Dataset Information

Brain-targeted nanoreactors prevent the development of organophosphate-induced delayed neurological damage.

ABSTRACT:

Background

Organophosphate (OP)-induced delayed neurological damage is attributed to permanent neuropathological lesions caused by irreversible OP-neurocyte interactions, without potent brain-targeted etiological antidotes to date. The development of alternative therapies to achieve intracerebral OP detoxification is urgently needed.

Methods

We designed a brain-targeted nanoreactor by integrating enzyme immobilization and biomimetic membrane camouflaging protocols with careful characterization, and then examined its blood-brain barrier (BBB) permeability both in vitro and in vivo. Subsequently, the oxidative stress parameters, neuroinflammatory factors, apoptotic proteins and histopathological changes were measured and neurobehavioral tests were performed.

Results

The well-characterized nanoreactors exerted favourable BBB penetration capability both in vitro and in vivo, significantly inhibiting OP-induced intracerebral damage. At the cellular and tissue levels, nanoreactors obviously blocked oxidative stress, cellular apoptosis, inflammatory reactions and brain histopathological damage. Furthermore, nanoreactors radically prevented the occurrence of OP-induced delayed cognitive deficits and psychiatric abnormality.

Conclusion

The nanoreactors significantly prevented the development of OP-induced delayed neurological damage, suggesting a potential brain-targeted etiological strategy to attenuate OP-related delayed neurological and neurobehavioral disorders.

SUBMITTER: Zou S

PROVIDER: S-EPMC10405429 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

Brain-targeted nanoreactors prevent the development of organophosphate-induced delayed neurological damage.

Zou Shuaijun S Wang Qianqian Q He Qian Q Liu Guoyan G Song Juxingsi J Li Jie J Wang Fan F Huang Yichao Y Hu Yanan Y Zhou Dayuan D Lv Yongfei Y Zhu Yuanjie Y Wang Beilei B Zhang Liming L

Journal of nanobiotechnology 20230807 1

<h4>Background</h4>Organophosphate (OP)-induced delayed neurological damage is attributed to permanent neuropathological lesions caused by irreversible OP-neurocyte interactions, without potent brain-targeted etiological antidotes to date. The development of alternative therapies to achieve intracerebral OP detoxification is urgently needed.<h4>Methods</h4>We designed a brain-targeted nanoreactor by integrating enzyme immobilization and biomimetic membrane camouflaging protocols with careful cha ...[more]

PMID: 37550745

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Project description:BackgroundNeuregulin-1 (NRG-1) has been shown to act as a neuroprotectant in animal models of nerve agent intoxication and other acute brain injuries. We recently demonstrated that NRG-1 blocked delayed neuronal death in rats intoxicated with the organophosphate (OP) neurotoxin diisopropylflurophosphate (DFP). It has been proposed that inflammatory mediators are involved in the pathogenesis of OP neurotoxin-mediated brain damage.MethodsWe examined the influence of NRG-1 on inflammatory responses in the rat brain following DFP intoxication. Microglial activation was determined by immunohistchemistry using anti-CD11b and anti-ED1 antibodies. Gene expression profiling was performed with brain tissues using Affymetrix gene arrays and analyzed using the Ingenuity Pathway Analysis software. Cytokine mRNA levels following DFP and NRG-1 treatment was validated by real-time reverse transcription polymerase chain reaction (RT-PCR).ResultsDFP administration resulted in microglial activation in multiple brain regions, and this response was suppressed by treatment with NRG-1. Using microarray gene expression profiling, we observed that DFP increased mRNA levels of approximately 1,300 genes in the hippocampus 24 h after administration. NRG-1 treatment suppressed by 50% or more a small fraction of DFP-induced genes, which were primarily associated with inflammatory responses. Real-time RT-PCR confirmed that the mRNAs for pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6) were significantly increased following DFP exposure and that NRG-1 significantly attenuated this transcriptional response. In contrast, tumor necrosis factor α (TNFα) transcript levels were unchanged in both DFP and DFP + NRG-1 treated brains relative to controls.ConclusionNeuroprotection by NRG-1 against OP neurotoxicity is associated with the suppression of pro-inflammatory responses in brain microglia. These findings provide new insight regarding the molecular mechanisms involved in the neuroprotective role of NRG-1 in acute brain injuries.

Project description:ImportancePreventing delayed neurological sequelae is a major goal of treating acute carbon monoxide poisoning, but to our knowledge there are no reliable tools for assessing the probability of these sequelae.ObjectivesTo determine whether acute brain lesions on diffusion-weighted imaging are related to subsequent development of delayed neurological sequelae after acute carbon monoxide poisoning.Design, setting, and participantsThis registry-based observational study was conducted at a university hospital in Seoul, Korea, between April 1, 2011, and December 31, 2015. Of 700 patients (aged ≥18 years) with acute carbon monoxide poisoning, 433 patients (61.9%) who underwent diffusion-weighted imaging at an emergency department were considered for the study. Patients who developed cardiac arrest before diffusion-weighted imaging (n = 3), had persistent neurological symptoms at discharge (n = 8), committed suicide soon after discharge (n = 1), and were lost to follow-up (n = 34) were excluded.ExposureThe presence of unambiguous, high-signal-intensity, acute brain lesions on diffusion-weighted imaging (b = 1000 s/mm2).Main outcomes and measuresDevelopment of delayed neurological sequelae defined as any neurological symptoms or signs that newly developed within 6 weeks of discharge.ResultsOf the 387 included patients (143 women [37.0%]; median age, 42.0 years [interquartile range, 32.0-56.0 years]), acute brain lesions on diffusion-weighted imaging were observed in 104 patients (26.9%). Among these, 77 patients (19.9%) had globus pallidus lesions, 13 (3.4%) had diffuse lesions, and 57 (14.7%) had focal lesions (37 patients [9.6%] had >1 pattern concurrently). Lesions were supratentorial and infratentorial in 101 and 23 patients, respectively. Delayed neurological sequelae occurred in 101 patients (26.1%). Multivariable logistic regression analysis indicated that the presence of acute brain lesions was independently associated with development of delayed neurological sequelae (adjusted odds ratio, 13.93; 95% CI, 7.16-27.11; P < .001). The sensitivity and specificity of acute brain lesions to assess the probability of delayed neurological sequelae were 75.2% (95% CI, 66.8%-83.7%) and 90.2% (95% CI, 86.8%-93.7%), respectively. In addition, the positive and negative predictive values were 73.1% (95% CI, 64.6%-81.6%) and 91.2% (95% CI, 87.9%-94.5%), respectively.Conclusions and relevanceThe presence of acute brain lesions was significantly associated with the development of delayed neurological sequelae. Diffusion-weighted imaging during the acute phase of carbon monoxide poisoning may therefore help identify patients at risk of developing these debilitating sequelae.

Dataset Information

Brain-targeted nanoreactors prevent the development of organophosphate-induced delayed neurological damage.

Background

Methods

Results

Conclusion

Publications

Brain-targeted nanoreactors prevent the development of organophosphate-induced delayed neurological damage.

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