Role of secondary mediators in caffeine-mediated neuroprotection in maneb- and paraquat-induced Parkinson's disease phenotype in the mouse.
Maneb and paraquat are known to induce Parkinson's disease (PD) phenotype, however, caffeine offers neuroprotection. Nitric oxide (NO) acts an important mediator in PD phenotype and tyrosine kinase (TK), nuclear factor kappa B (NF-kB), p38 mitogen activated protein kinase (p38 MAPK) are known to regulate its production. The present study aimed to elucidate the role of caffeine in the regulation of NO production and microglial activation and their subsequent contribution in dopaminergic neuroprotection. The animals were treated with caffeine and/or maneb and paraquat along with controls. In a few sets of experiments, the animals were also treated with aminoguanidine, an inhibitor of inducible NO synthase, pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-kB, genistein, an inhibitor of TK or SB202190, an inhibitor of p38 MAPK. Tyrosine hydroxylase (TH)-immunoreactivity and anti-integrin αM (OX-42) staining were performed to assess the number of dopaminergic neurons and activation of microglia, respectively. NO was measured in terms of nitrite, however, the expressions of p38 MAPK, interleukin (IL)-1β, NF-kB and TK were checked by western blot analyses. Maneb and paraquat induced the number of degenerating dopaminergic neurons, microglial cells, nitrite content, expressions of IL-1β, p38 MAPK, NF-kB and TK and caffeine co-treatment reduced the level of such alterations. Reductions were more pronounced in the animals co-treated with aminoguanidine, PDTC, genistein or SB202190. The results obtained thus demonstrate that caffeine down-regulates NO production, neuroinflammation and microglial activation, which possibly contribute to neuroprotection.
Council of Scientific and Industrial Research-Indian Institute of Toxicology Research-CSIR-IITR, Mahatma Gandhi Marg, Post Box-80, Lucknow 226001, UP, India.
Sharawan
S
Yadav
Satya Prakash
SP
Gupta
Garima
G
Srivastava
Pramod Kumar
PK
Srivastava
Mahendra Pratap
MP
Singh
D000818:Animals; D002110:Caffeine / Q000627:therapeutic use*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D008297:Male; D008344:Maneb / Q000633:toxicity*; D051379:Mice; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D010269:Paraquat / Q000633:toxicity*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D010641:Phenotype
D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D008344:Maneb; D009569:Nitric Oxide; D002110:Caffeine; D010269:Paraquat