l-DOPA reverses the hypokinetic behaviour and rigidity in rotenone-treated rats

Peripherally and locally administered rotenone (an inhibitor of mitochondrial complex I) has been proposed as a model of Parkinson's disease (PD) as it induces nigrostriatal degeneration associated with alpha-synuclein inclusions. If rotenone-induced symptoms represent a model of PD, than they should be counteracted by L-DOPA. To answer this question, rats were treated with rotenone 2.5 mg/kg over 48 days. Behavioural data showed a strong increase in catalepsy, a decrease in locomotor activity and biochemical data showed a significant depletion of dopamine levels in the striatum (Cpu) and substantia nigra in rotenone treated animals compared to vehicle. To examine the effectiveness of L-DOPA in reversing the motor deficit in rats, a dose of L-DOPA (10 mg/kg) in combination with the peripheral amino acid decarboxylase inhibitor benserazide were daily administrated intraperitonially for a period of 10 days in the rotenone-treated rats. This treatment counteracted catalepsy and increased locomotor activity and number of rearings but decreased inactive sitting. In this animal model (rotenone model), catalepsy tests and motor activities showed that the clinically used anti-parkinsonian drug L-DOPA substitutes rotenone-induced dopamine (DA) deficiency.

[1]  Jean Féger,et al.  Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats , 2003, Journal of neurochemistry.

[2]  W. Schmidt,et al.  Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats , 2002, Behavioural Brain Research.

[3]  N. Sone,et al.  Effects of 1‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine and 1‐Methyl‐4‐Phenylpyridinium Ion on Activities of the Enzymes in the Electron Transport System in Mouse Brain , 1987, Journal of neurochemistry.

[4]  P. Sanberg,et al.  Quinolinic acid lesions of rat striatum abolish D1- and D2-dopamine receptor-mediated catalepsy , 1988, Brain Research.

[5]  Y. Kagawa,et al.  Deficiencies in complex I subunits of the respiratory chain in Parkinson's disease. , 1989, Biochemical and biophysical research communications.

[6]  M. Vila,et al.  The rotenone model of Parkinson's disease , 2003, Trends in Neurosciences.

[7]  K. Takeshige,et al.  1-Methyl-4-phenylpyridinium (MPP+) induces NADH-dependent superoxide formation and enhances NADH-dependent lipid peroxidation in bovine heart submitochondrial particles. , 1990, Biochemical and biophysical research communications.

[8]  Hansjürgen Bratzke,et al.  Staging of the intracerebral inclusion body pathology associated with idiopathic Parkinson's disease (preclinical and clinical stages) , 2002, Journal of Neurology.

[9]  Todd B. Sherer,et al.  Chronic systemic pesticide exposure reproduces features of Parkinson's disease , 2000, Nature Neuroscience.

[10]  Todd B. Sherer,et al.  Subcutaneous Rotenone Exposure Causes Highly Selective Dopaminergic Degeneration and α-Synuclein Aggregation , 2003, Experimental Neurology.

[11]  C. Marsden,et al.  Mitochondrial Complex I Deficiency in Parkinson's Disease , 1990, Lancet.

[12]  J. Schulz,et al.  Systemic administration of rotenone produces selective damage in the striatum and globus pallidus, but not in the substantia nigra , 1997, Brain Research.

[13]  G. Davey,et al.  Energy Thresholds in Brain Mitochondria , 1998, The Journal of Biological Chemistry.

[14]  H. Braak,et al.  Pathoanatomy of Parkinson’s disease , 2000, Journal of Neurology.

[15]  J. Casida,et al.  Interaction of 1‐Methyl‐4‐Phenylpyridinium Ion (MPP+) and Its Analogs with the Rotenone/Piericidin Binding Site of NADH Dehydrogenase , 1991, Journal of neurochemistry.

[16]  A. Williams,et al.  An investigation into the role of reactive oxygen species in the mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity using neuronal cell lines. , 1993, Biochemical pharmacology.

[17]  T. Heffner,et al.  A rapid method for the regional dissection of the rat brain , 1980, Pharmacology Biochemistry and Behavior.