Abstract
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.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) caused by a progressive loss of nigrostriatal dopaminergic neurons
Statistical analysis demonstrated a significant reduction in the extracellular dopamine concentration in the basal samples 7 days after unilateral lactacystin lesion in comparison with that in the control group (Fig. 2)
There are a number of different animal models of PD, among which intranigral administration of the proteasome inhibitor, The Rate of Dopamine Reuptake in the Extracellular Space
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder of the central nervous system (CNS) caused by a progressive loss of nigrostriatal dopaminergic neurons. This degeneration leads to typical clinical symptoms, such as bradykinesia, tremor, and rigidity. Experimental studies have provided evidence that the dysfunction of the ubiquitin-proteasome system (UPS) plays a vital role in the pathogenesis of PD (Martins-Bianco et al 2012; McNaught and Jenner 2001). Lactacystin, a selective proteasome inhibitor, has been used to model PD in animals (Fenteany and Schreiber 1998). The lactacystin model can be valuable for investigating putative neuroprotective treatments for PD
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