Loss of substance P and inflammation precede delayed neurodegeneration in the substantia nigra after cerebral ischemia

Rodriguez‐Grande, Beatriz; Blackabey, Victoria; Gittens, Beatrice; Pinteaux, Emmanuel

doi:10.1016/j.bbi.2012.11.017

Cited by 57 publications

(56 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Early inflammatory changes in the SN occurring before neuronal alterations have been reported recently. 8 Importantly, this finding might also explain the fact that, in our study, treatment with the calcineurin inhibitor FK506, a potent anti-inflammatory agent, failed to confer neuroprotection, since, in all probability, it was administered too late. However, treatment with MK-801 exerted neuroprotective effects even when treatment was begun on day 5 post event.…”

Section: Discussionmentioning

confidence: 82%

MRI Heralds Secondary Nigral Lesion after Brain Ischemia in Mice: A Secondary Time Window for Neuroprotection

Prinz

Hetzer

Müller

et al. 2015

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

Cerebral ischemia in the territory of the middle cerebral artery (MCA) can induce delayed neuronal cell death in the ipsilateral substantia nigra (SN) remote from the primary ischemic lesion. This exofocal postischemic neuronal degeneration (EPND) may worsen stroke outcomes. However, the mechanisms leading to EPND are poorly understood. Here, we studied the time course of EPND via sequential magnetic resonance imaging (MRI) and immunohistochemistry for up to 28 days after 30 minutes' occlusion of the MCA (MCAo) and reperfusion in the mouse. Furthermore, the effects of delayed treatment with FK506 and MK-801 on the development of EPND were investigated. Secondary neuronal degeneration in the SN occurred within the first week after MCAo and was characterized by a marked neuronal cell loss on histology. Sequential neuroimaging examinations revealed transient MRI changes, which were detectable as early as day 4 after MCAo and thus heralding histologic evidence of EPND. Treatment with MK-801, an established anti-excitotoxic agent, conferred protection against EPND even when initiated days after the initial ischemic event, which was not evident with FK506. Our findings define a secondary time window for delayed neuroprotection after stroke, which may provide a promising target for the development of novel therapies.

show abstract

Section: Discussionmentioning

confidence: 82%

MRI Heralds Secondary Nigral Lesion after Brain Ischemia in Mice: A Secondary Time Window for Neuroprotection

Prinz

Hetzer

Müller

et al. 2015

J Cereb Blood Flow Metab

View full text Add to dashboard Cite

show abstract

“…Furthermore, as the morbidity of PD is greater among older people, it might be associated with age-related conditions such as prolonged ischemia or hypoxia in the brain. There is ample evidence to show that an insufficient blood or oxygen supply to the brain, could attenuate neurons’ resistance to environmental damage, and it can even trigger cell death [5,6,7]. Therefore, hypoxia/ischemia and neurotoxins should also be recognized as critical pathogenic factors that contribute to the development of PD.…”

Section: Introductionmentioning

confidence: 99%

Cytoprotection against Hypoxic and/or MPP+ Injury: Effect of δ–Opioid Receptor Activation on Caspase 3

Zhi

Shao

et al. 2016

IJMS

View full text Add to dashboard Cite

The pathological changes of Parkinson’s disease (PD) are, at least partially, associated with the dysregulation of PTEN-induced putative kinase 1 (PINK1) and caspase 3. Since hypoxic and neurotoxic insults are underlying causes of PD, and since δ-opioid receptor (DOR) is neuroprotective against hypoxic/ischemic insults, we sought to determine whether DOR activation could protect the cells from damage induced by hypoxia and/or MPP+ by regulating PINK1 and caspase 3 expressions. We exposed PC12 cells to either severe hypoxia (0.5%–1% O2) for 24–48 h or to MPP+ at different concentrations (0.5, 1, 2 mM) and then detected the levels of PINK1 and cleaved caspase 3. Both hypoxia and MPP+ reduced cell viability, progressively suppressed the expression of PINK1 and increased the cleaved caspase 3. DOR activation using UFP-512, effectively protected the cells from hypoxia and/or MPP+ induced injury, reversed the reduction in PINK1 protein and significantly attenuated the increase in the cleaved caspase 3. On the other hand, the application of DOR antagonist, naltrindole, greatly decreased cell viability and increased cleaved caspase 3. These findings suggest that DOR is cytoprotective against both hypoxia and MPP+ through the regulation of PINK1 and caspase 3 pathways.

show abstract

“…These levels represent average brain concentrations, but it is predicted that local cellular and intracellular concentrations of PGJ2 could be much higher [52]. Importantly, stroke and TBI increase the long-term risk for PD [8,35,73,86]. Moreover, PGJ2 impairs the ubiquitin/proteasome pathway (UPP) [41,47,76,90] and mitochondrial function [42,43,54], and potentiates dopamine toxicity [64].…”

Section: Introductionmentioning

confidence: 99%

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2

Shivers

Nikolopoulou

Machlovi

et al. 2014

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

View full text Add to dashboard Cite

Neuroinflammation is a major risk factor in Parkinson disease (PD). Alternative approaches are needed to treat inflammation, as anti-inflammatory drugs such as NSAIDs that inhibit cyclooxygenase-2 (COX-2) can produce devastating side effects, including heart attack and stroke. New therapeutic strategies that target factors downstream of COX-2, such as prostaglandin J2 (PGJ2), hold tremendous promise because they will not alter the homeostatic balance offered by COX-2 derived prostanoids. In the current studies, we report that repeated microinfusion of PGJ2 into the substantia nigra of non-transgenic mice, induces three stages of pathology that mimic the slow-onset cellular and behavioral pathology of PD: mild (one injection) when only motor deficits are detectable, intermediate (two injections) when neuronal and motor deficits as well as microglia activation are detectable, and severe (four injections) when dopaminergic neuronal loss is massive accompanied by microglia activation and motor deficits. Microglia activation was evaluated in vivo by positron emission tomography (PET) with [11C](R)PK11195 to provide a regional estimation of brain inflammation. PACAP27 reduced dopaminergic neuronal loss and motor deficits induced by PGJ2, without preventing microglia activation. The latter could be problematic in that persistent microglia activation can exert long-term deleterious effects on neurons and behavior. In conclusion, this PGJ2-induced mouse model that mimics in part chronic inflammation, exhibits slow-onset PD-like pathology and is optimal for testing diagnostic tools such as PET, as well as therapies designed to target the integrated signaling across neurons and microglia, to fully benefit patients with PD.

show abstract

Loss of substance P and inflammation precede delayed neurodegeneration in the substantia nigra after cerebral ischemia

Cited by 57 publications

References 34 publications

MRI Heralds Secondary Nigral Lesion after Brain Ischemia in Mice: A Secondary Time Window for Neuroprotection

MRI Heralds Secondary Nigral Lesion after Brain Ischemia in Mice: A Secondary Time Window for Neuroprotection

Cytoprotection against Hypoxic and/or MPP+ Injury: Effect of δ–Opioid Receptor Activation on Caspase 3

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2

Contact Info

Product

Resources

About