Nicotine-encapsulated poly(lactic-co-glycolic) acid nanoparticles improve neuroprotective efficacy against MPTP-induced parkinsonism.
For some instances of Parkinson disease (PD), current evidence in the literature is consistent with reactive oxygen species being involved in the etiology of the disease. The management of PD is still challenging owing to its ambiguous etiology and lack of permanent cure. Because nicotine offers neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, the neuroprotective efficacy of nicotine-encapsulated poly(lactic-co-glycolic) acid (PLGA) nanoparticles and the underlying mechanism of improved efficacy, if any, over bulk nicotine were assessed in this study. The selected indicators of oxidative stress, dopaminergic neurodegeneration and apoptosis, were measured in both in vitro and rodent models of parkinsonism in the presence or absence of "nanotized" or bulk nicotine. The levels of dopamine and its metabolites were measured in the striatum, nicotine and its metabolite in the nigrostriatal tissues while the immunoreactivities of tyrosine hydroxylase (TH), metallothionein-III (MT-III), inducible nitric oxide synthase (iNOS) and microglial activation were checked in the substantia nigra of controls and treated mice. GSTA4-4, heme oxygenase (HO)-1, tumor suppressor protein 53 (p53), caspase-3, lipid peroxidation (LPO), and nitrite levels were measured in the nigrostriatal tissues. Nicotine-encapsulated PLGA nanoparticles improved the endurance of TH-immunoreactive neurons and the number of fiber outgrowths and increased the mRNA expression of TH, neuronal cell adhesion molecule, and growth-associated protein-43 over bulk against 1-methyl-4-phenyl pyridinium ion-induced degeneration in the in vitro model. MPTP reduced TH immunoreactivity and levels of dopamine and its metabolites and increased microglial activation, expression of GSTA4-4, iNOS, MT-III, HO-1, p53, and caspase-3, and levels of nitrite and LPO. Whereas both bulk nicotine and nicotine-encapsulated PLGA nanoparticles modulated the changes toward controls, the modulation was more pronounced in nicotine-encapsulated PLGA nanoparticle-treated parkinsonian mice. The levels of nicotine and cotinine were elevated in nicotine-encapsulated PLGA nanoparticle-treated PD mouse brain compared with bulk. The results obtained from this study demonstrate that nanotization of nicotine improves neuroprotective efficacy by enhancing its bioavailability and subsequent modulation in the indicators of oxidative stress and apoptosis.
CSIR-Indian Institute of Toxicology Research, Lucknow 226 001, UP, India.
Manindra Nath
MN
Tiwari
CSIR-Indian Institute of Toxicology Research, Lucknow 226 001, UP, India; Academy of Scientific and Innovative Research (AcSIR), India.
Swati
S
Agarwal
CSIR-Institute of Genomics and Integrative Biology, CSIR, Delhi 110 007, India.
Priyanka
P
Bhatnagar
CSIR-Indian Institute of Toxicology Research, Lucknow 226 001, UP, India.
Naveen Kumar
NK
Singhal
CSIR-Indian Institute of Toxicology Research, Lucknow 226 001, UP, India; Academy of Scientific and Innovative Research (AcSIR), India.
Shashi Kant
SK
Tiwari
CSIR-Institute of Genomics and Integrative Biology, CSIR, Delhi 110 007, India.
Pradeep
P
Kumar
CSIR-Indian Institute of Toxicology Research, Lucknow 226 001, UP, India.
Lalit Kumar Singh
LKS
Chauhan
CSIR-Indian Institute of Toxicology Research, Lucknow 226 001, UP, India.
Devendra Kumar
DK
Patel
CSIR-Indian Institute of Toxicology Research, Lucknow 226 001, UP, India; Academy of Scientific and Innovative Research (AcSIR), India. Electronic address: rajnish@iitr.res.in.
Rajnish Kumar
RK
Chaturvedi
CSIR-Indian Institute of Toxicology Research, Lucknow 226 001, UP, India. Electronic address: mahendraiitr@gmail.com.
Mahendra Pratap
MP
Singh
CSIR-Indian Institute of Toxicology Research, Lucknow 226 001, UP, India; CSIR-Institute of Genomics and Integrative Biology, CSIR, Delhi 110 007, India. Electronic address: kcgupta@iitr.res.in.
Kailash Chand
KC
Gupta
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D005434:Flow Cytometry; D007150:Immunohistochemistry; D019344:Lactic Acid / Q000494:pharmacology; D051379:Mice; D058726:Nanoconjugates; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009538:Nicotine / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects; D020734:Parkinsonian Disorders / Q000473:pathology*; D011100:Polyglycolic Acid / Q000494:pharmacology; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D060888:Real-Time Polymerase Chain Reaction
D058726:Nanoconjugates; D018696:Neuroprotective Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D009538:Nicotine
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Free radicals; Neuroprotection; Nicotine-encapsulated PLGA nanoparticles; Parkinson disease