Copper sulfate prevents tyrosine hydroxylase reduced activity and motor deficits in a Parkinson's disease model in mice.
BACKGROUND
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the presence of motor disturbances, derived from the striatal dopamine depletion. Previously, we reported that CuSO4 pretreatment blocked an oxidative stress marker (lipid peroxidation) and prevented the striatal dopamine depletion induced by the administration of the 1-methyl-4-phenylpiridinium (MPP+), the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a model of PD.


OBJECTIVE
. To determine if tyrosine hydroxylase (TH), the rate-limiting synthetic enzyme of dopamine, is implicated in the neuroprotective effect of CuSO4 pretreatment, and if this neuroprotective effect is able to prevent the hypokinetic state (measured as spontaneous locomotor activity, SLA) induced by the experimental model of PD.


METHODS
C57 Black/6J mice received a single dose of CuSO4 (2.5 mg/kg, i.p.) either 16 or 24 h before the administration of MPP+ (18 microg/3 microl, i.c.v.). Twenty four hours later, mice SLA was registered and animals sacrificed. Striatal L-DOPA accumulation derived from the administration of a central dopamine descarboxilase inhibitor was evaluated, a strategy considered as a reliable indirect analysis of tyrosine hydroxylase activity (THA).


RESULTS
Administration of, MPP+ decreased SLA (-52%; p = 0.003) as compared to control group values, whereas those mice pretreated with CuSO4 16 h before MPP+, increased SLA by 47% as compared with control group (p = 0.015). Mice pretreated with CuSO4 24 h before MPP+, also showed a statistically significant increase in SLA (71%; p = 0.02), when compared with control group. As a consequence of MPP+ administration, THA was also reduced as compared to control group values (32%; p < 0.05). Reduction of THA was blocked when mice were pretreated with CuSO4 16 h before MPP+. Moreover, mice receiving the CuSO4 24 h before MPP+ showed a significant increase (38%; p < 0.05) in THA when compared with control group.


CONCLUSIONS
Results suggest that preservation of THA participates in the neuroprotective effects derived from the copper supplementation, a phenomenon that avoid the hypokinetic state induced by the MPP+ experimental model of PD.
Alcaraz-Zubeldia
Mireya
M
Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez.
Boll-Woehrlen
Marie Catherine
MC
Montes-López
Sergio
S
Pérez-Severiano
Francisca
F
Martínez-Lazcano
Juan Carlos
JC
Díaz-Ruiz
Araceli
A
Ríos
Camilo
C
D000818:Animals; D019327:Copper Sulfate / Q000627:therapeutic use*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D014446:Tyrosine 3-Monooxygenase; D019327:Copper Sulfate