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Central nervous system toxicity of metallic nanoparticles.

Feng X, Chen A, Zhang Y, Wang J, Shao L, Wei L - Int J Nanomedicine (2015)

Bottom Line: However, NPs can also be potentially hazardous to the CNS in terms of nano-neurotoxicity via several possible mechanisms, such as oxidative stress, autophagy, and lysosome dysfunction, and the activation of certain signaling pathways.In this review, we discuss the dual effect of NMs on the CNS and the mechanisms involved.The limitations of the current research are also discussed.

View Article: PubMed Central - PubMed

Affiliation: Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.

ABSTRACT
Nanomaterials (NMs) are increasingly used for the therapy, diagnosis, and monitoring of disease- or drug-induced mechanisms in the human biological system. In view of their small size, after certain modifications, NMs have the capacity to bypass or cross the blood-brain barrier. Nanotechnology is particularly advantageous in the field of neurology. Examples may include the utilization of nanoparticle (NP)-based drug carriers to readily cross the blood-brain barrier to treat central nervous system (CNS) diseases, nanoscaffolds for axonal regeneration, nanoelectromechanical systems in neurological operations, and NPs in molecular imaging and CNS imaging. However, NPs can also be potentially hazardous to the CNS in terms of nano-neurotoxicity via several possible mechanisms, such as oxidative stress, autophagy, and lysosome dysfunction, and the activation of certain signaling pathways. In this review, we discuss the dual effect of NMs on the CNS and the mechanisms involved. The limitations of the current research are also discussed.

No MeSH data available.


Related in: MedlinePlus

Overview of the mechanistic steps of NP-induced autophagy.Notes: NPs induce autophagy in two ways: ROS-dependent autophagy and lysosome-dependent autophagy. During autophagy, a phagophore is created and it then elongates into a double-membrane autophagosome while sequestering cytoplasmic material. This autophagosome then fuses with a lysosome, resulting in an autolysosome. The enzymes present in the autolysosome lumen eventually degrade the inner membrane and autophagic cargo, thus providing macromolecules that can be transported into the cytosol via permeases. TFEB is a transcription factor that translocates to the nucleus upon activation (similar to dysfunction of the lysosome), where it promotes the transcription of the lysosomal and autophagic genes. Proper stimulation will help cells survive; however, under- and overstimulation of autophagy will lead to cell death.Abbreviations: NP, nanoparticle; TFEB, transcription factor EB; ROS, reactive oxygen species; Atg, autophagy protein.
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f3-ijn-10-4321: Overview of the mechanistic steps of NP-induced autophagy.Notes: NPs induce autophagy in two ways: ROS-dependent autophagy and lysosome-dependent autophagy. During autophagy, a phagophore is created and it then elongates into a double-membrane autophagosome while sequestering cytoplasmic material. This autophagosome then fuses with a lysosome, resulting in an autolysosome. The enzymes present in the autolysosome lumen eventually degrade the inner membrane and autophagic cargo, thus providing macromolecules that can be transported into the cytosol via permeases. TFEB is a transcription factor that translocates to the nucleus upon activation (similar to dysfunction of the lysosome), where it promotes the transcription of the lysosomal and autophagic genes. Proper stimulation will help cells survive; however, under- and overstimulation of autophagy will lead to cell death.Abbreviations: NP, nanoparticle; TFEB, transcription factor EB; ROS, reactive oxygen species; Atg, autophagy protein.

Mentions: Because the majority of NPs enter cells through endocy-tosis, lysosomes are also frequently a target for their toxicity. NPs can cause lysosomal dysfunction by alkalization of the lysosomal lumen, NP overload, or cytoskeleton disruption.106,107 This dysfunction can indirectly upregulate autophagy as a mechanism for the cell to compensate for insufficient degradative capacity.108 The signaling link between the lysosomal sensing of stress and autophagy is affected by the transcription factor EB (TFEB), a main regulator of the coordinated lysosomal expression and regulation network. TFEB is a molecule proven to play an important role in cellular deg-radative processes. TFEB is able to reduce neurofibrillary tangle pathology, rescue behavioral and synaptic deficits, and effectively compensate for neurodegeneration in the rTg4510 mouse model of autopathy.109 Based on these studies, Stern et al107 proposed that autophagy and lysosomal dysfunction may be emerging mechanisms of NM toxicity (ie, NP-mediated lysosome-dependent autophagy). Autophagy can play dual roles in cell survival after interaction with NPs: autophagy can play a cytoprotective role or a cytotoxic role under different conditions. It has gradually been revealed that autophagy and apoptosis are interconnected at several levels. Dysfunctions of autophagy, including both overstimulation and understimulation, lead to cell apoptosis or necrosis.110 Cell death is a dynamic phenomenon, and multiple cell death types are often observed within the same cell.111 Autophagy and apoptosis are often simultaneously detected upon treatment with NMs (Figure 3 shows the mechanistic steps of NP-induced autophagy). Freyre-Fonseca et al66 reported that cellular changes induced by TiO2 NPs, including alteration in the redox state, reduced antioxidant enzymatic defense ability, and mitochondrial depolarization, can activate apoptotic pathways. Márquez-Ramírez et al112 found that glial cells exposed to TiO2 NPs exhibited apoptotic death. Furthermore, TiO2 NPs at a concentration above 1 µg/mL have been shown to cause cell death in human astrocytes-like astrocytoma U87 cells.113 Different concentrations of TiO2 NPs decreased the cell viability of PC12 cells after different exposure times, leading to the intracellular accumulation of ROS and apoptosis. Similar toxic effects have also been found in brain microglia cells (BV2).114,115


Central nervous system toxicity of metallic nanoparticles.

Feng X, Chen A, Zhang Y, Wang J, Shao L, Wei L - Int J Nanomedicine (2015)

Overview of the mechanistic steps of NP-induced autophagy.Notes: NPs induce autophagy in two ways: ROS-dependent autophagy and lysosome-dependent autophagy. During autophagy, a phagophore is created and it then elongates into a double-membrane autophagosome while sequestering cytoplasmic material. This autophagosome then fuses with a lysosome, resulting in an autolysosome. The enzymes present in the autolysosome lumen eventually degrade the inner membrane and autophagic cargo, thus providing macromolecules that can be transported into the cytosol via permeases. TFEB is a transcription factor that translocates to the nucleus upon activation (similar to dysfunction of the lysosome), where it promotes the transcription of the lysosomal and autophagic genes. Proper stimulation will help cells survive; however, under- and overstimulation of autophagy will lead to cell death.Abbreviations: NP, nanoparticle; TFEB, transcription factor EB; ROS, reactive oxygen species; Atg, autophagy protein.
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Related In: Results  -  Collection

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f3-ijn-10-4321: Overview of the mechanistic steps of NP-induced autophagy.Notes: NPs induce autophagy in two ways: ROS-dependent autophagy and lysosome-dependent autophagy. During autophagy, a phagophore is created and it then elongates into a double-membrane autophagosome while sequestering cytoplasmic material. This autophagosome then fuses with a lysosome, resulting in an autolysosome. The enzymes present in the autolysosome lumen eventually degrade the inner membrane and autophagic cargo, thus providing macromolecules that can be transported into the cytosol via permeases. TFEB is a transcription factor that translocates to the nucleus upon activation (similar to dysfunction of the lysosome), where it promotes the transcription of the lysosomal and autophagic genes. Proper stimulation will help cells survive; however, under- and overstimulation of autophagy will lead to cell death.Abbreviations: NP, nanoparticle; TFEB, transcription factor EB; ROS, reactive oxygen species; Atg, autophagy protein.
Mentions: Because the majority of NPs enter cells through endocy-tosis, lysosomes are also frequently a target for their toxicity. NPs can cause lysosomal dysfunction by alkalization of the lysosomal lumen, NP overload, or cytoskeleton disruption.106,107 This dysfunction can indirectly upregulate autophagy as a mechanism for the cell to compensate for insufficient degradative capacity.108 The signaling link between the lysosomal sensing of stress and autophagy is affected by the transcription factor EB (TFEB), a main regulator of the coordinated lysosomal expression and regulation network. TFEB is a molecule proven to play an important role in cellular deg-radative processes. TFEB is able to reduce neurofibrillary tangle pathology, rescue behavioral and synaptic deficits, and effectively compensate for neurodegeneration in the rTg4510 mouse model of autopathy.109 Based on these studies, Stern et al107 proposed that autophagy and lysosomal dysfunction may be emerging mechanisms of NM toxicity (ie, NP-mediated lysosome-dependent autophagy). Autophagy can play dual roles in cell survival after interaction with NPs: autophagy can play a cytoprotective role or a cytotoxic role under different conditions. It has gradually been revealed that autophagy and apoptosis are interconnected at several levels. Dysfunctions of autophagy, including both overstimulation and understimulation, lead to cell apoptosis or necrosis.110 Cell death is a dynamic phenomenon, and multiple cell death types are often observed within the same cell.111 Autophagy and apoptosis are often simultaneously detected upon treatment with NMs (Figure 3 shows the mechanistic steps of NP-induced autophagy). Freyre-Fonseca et al66 reported that cellular changes induced by TiO2 NPs, including alteration in the redox state, reduced antioxidant enzymatic defense ability, and mitochondrial depolarization, can activate apoptotic pathways. Márquez-Ramírez et al112 found that glial cells exposed to TiO2 NPs exhibited apoptotic death. Furthermore, TiO2 NPs at a concentration above 1 µg/mL have been shown to cause cell death in human astrocytes-like astrocytoma U87 cells.113 Different concentrations of TiO2 NPs decreased the cell viability of PC12 cells after different exposure times, leading to the intracellular accumulation of ROS and apoptosis. Similar toxic effects have also been found in brain microglia cells (BV2).114,115

Bottom Line: However, NPs can also be potentially hazardous to the CNS in terms of nano-neurotoxicity via several possible mechanisms, such as oxidative stress, autophagy, and lysosome dysfunction, and the activation of certain signaling pathways.In this review, we discuss the dual effect of NMs on the CNS and the mechanisms involved.The limitations of the current research are also discussed.

View Article: PubMed Central - PubMed

Affiliation: Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.

ABSTRACT
Nanomaterials (NMs) are increasingly used for the therapy, diagnosis, and monitoring of disease- or drug-induced mechanisms in the human biological system. In view of their small size, after certain modifications, NMs have the capacity to bypass or cross the blood-brain barrier. Nanotechnology is particularly advantageous in the field of neurology. Examples may include the utilization of nanoparticle (NP)-based drug carriers to readily cross the blood-brain barrier to treat central nervous system (CNS) diseases, nanoscaffolds for axonal regeneration, nanoelectromechanical systems in neurological operations, and NPs in molecular imaging and CNS imaging. However, NPs can also be potentially hazardous to the CNS in terms of nano-neurotoxicity via several possible mechanisms, such as oxidative stress, autophagy, and lysosome dysfunction, and the activation of certain signaling pathways. In this review, we discuss the dual effect of NMs on the CNS and the mechanisms involved. The limitations of the current research are also discussed.

No MeSH data available.


Related in: MedlinePlus