Mechanism of Nanotization-Mediated Improvement in the Efficacy of Caffeine Against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism.
The study aimed to measure the neuroprotective efficacy of caffeine-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles over bulk and to delineate the mechanism of improvement in efficacy both in vitro and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinsonism. Caffeine-encapsulated PLGA nanoparticles exhibited more pronounced increase in the endurance of dopaminergic neurons, fibre outgrowth and expression of tyrosine hydroxylase (TH) and growth-associated protein-43 (GAP-43) against 1-methyl-4-phenylpyridinium (MPP+)-induced alterations in vitro. Caffeine-encapsulated PLGA nanoparticles also inhibited MPP(+)-mediated nuclear translocation of nuclear factor-kappa B (NF-κB) and augmented protein kinase B phosphorylation more potentially than bulk counterpart. Conversely, MPTP reduced the striatal dopamine and its metabolites and nigral TH immunoreactivity whereas augmented the nigral microglial activation and nigrostriatal lipid peroxidation and nitrite content, which were shifted towards normalcy by caffeine. The modulations were more evident in caffeine-encapsulated PLGA nanoparticles treated animals as compared with bulk. Moreover, the striatal caffeine and its metabolites were found to be significantly higher in caffeine-encapsulated PLGA nanoparticles-treated mice as compared with bulk. The results thus suggest that nanotization improves the protective efficacy of caffeine against MPTP-induced Parkinsonism owing to enhanced bioavailability, inhibition of the nuclear translocation of NF-κB and activation of protein kinase B phosphorylation.
Naveen Kumar
NK
Singhal
Swati
S
Agarwal
Priyanka
P
Bhatnagar
Manindra Nath
MN
Tiwari
Shashi Kant
SK
Tiwari
Garima
G
Srivastava
Pradeep
P
Kumar
Seth
S
Brashket
Devendra Kumar
DK
Patel
Rajnish Kumar
RK
Chaturvedi
Mahendra Pratap
MP
Singh
Kailash Chand
KC
Gupta
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000009:adverse effects*; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D001692:Biological Transport; D002110:Caffeine / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002452:Cell Count; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation; D016650:Fluorescein-5-isothiocyanate / Q000737:chemistry; D019922:GAP-43 Protein / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D019344:Lactic Acid / Q000737:chemistry; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009573:Nitrites / Q000378:metabolism; D020734:Parkinsonian Disorders / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010750:Phosphoproteins / Q000378:metabolism; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D004337:Drug Carriers; D019922:GAP-43 Protein; D016328:NF-kappa B; D018696:Neuroprotective Agents; D009573:Nitrites; D010750:Phosphoproteins; D012333:RNA, Messenger; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D002110:Caffeine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D051057:Proto-Oncogene Proteins c-akt; D016650:Fluorescein-5-isothiocyanate; D004298:Dopamine