Evidence map›Paper›PMID 33100217›Full record

ArticleJournal of neuroinflammation2020

Systemic dendrimer-drug nanomedicines for long-term treatment of mild-moderate cerebral palsy in a rabbit model.

Zhi Zhang, Yi-An Lin, Soo-Young Kim, Lilly Su, Jinhuan Liu, Rangaramanujam M Kannan, Sujatha Kannan

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of neuroinflammation, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
16citing papers in PubMed, 1 pooled it
1.2field-weighted citation impact, top 20% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

16 citing papers in PubMed, 1 synthesis or guideline pooled it, 25 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 4 institutions in 1 country.

Zhi ZhangDepartment of Anesthesiology and Critical Care, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Yi-An LinCenter for Nanomedicine, Wilmer Eye Institute, Johns Hopkins School of Medicine, 400 North Broadway, Baltimore, MD, 21287, USA.
Soo-Young KimCenter for Nanomedicine, Wilmer Eye Institute, Johns Hopkins School of Medicine, 400 North Broadway, Baltimore, MD, 21287, USA.
Lilly SuDepartment of Anesthesiology and Critical Care, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Jinhuan LiuDepartment of Anesthesiology and Critical Care, Johns Hopkins School of Medicine, Baltimore, MD, USA.
Rangaramanujam M KannanCenter for Nanomedicine, Wilmer Eye Institute, Johns Hopkins School of Medicine, 400 North Broadway, Baltimore, MD, 21287, USA. krangar1@jhmi.edu.
Sujatha KannanDepartment of Anesthesiology and Critical Care, Johns Hopkins School of Medicine, Baltimore, MD, USA. skannan3@jhmi.edu.
Johns Hopkins University · USJohns Hopkins Medicine · USBloomberg (United States) · USUniversity of Michigan–Dearborn · US

Funding

Targeting glutamate carboxypeptidase in perinatal brain injuryR01NS093416 · NINDS · JOHNS HOPKINS UNIVERSITY · PI Sujatha Kannan, Kannan Rangaramanujam · 2016 to 2026
$4.8M
Translational Technologies for Ameliorating Brain InjuryR01HL139158 · NHLBI · JOHNS HOPKINS UNIVERSITY · PI KANNAN, SUJATHA, THAKOR, NITISH VYOMESH · 2018 to 2021
$2.1M
Postnatal combination therapy for cerebral palsyR01HD076901 · NICHD · JOHNS HOPKINS UNIVERSITY · PI RANGARAMANUJAM, KANNAN · 2014 to 2018
$1.7M
NHLBI NIH HHS R01 HL139158NIBIB NIH HHS R01HD076901NICHD NIH HHS R01 HD076901NINDS NIH HHS R01 NS093416NINDS NIH HHS R01NS093416
6 · The paper itself

Abstract

backgroundNeuroinflammation mediated by microglia plays a central role in the pathogenesis of perinatal/neonatal brain injury, including cerebral palsy (CP). Therapeutics mitigating neuroinflammation potentially provide an effective strategy to slow the disease progression and rescue normal brain development. Building on our prior results which showed that a generation-4 hydroxyl poly(amidoamine) (PAMAM) dendrimer could deliver drugs specifically to activated glia from systemic circulation, we evaluated the sustained efficacy of a generation-6 (G6) hydroxyl-terminated PAMAM dendrimer that showed a longer blood circulation time and increased brain accumulation. N-acetyl-L-cysteine (NAC), an antioxidant and anti-inflammatory agent that has high plasma protein binding properties and poor brain penetration, was conjugated to G6-PAMAM dendrimer-NAC (G6D-NAC). The efficacy of microglia-targeted G6D-NAC conjugate was evaluated in a clinically relevant rabbit model of CP, with a mild/moderate CP phenotype to provide a longer survival of untreated CP kits, enabling the assessment of sustained efficacy over 15 days of life.

methodsG6D-NAC was conjugated and characterized. Cytotoxicity and anti-inflammatory assays were performed in BV-2 microglial cells. The efficacy of G6D-NAC was evaluated in a rabbit model of CP. CP kits were randomly divided into 5 groups on postnatal day 1 (PND1) and received an intravenous injection of a single dose of PBS, or G6D-NAC (2 or 5 mg/kg), or NAC (2 or 5 mg/kg). Neurobehavioral tests, microglia morphology, and neuroinflammation were evaluated at postnatal day 5 (PND5) and day 15 (PND15).

resultsA single dose of systemic 'long circulating' G6D-NAC showed a significant penetration across the impaired blood-brain-barrier (BBB), delivered NAC specifically to activated microglia, and significantly reduced microglia-mediated neuroinflammation in both the cortex and cerebellum white matter areas. Moreover, G6D-NAC treatment significantly improved neonatal rabbit survival rate and rescued motor function to nearly healthy control levels at least up to 15 days after birth (PND15), while CP kits treated with free NAC died before PND9.

conclusionsTargeted delivery of therapeutics to activated microglia in neonatal brain injury can ameliorate pro-inflammatory microglial responses to injury, promote survival rate, and improve neurological outcomes that can be sustained for a long period. Appropriate manipulation of activated microglia enabled by G6D-NAC can impact the injury significantly beyond inflammation.

Indexed as

Disease Models, AnimalAnimalsAnimals, NewbornBiocompatible MaterialsCell LineCerebral PalsyDendrimersDose-Response Relationship, DrugFemaleLipopolysaccharidesMaleMiceMicrogliaNanomedicinePregnancyRabbitsBiocompatible MaterialsDendrimersLipopolysaccharidesPAMAM StarburstCerebral palsyMicrogliaNACNeurobehaviorNeuroinflammationPAMAM dendrimers

Identifiers

PMID33100217
PMCPMC7586697
OpenAlexW3094070068

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.