Paraquat induces oxidative stress, neuronal loss in substantia nigra region and Parkinsonism in adult rats: Neuroprotection and amelioration of symptoms by water-soluble formulation of Coenzyme Q10

<p>Abstract</p> <p>Background</p> <p>Parkinson's disease, for which currently there is no cure, develops as a result of progressive loss of dopamine neurons in the brain; thus, identification of any potential therapeutic intervention for disease management is of a great importance.</p> <p>Results</p> <p>Here we report that prophylactic application of water-soluble formulation of coenzyme Q₁₀could effectively offset the effects of environmental neurotoxin paraquat, believed to be a contributing factor in the development of familial PD. In this study we utilized a model of paraquat-induced dopaminergic neurodegeneration in adult rats that received three weekly intra-peritoneal injections of the herbicide paraquat. Histological and biochemical analyses of rat brains revealed increased levels of oxidative stress markers and a loss of approximately 65% of dopamine neurons in the <it>substantia nigra </it>region. The paraquat-exposed rats also displayed impaired balancing skills on a slowly rotating drum (rotorod) evidenced by their reduced spontaneity in gait performance. In contrast, paraquat exposed rats receiving a water-soluble formulation of coenzyme Q₁₀in their drinking water prior to and during the paraquat treatment neither developed neurodegeneration nor reduced rotorod performance and were indistinguishable from the control paraquat-untreated rats.</p> <p>Conclusion</p> <p>Our data confirmed that paraquat-induced neurotoxicity represents a convenient rat model of Parkinsonian neurodegeneration suitable for mechanistic and neuroprotective studies. This is the first preclinical evaluation of a water-soluble coenzyme Q₁₀formulation showing the evidence of prophylactic neuroprotection at clinically relevant doses.</p

Role of mitochondria in neuronal cell death induced by oxidative stress: Neuro-protection by Coenzyme Q10.

NRC publication: Ye

Paraquat induces oxidative stress and neuronal cell death: Neuro-protection by water-soluble coenzyme Q 10.: Toxicol.Appl.Pharmacol.

NRC publication: Ye

Unique technologhy for solubilization and delivery of highly lipophilic bioactive molecules.

NRC publication: Ye

Analysis of coenzyme Q10 content in human plasma and other biological samples

NRC publication: Ye

Water-soluble formulation of coenzyme Q10 inhibits Bax-induced destablization of mitochondria in mammalian cells.

NRC publication: Ye

Molecular mechanisms of glutamate neurotoxicity in mixed cultures of NT2-derived neurons and astrocytes: protective effects of coenzyme Q10

In press: YesNRC publication: Ye

Identification of Ataxia-associated mtDNA mutations (m.4052T>C and m.9035T>C) and evaluation of their pathogenicity in transmitochondrial cybrids

The potential pathogenicity of two homoplasmic mtDNA point mutations, 9035T>C and 4452T>C, found in a family afflicted with maternally transmitted cognitive developmental delay, learning disability, and progressive ataxia was evaluated using transmitochondrial cybrids. We confirmed that the 4452T>C transition in tRNAMet represented a polymorphism; however, 9035T>C conversion in the ATP6 gene was responsible for a defective F\u2080-ATPase. Accordingly, mutant cybrids had a reduced oligomycin-sensitive ATP hydrolyzing activity. They had less than half of the steady-state content of ATP and nearly an 8-fold higher basal level of reactive oxygen species (ROS). Mutant cybrids were unable to cope with additional insults, i.e., glucose deprivation or tertiary-butyl hydroperoxide, and they succumbed to either apoptotic or necrotic cell death. Both of these outcomes were prevented by the antioxidants CoQ\u2081\u2080 and vitamin E, suggesting that the abnormally high levels of ROS were the triggers of cell death. In conclusion, the principal metabolic defects, i.e., energy deficiency and ROS burden, resulted from the 9035T>C mutation and could be responsible for the development of clinical symptoms in this family. Furthermore, antioxidant therapy might prove helpful in the management of this disease.Peer reviewed: YesNRC publication: Ye