Intrastriatal administration of erythropoietin protects dopaminergic neurons and improves neurobehavioral outcome in a rat model of Parkinson’s disease

Xue, Yue-Qiang; Zhao, Li-Ru; Guo, Wei; Duan, Wenjun

doi:10.1016/j.neuroscience.2007.02.004

Cited by 70 publications

(55 citation statements)

References 40 publications

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“…36 We have recently showed that intrastriatal administration of EPO protects nigral DA neurons from cell death induced by 6-OHDA in part through an anti-inflammatory mechanism. 6 In the present study, the evidence of EPO protein accumulation in the ipsilateral SN induced by AAV9-mediated EPO gene delivery into the striatum highlights the notion that EPO protein protects DA neurons in the SN directly through a receptor-mediated mechanism, as DA neurons have EPORs, 1,2 but does not exclude local antioxidant, anti-apoptotic and anti-inflammatory mechanisms. Indeed, we observed that EPORs are expressed in striatal and SN neurons in the present study (Figures 2d and e).…”

Section: Discussionmentioning

confidence: 55%

“…Our previous study with EPO protein administration showed that systemic administration of EPO protein was insufficient for DA neuroprotection in the brain. 6 In contrast, the EPO gene transfer approach used here was successful for long-term expression and neuroprotection derived from a single surgical treatment. The AAV9 vector produced widespread neuronal expression of either EPO or GFP transgenes in the striatum, which recapitulated the high-efficiency neuronal transduction observed previously with this vector in the rat hippocampus or SN.…”

Section: Discussionmentioning

confidence: 84%

“…Accumulating evidence has shown that EPO protein and EPO receptors (EPORs) exist in CNS neurons. 1,2 EPO has been found to protect dopaminergic (DA) neurons from experimental insults and druginduced degeneration, 1,[3][4][5][6] suggesting its therapeutic potential for Parkinson's disease (PD). In our previous study with EPO protein infusions, although intrastriatal delivery was protective, systemic administration of EPO did not protect DA neurons from 6-hydroxydopamine (6-OHDA) toxicity in a rat model of PD.…”

Section: Introductionmentioning

confidence: 99%

“…In our previous study with EPO protein infusions, although intrastriatal delivery was protective, systemic administration of EPO did not protect DA neurons from 6-hydroxydopamine (6-OHDA) toxicity in a rat model of PD. 6 The bloodbrain barrier may therefore limit the passage of EPO protein into the brain, preventing it from reaching a therapeutic level. We hypothesized that in vivo gene delivery may circumvent this limitation and lead to persistent therapeutic protein production in the brain, which is required for treating the chronic pathological processes of PD.…”

Section: Introductionmentioning

confidence: 99%

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AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease

Zhao

et al. 2009

Gene Ther

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We have recently shown that intrastriatal injection of recombinant human erythropoietin (EPO) protects dopaminergic (DA) neurons in the substantia nigra (SN) from 6-hydroxydopamine (6-OHDA) toxicity in a rat model of Parkinson's disease. However, systemic administration of EPO did not protect nigral DA neurons, suggesting that the blood-brain barrier limits the passage of EPO protein into the brain. In the present study, we used an adenoassociated viral (AAV) serotype 9 (AAV9) vector to deliver the human EPO gene into the brain of 6-OHDA-lesioned rats. We observed that expression of the human EPO gene was robust and stable in the striatum and the SN for up to 10 weeks. EPO-immunoreactive (IR) cells were widespread throughout the injected striatum, and EPO-IR neurons and fibers were also found in the ipsilateral SN. Enzyme-linked immunosorbent assay and western blot analyses exhibited dramatic levels of EPO protein in the injected striatum. As a result, nigral DA neurons were protected against 6-OHDA-induced toxicity. Amphetamine-induced rotational asymmetry and spontaneous forelimb use asymmetry were both attenuated. Interestingly, we also observed that intrastriatal injection of AAV9-EPO vectors led to increased numbers of red blood cells in peripheral blood. This highlights the importance of using an inducible gene delivery system for EPO gene delivery.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease

Zhao

et al. 2009

Gene Ther

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“…Like neurturin, erythropoietin generated in situ has been proposed as another means for protection against degenerative changes in PD. 110 Based on its cytokine properties, erythropoietin can diminish effects of the neurotoxins 6-OHDA and MPTP in rodent experiments (possibly through an anti-inflammatory response against microglial activation). Another proposal from laboratory research comes from a rodent model of parkinsonism in which motor deficits and neuronal dropout were induced by overexpression of ␣-synuclein in dopaminergic SN neurons.…”

Section: Discussionmentioning

confidence: 99%

Protection Against Parkinson’s Disease Progression: Clinical Experience

LeWitt

Taylor

2008

Neurotherapeutics

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Summary:Treatments with potential neuroprotective capability for Parkinson's disease (PD) have been investigated in randomized, controlled, clinical trials and other studies since the mid-1980s. Although promising leads have arisen, no therapy has been proven to halt or slow disease progression. Several large-scale studies have highlighted progress in methodology, as well as the frustrations of translating laboratory science to practical applications. This review summarizes findings from clinical trials with several classes of compounds, including monoamine oxidase-B inhibitors (selegiline, lazabemide, rasagiline), dopaminergic drugs (ropinirole, pramipexole, levodopa), antioxidant strategies (␣-tocopherol), mitochondrial energy enhancers (coenzyme Q 10 , creatine), antiapoptotic agents (TCH346, minocycline, CEP-1347), and antiglutamatergic compounds (riluzole). Beyond small-molecule pharmacology, gene therapy approaches, such as delivering neurotrophic substances (e.g., neurturin) by viral vector, are the next generation of treatment options.

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Recent Advances in Modified Brain‐Targeting Drug Delivery Systems for Erythropoietin

Yao

Xiao

et al. 2023

Advanced Therapeutics

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Erythropoietin (EPO) is an excellent neuroprotective molecule that decreases the extent of injury caused by various pathologies of the brain, such as Alzheimer's disease, Parkinson's disease, and stroke. However, due to the low permeability of the blood‒brain barrier (BBB), a high dose or even an overdose of EPO injections is often administered to achieve a sufficient EPO concentration in the brain. This often leads to many serious adverse reactions. Several studies have presented promising strategies for overcoming the BBB to deliver EPO. These methods include the formation of EPO modified by receptor‐mediated transcytosis targeting fusion proteins, cell‐penetrating peptides, and nanomaterials. In this review, the clinical progress of modified brain‐targeting drug delivery systems of EPO is summarized to provide a scientific basis and new information on the application of EPO in treating diseases of the central nervous system. Here, the production, pharmacological effects, and mechanism of action of the modified EPO, as well as the limiting factors and countermeasures are discussed.

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Intrastriatal administration of erythropoietin protects dopaminergic neurons and improves neurobehavioral outcome in a rat model of Parkinson’s disease

Cited by 70 publications

References 40 publications

AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease

AAV9-mediated erythropoietin gene delivery into the brain protects nigral dopaminergic neurons in a rat model of Parkinson's disease

Protection Against Parkinson’s Disease Progression: Clinical Experience

Recent Advances in Modified Brain‐Targeting Drug Delivery Systems for Erythropoietin

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