N-Acetylcysteine Nanocarriers Protect against Oxidative Stress in a Cellular Model of Parkinson’s Disease

Abstract

<jats:p>Oxidative stress is a key mediator in the development and progression of Parkinson’s disease (PD). The antioxidant n-acetylcysteine (NAC) has generated interest as a disease-modifying therapy for PD but is limited due to poor bioavailability, a short half-life, and limited access to the brain. The aim of this study was to formulate and utilise mitochondria-targeted nanocarriers for delivery of NAC alone and in combination with the iron chelator deferoxamine (DFO), and assess their ability to protect against oxidative stress in a cellular rotenone PD model. Pluronic F68 (P68) and dequalinium (DQA) nanocarriers were prepared by a modified thin-film hydration method. An MTT assay assessed cell viability and iron status was measured using a ferrozine assay and ferritin immunoassay. For oxidative stress, a modified cellular antioxidant activity assay and the thiobarbituric acid-reactive substances assay and mitochondrial hydroxyl assay were utilised. Overall, this study demonstrates, for the first time, successful formulation of NAC and NAC + DFO into P68 + DQA nanocarriers for neuronal delivery. The results indicate that NAC and NAC + DFO nanocarriers have the potential characteristics to access the brain and that 1000 μM P68 + DQA NAC exhibited the strongest ability to protect against reduced cell viability (p = 0.0001), increased iron (p = 0.0033) and oxidative stress (p ≤ 0.0003). These NAC nanocarriers therefore demonstrate significant potential to be transitioned for further preclinical testing for PD.</jats:p>

Mitochondria-Targeted Antioxidants: A Step towards Disease Treatment

“…The nanocarrier delivery system that consisted of FDA-approved Pluronic F68 and dequalinium has been revealed to enhance the bioavailability of NAC protecting against the reduced cell viability and oxidative stress in the cellular model of PD, which raises a significant prospect of nanocarrier-based NAC to be transitioned for clinical trials [ 95 ]. As indicated by the results from previous clinical trials, the available clinical therapies using antioxidants for PD can only alleviate the symptoms; but none can prevent neuronal degeneration via regulating the dopaminergic system; thus, the combination of MTAs with the traditional drugs (dopamine receptor activator, such as pramipexole) could be a considerable strategy for the further experiments and clinical trials.…”

Micellar Nanocarriers of Hydroxytyrosol Are Protective against Parkinson’s Related Oxidative Stress in an In Vitro hCMEC/D3-SH-SY5Y Co-Culture System

“…All nanoformulations were prepared using a modified thin-film hydration method [22,24,25,44]. Briefly, 10 mL of methanol was used to dissolve P68 and DQA with HT or HT + DFO at certain ratios (Table 1).…”

“…Nanocarriers can enhance the potency, stability, bioavailability, and the passage across biological membranes of incorporated compounds [21][22][23][24]. Pluronic F68 (P68) + dequalinium (DQA) nanocarriers have been successfully used to deliver the antioxidants curcumin and N-acetylcysteine, alone and in combination with the iron chelator deferoxamine (DFO), to mitochondria within SH-SY5Y cells to protect against a rotenone model of PD [24,25]. These nanocarriers exhibit many characteristics that make them suitable for brain penetrance, for example small particle size (<200 nm) and relatively neutral charge (<10 mV) [23,[26][27][28][29][30][31][32][33].…”

“…These nanocarriers exhibit many characteristics that make them suitable for brain penetrance, for example small particle size (<200 nm) and relatively neutral charge (<10 mV) [23,[26][27][28][29][30][31][32][33]. They also target the mitochondria, the main site of iron-induced oxidative stress and the associated dopaminergic cell death evident in PD [24,25,[34][35][36][37][38][39][40][41][42][43]. The combination of antioxidants and iron chelators for the treatment of PD may provide a promising strategy to limit the degenerative process in PD due to the dual approach of free radical scavenging and iron chelation to limit detrimental free iron availability.…”

Antioxidant Capability and Physical Exercise in Neurobiology: A Focus in Neurodegeneration

“…In terms of neuroprotection, this is fundamental since BDNF regulates brain plasticity, energy homeostasis and cognitive capabilities. In another study, Mursaleen et al [2] considered the antioxidant N-acetylcystein (NAC) alone and associated with deferoxamine (DFO) that is an iron chelator. In particular, they formulated NAC and NAC+DFO nanocarriers targeted to mitochondria of Parkinson's disease cellular models demonstrating a better brain availability and a more effective protection against the oxidative stress.…”