ABSTRACT
When nanoparticles enter biological environments, proteins adsorb to form the "protein corona" which alters nanoparticle biodistribution and toxicity. Herein, we measure protein corona formation on DNA-functionalized single-walled carbon nanotubes (ssDNA-SWCNTs), a nanoparticle used widely for sensing and delivery, in blood plasma and cerebrospinal fluid. We characterize corona composition by mass spectrometry, revealing high-abundance corona proteins involved in lipid binding, complement activation, and coagulation. We investigate roles of electrostatic and entropic interactions driving selective corona formation. Lastly, we study real-time protein binding on ssDNA-SWCNTs, obtaining agreement between enriched proteins binding strongly and depleted proteins binding marginally, while highlighting cooperative adsorption mechanisms. Knowledge of protein corona composition, formation mechanisms, and dynamics informs nanoparticle translation from in vitro design to in vivo application.
Subject(s)
Nanoparticles/chemistry , Nanotechnology/methods , Nanotubes, Carbon/chemistry , Protein Corona/chemistry , HumansABSTRACT
Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder which affects medium spiny GABAergic neurons mainly in the striatum. Oxidative damage, neuro-inflammation, apoptosis, protein aggregation, and signaling of neurotrophic factors are some of the common cellular pathways involved in HD. Quinolinic acid (QA) causes excitotoxicity by stimulating N-methyl-D-aspartate receptors via calcium overload leading to neurodegeneration. Neuroprotective potential of peroxisome proliferator activated receptor-γ (PPARγ) agonists and histone deacetylase (HDAC) inhibitors have been well documented in experimental models of neurodegenerative disorders; however, their exact mechanisms are not clear. Therefore, present study has been designed to explore possible neuroprotective mechanism of valproic acid (VPA) and its interaction with rosiglitazone against QA induced HD-like symptoms in rats. Single bilateral intrastriatal QA (200 nmol/2 µl saline) administration significantly caused motor incoordination, memory impairment, oxidative damage, mitochondrial dysfunction (complex I, II, II and IV), cellular alterations [tumor necrosis factor-alpha (TNF-α), caspase-3, brain derived neurotrophic factor, acetylcholinesterase], and striatal neurodegeneration as compared to sham group. Treatment with rosiglitazone (5, 10 mg/kg) and VPA (100, 200 mg/kg) for 21 days significantly attenuated these behavioral, biochemical, and cellular alterations as compared to control (QA 200 nmol) group. However, VPA (100 mg/kg) treatment in combination with rosiglitazone (5 mg/kg) for 21 days synergized their neuroprotective effect, which was significant as compared to their effects per se in QA-treated animals. The present study provides an evidence of possible interplay of PPARγ agonists and HDAC inhibitors as a novel therapeutic strategy in the management of HD.
Subject(s)
Histone Deacetylases/metabolism , Neurodegenerative Diseases/drug therapy , Neurotoxicity Syndromes/drug therapy , PPAR gamma/metabolism , Thiazolidinediones/pharmacology , Valproic Acid/pharmacology , Animals , Body Weight/drug effects , Brain/drug effects , Brain/pathology , Brain/physiopathology , Disease Models, Animal , Drug Synergism , Histone Deacetylase Inhibitors/pharmacology , Huntington Disease , Male , Maze Learning/drug effects , Maze Learning/physiology , Motor Activity/drug effects , Motor Activity/physiology , Neurodegenerative Diseases/pathology , Neurodegenerative Diseases/physiopathology , Neuroprotective Agents/pharmacology , Neurotoxicity Syndromes/pathology , Neurotoxicity Syndromes/physiopathology , PPAR gamma/agonists , Quinolinic Acid , Rats, Wistar , Rosiglitazone , Signal Transduction/drug effectsABSTRACT
Emerging evidences indicate hesperidin, a citrus flavanone, attenuates neurodegenerative processes and related complications. Besides its anti-oxidant properties, the other probable mechanisms which underpin its neuroprotective potential are still not clear. In light of emerging role of flavonoids in modulating oxidative stress and neuro-inflammation, the study has been designed to explore the possible neuroprotective effect of hesperidin and its combination with minocycline (microglial inhibitor), against quinolinic acid (QA) induced Huntington's disease (HD) like symptoms in rats. Unilateral intrastriatal administration of QA (300 nmol/4 µl) significantly reduced body weight, impaired behavior (locomotor activity, beam balance and memory performance), caused oxidative damage (increased lipid peroxidation, nitrite concentration, depleted super oxide dismutase and reduced glutathione), demonstrated mitochondrial dysfunction (decreased Complex-I, II, III, and IV activities), increased striatal lesion volume and altered the levels of TNF-α, caspase-3 as well as BDNF expression, as compared to sham group. Meanwhile, chronic hesperidin (100mg/kg, p.o.) and minocycline (25mg/kg, p.o.) treatment for 21 days significantly attenuated the behavioral, biochemical and cellular alterations as compared to QA treated (control) animals, whereas hesperidin (50mg/kg, p.o.) treatment was found to be non-significant. However, treatment of hesperidin (50mg/kg) in combination with minocycline (25mg/kg) potentiated their neuroprotective effect, which was significant as compared to their effects per se in QA treated animals. Taken altogether, the results of the present study suggest a possible interplay of microglial modulation and anti-oxidant effect in neuroprotective potential of hesperidin against QA induced HD like symptoms in rats.
