Manganese nanoparticles induce blood-brain barrier disruption, cerebral blood flow reduction, edema formation and brain pathology associated with cognitive and motor dysfunctions

Sharma, Aruna; Feng, Lei; Mureșanu, Dafin F.; Sahib, Seaab; Tian, Z. Ryan; Lafuente, José Vicente; Castellani, Rudy J.; Nozari, Ala; Wiklund, Lars; Sharma, Hari Shanker

doi:10.1016/bs.pbr.2021.06.015

Cited by 16 publications

(6 citation statements)

References 76 publications

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“…The investigated NPs represent reactive particles that may induce toxic effects, partly related to ROS formation. Even though Mn is an essential element required, for example, for proper functioning of the brain as well as the nervous and enzyme systems, excess exposure has been associated with negative effects on the nervous system like cognitive and motor dysfunctions. − Exposure to Ni NPs may increase the risk of lung damage such as lung fibrosis, respiratory tract disease, and chromosomal destruction in human lung cells and skin allergies. − Human exposure of Cu NPs may occur, for example, through contact with inks, plastics, and particles generated in the subway. , Cu is, similar to Mn, an essential metal for life. Exposure to Cu NPs has though been shown to increase the risk of pulmonary inflammation and to reduce the natural defense and clearance of hostile bacteria in the lungs. , …”

Section: Introductionmentioning

confidence: 99%

Adsorption of Horseradish Peroxidase on Metallic Nanoparticles: Effects on Reactive Oxygen Species Detection Using 2′,7′-Dichlorofluorescin Diacetate

Kessler

Hedberg

McCarrick

et al. 2021

Chem. Res. Toxicol.

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The fluorescent probe 2′,7′-dichlorofluorescein diacetate (DCFH-DA) together with the enzyme horseradish peroxidase (HRP) is widely used in nanotoxicology to study acellular reactive oxygen species (ROS) production from nanoparticles (NPs). This study examined whether HRP adsorbs onto NPs of Mn, Ni, and Cu and if this surface process influences the extent of metal release and hence the ROS production measurements using the DCFH assay in phosphate buffered saline (PBS), saline, or Dulbecco’s modified Eagle’s medium (DMEM). Adsorption of HRP was evident onto all NPs and conditions, except for Mn NPs in PBS. The presence of HRP resulted in an increased release of copper from the Cu NPs in PBS and reduced levels of nickel from the Ni NPs in saline. Both metal ions in solution and the adsorption of HRP onto the NPs can change the activity of HRP and thus influence the ROS results. The effect of HRP on the NP reactivity was shown to be solution chemistry dependent. Most notable was the evident affinity/adsorption of phosphate toward the metal NPs, followed by a reduced adsorption of HRP, the concomitant reduction in released manganese from the Mn NPs, and increased levels of released metals from the Cu NPs in PBS. Minor effects were observed for the Ni NPs. The solution pH should be monitored since the release of metals can change the solution pH and the activity of HRP is known to be pH-dependent. It is furthermore essential that solution pH adjustments are made following the addition of NaOH during diacetyl removal of DCFH-DA. Even though not observed for the given exposure conditions of this study, released metal ions could possibly induce agglomeration or partial denaturation of HRP, which in turn could result in steric hindrance for H 2 O 2 to reach the active site of HRP. This study further emphasizes the influence of HRP on the background kinetics, its solution dependence, and effects on measured ROS signals. Different ways of correcting for the background are highlighted, as this can result in different interpretations of generated results. The results show that adsorption of HRP onto the metal NPs influenced the extent of metal release and may, depending on the investigated system, result in either under- or overestimated ROS signals if used together with the DCFH assay. HRP should hence be used with caution when measuring ROS in the presence of reactive metallic NPs.

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Section: Introductionmentioning

confidence: 99%

Adsorption of Horseradish Peroxidase on Metallic Nanoparticles: Effects on Reactive Oxygen Species Detection Using 2′,7′-Dichlorofluorescin Diacetate

Kessler

Hedberg

McCarrick

et al. 2021

Chem. Res. Toxicol.

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“…BBB disruption and reduction in cerebral blood flow were found in rats intraperitoneally injected with Mn nanoparticles (30–40 nm size). 32 The interplay between brain CYP1B1 and Mn may result in a sustained increase in BBB permeability. BBB disruption has been observed in both patients with Parkinson's disease and MPTP‐induced animal model.…”

Section: Discussionmentioning

confidence: 99%

“…Excessive Mn exposure reduced BBB tight junctions in mice. BBB disruption and reduction in cerebral blood flow were found in rats intraperitoneally injected with Mn nanoparticles (30–40 nm size) 32 . The interplay between brain CYP1B1 and Mn may result in a sustained increase in BBB permeability.…”

Section: Discussionmentioning

confidence: 99%

CYP1B1 affects the integrity of the blood–brain barrier and oxidative stress in the striatum: An investigation of manganese‐induced neurotoxicity

Wu,

Li,

Tian

et al. 2024

CNS Neurosci Ther

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AimsExcessive influx of manganese (Mn) into the brain across the blood–brain barrier induces neurodegeneration. CYP1B1 is involved in the metabolism of arachidonic acid (AA) that affects vascular homeostasis. We aimed to investigate the effect of brain CYP1B1 on Mn‐induced neurotoxicity.MethodBrain Mn concentrations and α‐synuclein accumulation were measured in wild‐type and CYP1B1 knockout mice treated with MnCl2 (30 mg/kg) and biotin (0.2 g/kg) for 21 continuous days. Tight junctions and oxidative stress were analyzed in hCMEC/D3 and SH‐SY5Y cells after the treatment with MnCl2 (200 μM) and CYP1B1‐derived AA metabolites (HETEs and EETs).ResultsMn exposure inhibited brain CYP1B1, and CYP1B1 deficiency increased brain Mn concentrations and accelerated α‐synuclein deposition in the striatum. CYP1B1 deficiency disrupted the integrity of the blood–brain barrier (BBB) and increased the ratio of 3, 4‐dihydroxyphenylacetic acid (DOPAC) to dopamine in the striatum. HETEs attenuated Mn‐induced inhibition of tight junctions by activating PPARγ in endothelial cells. Additionally, EETs attenuated Mn‐induced up‐regulation of the KLF/MAO‐B axis and down‐regulation of NRF2 in neuronal cells. Biotin up‐regulated brain CYP1B1 and reduced Mn‐induced neurotoxicity in mice.ConclusionsBrain CYP1B1 plays a critical role in both cerebrovascular and dopamine homeostasis, which might serve as a novel therapeutic target for the prevention of Mn‐induced neurotoxicity.

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“…In this study, we used intraperitoneal administration of nanoparticles in spinal nerve lesion model to study their effects on neuropathic pain. This dose and route was used to understand the effects of nanoparticles systemic administration on brain and spinal cord function [22,23,[25][26][27]. Administration of similar doses of engineered metal nanoparticles of Ag, Cu or Al did not alter brain or spinal cord pathology under physiological conditions.…”

Section: Nanoparticles Are Abundant In the Environmentmentioning

confidence: 99%

“…It is quite likely that exposure of nanoparticles may affect the severity of neuropathic pain. This is evident from the findings that exposure of engineered metal nanoparticles induces blood-brain barrier (BBB) disruption and enhances morphine withdrawal induced brain pathology [22][23][24][25]. Nanoparticles exposure also adversely affects spinal cord trauma induced pathophysiology and exacerbates blood-spinal cord barrier breakdown to proteins [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Cerebrolysin Attenuates Exacerbation of Neuropathic Pain, Blood-spinal Cord Barrier Breakdown and Cord Pathology Following Chronic Intoxication of Engineered Ag, Cu or Al (50–60 nm) Nanoparticles

et al. 2023

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Neuropathic pain is associated with abnormal sensations and/or pain induced by non-painful stimuli, i.e., allodynia causing burning or cold sensation, pinching of pins and needles like feeling, numbness, aching or itching. However, no suitable therapy exists to treat these pain syndromes. Our laboratory explored novel potential therapeutic strategies using a suitable composition of neurotrophic factors and active peptide fragments-Cerebrolysin (Ever Neuro Pharma, Austria) in alleviating neuropathic pain induced spinal cord pathology in a rat model. Neuropathic pain was produced by constrictions of L-5 spinal sensory nerves for 2–10 weeks period. In one group of rats cerebrolysin (2.5 or 5 ml/kg, i.v.) was administered once daily after 2 weeks until sacrifice (4, 8 and 10 weeks). Ag, Cu and Al NPs (50 mg/kg, i.p.) were delivered once daily for 1 week. Pain assessment using mechanical (Von Frey) or thermal (Hot-Plate) nociceptive showed hyperalgesia from 2 weeks until 10 weeks progressively that was exacerbated following Ag, Cu and Al NPs intoxication in nerve lesioned groups. Leakage of Evans blue and radioiodine across the blood-spinal cord barrier (BSCB) is seen from 4 to 10 weeks in the rostral and caudal cord segments associated with edema formation and cell injury. Immunohistochemistry of albumin and GFAP exhibited a close parallelism with BSCB leakage that was aggravated by NPs following nerve lesion. Light microscopy using Nissl stain exhibited profound neuronal damages in the cord. Transmission electron microcopy (TEM) show myelin vesiculation and synaptic damages in the cord that were exacerbated following NPs intoxication. Using ELISA spinal tissue exhibited increased albumin, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and heat shock protein (HSP 72kD) upregulation together with cytokines TNF-α, IL-4, IL-6, IL-10 levels in nerve lesion that was exacerbated following NPs intoxication. Cerebrolysin treatment significantly reduced hyperalgesia and attenuated BSCB disruption, edema formation and cellular changes in nerve lesioned group. The levels of cytokines were also restored near normal levels with cerebrolysin treatment. Albumin, GFAP, MABP and HSP were also reduced in cerebrolysin treated group and thwarted neuronal damages, myelin vesiculation and cell injuries. These neuroprotective effects of cerebrolysin with higher doses were also effective in nerve lesioned rats with NPs intoxication. These observations suggest that cerebrolysin actively protects spinal cord pathology and hyperalgesia following nerve lesion and its exacerbation with metal NPs, not reported earlier.

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Manganese nanoparticles induce blood-brain barrier disruption, cerebral blood flow reduction, edema formation and brain pathology associated with cognitive and motor dysfunctions

Cited by 16 publications

References 76 publications

Adsorption of Horseradish Peroxidase on Metallic Nanoparticles: Effects on Reactive Oxygen Species Detection Using 2′,7′-Dichlorofluorescin Diacetate

Adsorption of Horseradish Peroxidase on Metallic Nanoparticles: Effects on Reactive Oxygen Species Detection Using 2′,7′-Dichlorofluorescin Diacetate

CYP1B1 affects the integrity of the blood–brain barrier and oxidative stress in the striatum: An investigation of manganese‐induced neurotoxicity

Cerebrolysin Attenuates Exacerbation of Neuropathic Pain, Blood-spinal Cord Barrier Breakdown and Cord Pathology Following Chronic Intoxication of Engineered Ag, Cu or Al (50–60 nm) Nanoparticles

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