The Protective Effect of Repeated 1MeTIQ Administration on the Lactacystin-Induced Impairment of Dopamine Release and Decline in TH Level in the Rat Brain

Parkinson's disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) caused by a progressive loss of nigrostriatal dopaminergic neurons. Dysfunction of the ubiquitin-proteasome system (UPS) plays an important role in the pathogenesis of PD. Intranigral administration of the UPS inhibitor lactacystin is used to obtain a valuable animal model for investigating putative neuroprotective treatments for PD. 1-Methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) is an endogenous amine that displays neuroprotective properties. This compound acts as a reversible monoamine oxidase (MAO) inhibitor and a natural free radical scavenger. In the present experiment, we investigated the effect of acute and chronic treatment with 1MeTIQ on locomotor activity and the release of dopamine as well as its metabolites in the striatum of unilaterally lactacystin-lesioned and sham-operated rats using in vivo microdialysis. Additionally, changes in the level of tyrosine hydroxylase (TH) in the substantia nigra were measured. Unilateral lactacystin injection into the substantia nigra caused significant impairment of dopamine release (approx. 45%) and a marked decline in the TH level. These effects were completely antagonized by multiple treatments with 1MeTIQ. The results obtained from the in vivo microdialysis study as well as from the ex vivo experiments suggest that multiple administration of 1MeTIQ protects dopaminergic neurons against the lactacystin-induced decline in TH concentration in the substantia nigra and prevents disturbances of dopamine release in the striatum. We have demonstrated that 1MeTIQ is capable of maintaining the physiological functions of the striatal dopamine neurons damaged by unilateral lactacystin lesion.