Quercetin up-regulates mitochondrial complex-I activity to protect against programmed cell death in rotenone model of Parkinson's disease in rats.
We tested quercetin, a dietary bioflavonoid with potent free radical scavenging action and antioxidant activity, for its neuroprotective effects in rotenone-induced hemi-parkinsonian rats. Rats were infused unilaterally with rotenone into the substantia nigra, and quercetin (25-75mg/kg, i.p.) was administered at 12-h intervals for 4days, and analyzed on the 5th day. Amphetamine- or apomorphine-induced unilateral rotations were significantly reduced in quercetin-treated rats, when analyzed on 14th or 16th day post-surgery, respectively. Quercetin possessed potent hydroxyl radical scavenging action in a cells-free, Fenton-like reaction in test tubes, and in isolated mitochondria when measured by salicylate hydroxylation method. We observed dose-dependent attenuation of the rotenone-induced loss in striatal dopamine, and nigral oxidized and reduced glutathione, as well as the increases in endogenous antioxidant enzymes (catalase and superoxide dismutase) activities supporting the notion that quercetin-effect is mediated via its powerful hydroxyl radicals-scavenging and antioxidant actions. Quercetin's dose-dependent ability to up-regulate mitochondrial complex-I activity, as evidenced by NADH-oxidation, and as seen in blue native-polyacrylamide gel electrophoresis (PAGE) staining in both the contra- and ipsi-lateral nigra suggests the containment of reactive oxygen production at the mitochondrial level. Rotenone-induced induction of NADH-diaphorase activity in the nigral neurons, and its attenuation by quercetin pointed to the possible involvement of nitric oxide too. Reversal of neuronal death induced by rotenone as observed by increased tyrosine hydroxylase-positive cells and decreased TdT-mediated dUTP nick end-labeling (TUNEL) staining in the substantia nigra confirmed the potential of quercetin to revamp dopaminergic cells following oxidative stress mediated programmed cell death and neuronal demise. The present study strongly implicates quercetin's potential ability to repair mitochondrial electron transport defects and to up-regulate its function as the basis of neuroprotection observed in a mitochondrial neurotoxin-induced Parkinsonism.
Division of Cell Biology & Physiology, Laboratory of Clinical and Experimental Neuroscience, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Jadavpur, Kolkata 700 032, India. ssk2004@med.cornell.edu
S S
SS
Karuppagounder
S K
SK
Madathil
M
M
Pandey
R
R
Haobam
U
U
Rajamma
K P
KP
Mohanakumar
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D004195:Disease Models, Animal; D042967:Electron Transport Complex I / Q000096:biosynthesis*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020734:Parkinsonian Disorders / Q000378:metabolism*; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012402:Rotenone / Q000633:toxicity; D014475:Uncoupling Agents / Q000633:toxicity; D015854:Up-Regulation
D000975:Antioxidants; D018696:Neuroprotective Agents; D014475:Uncoupling Agents; D012402:Rotenone; D011794:Quercetin; D042967:Electron Transport Complex I