential therapeutic agents. Preventing the deleterious effects of SP through the use of NK1R antagonists has been shown to be a promising therapeutic strategy, as these antagonists are selective, potent, and safe. Here we evaluate their utility in the treatment of different neuroinfectious and neuroinflammatory diseases, as a novel approach to clinical management of CNS inflammation.

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Section: Nk1r Antagonists and Neurodegenerative Diseasesmentioning

confidence: 85%

Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System

Martínez

Philipp

2016

J Neurol Neuromedicine

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“…SP increases dopaminergic neuronal death directly and is also induced by LPS or MPP + (Wang et al, 2014). Dopamine induces the release of SP in substantia nigra and the SP potentiate dopamine release in a positive feedback pathway mechanism (Thornton et al, 2010). The substantia nigra has bidirectional neuronal connections with the striatum.…”

Section: Neuropeptides Sp and Crh In Neuroinflammationmentioning

confidence: 99%

Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration

Kempuraj

Thangavel

Selvakumar

et al. 2017

Front. Cell. Neurosci.

318

265

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Neuroinflammatory response is primarily a protective mechanism in the brain. However, excessive and chronic inflammatory responses can lead to deleterious effects involving immune cells, brain cells and signaling molecules. Neuroinflammation induces and accelerates pathogenesis of Parkinson’s disease (PD), Alzheimer’s disease (AD) and Multiple sclerosis (MS). Neuroinflammatory pathways are indicated as novel therapeutic targets for these diseases. Mast cells are immune cells of hematopoietic origin that regulate inflammation and upon activation release many proinflammatory mediators in systemic and central nervous system (CNS) inflammatory conditions. In addition, inflammatory mediators released from activated glial cells induce neurodegeneration in the brain. Systemic inflammation-derived proinflammatory cytokines/chemokines and other factors cause a breach in the blood brain-barrier (BBB) thereby allowing for the entry of immune/inflammatory cells including mast cell progenitors, mast cells and proinflammatory cytokines and chemokines into the brain. These peripheral-derived factors and intrinsically generated cytokines/chemokines, α-synuclein, corticotropin-releasing hormone (CRH), substance P (SP), beta amyloid 1–42 (Aβ1–42) peptide and amyloid precursor proteins can activate glial cells, T-cells and mast cells in the brain can induce additional release of inflammatory and neurotoxic molecules contributing to chronic neuroinflammation and neuronal death. The glia maturation factor (GMF), a proinflammatory protein discovered in our laboratory released from glia, activates mast cells to release inflammatory cytokines and chemokines. Chronic increase in the proinflammatory mediators induces neurotoxic Aβ and plaque formation in AD brains and neurodegeneration in PD brains. Glial cells, mast cells and T-cells can reactivate each other in neuroinflammatory conditions in the brain and augment neuroinflammation. Further, inflammatory mediators from the brain can also enter into the peripheral system through defective BBB, recruit immune cells into the brain, and exacerbate neuroinflammation. We suggest that mast cell-associated inflammatory mediators from systemic inflammation and brain could augment neuroinflammation and neurodegeneration in the brain. This review article addresses the role of some atypical inflammatory mediators that are associated with mast cell inflammation and their activation of glial cells to induce neurodegeneration.

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“…Recently, 6-OHDA treatment of dopaminergic neurons in vitro produced an early and sustained increase in SP content, which significantly correlated with lactate dehydrogenase expression, a marker of cell death [15], suggesting that SP may play a role in dopaminergic cell. In the current study, we investigated whether SP may also be increased in vivo following induction of intrastriatal 6-OHDA lesions, a model of early PD, thereby initiating DA cell death by facilitating inflammation and BBB dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Treatment with a Substance P Receptor Antagonist Is Neuroprotective in the Intrastriatal 6-Hydroxydopamine Model of Early Parkinson's Disease

Thornton¹,

Vink

2012

PLoS ONE

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Neuroinflammation and blood brain barrier (BBB) dysfunction have been implicated in the pathogenesis of Parkinson's disease (PD). The neuropeptide substance P (SP) is an important mediator of both neuroinflammation and BBB dysfunction through its NK1 receptor in a process known as neurogenic inflammation. Increased SP content has previously been reported following 6-OHDA treatment in vitro, with the levels of SP correlating with cell death. The present study used an in vivo 6-OHDA lesion model to determine if dopaminergic degeneration was associated with increased SP in the substantia nigra and whether this degeneration could be prevented by using a SP, NK1 receptor antagonist. Unilateral, intrastriatal 6-OHDA lesions were induced and SP (10 µg/2 µL) or the NK1 receptor antagonists, N-acetyl-L-tryptophan (2 µL at 50 nM) or L-333,060 (2 µL at 100 nM), administered immediately after the neurotoxin. Nigral SP content was then determined using immunohistochemical and ELISA methods, neuroinflammation and barrier integrity was assessed using Iba-1, ED-1, GFAP and albumin immunohistochemistry, while dopaminergic cell loss was assessed with tyrosine hydroxylase immunohistochemistry. Motor function in all animals was assessed using the rotarod task. Intrastriatal 6-OHDA lesioning produced an early and sustained increase in ipsilateral nigral SP content, along with a breakdown of the BBB and activation of microglia and astrocytes. Further exacerbation of SP levels accelerated disease progression, whereas NK1 receptor antagonist treatment protected dopaminergic neurons, preserved barrier integrity, reduced neuroinflammation and significantly improved motor function. We propose that neurogenic inflammation contributes to dopaminergic degeneration in early experimental PD and demonstrate that an NK1 receptor antagonist may represent a novel neuroprotective therapy.

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A substance P mediated pathway contributes to 6-hydroxydopamine induced cell death

Cited by 33 publications

References 22 publications

Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System

Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System

Brain and Peripheral Atypical Inflammatory Mediators Potentiate Neuroinflammation and Neurodegeneration

Treatment with a Substance P Receptor Antagonist Is Neuroprotective in the Intrastriatal 6-Hydroxydopamine Model of Early Parkinson's Disease

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