MPTP‐induced oxidative stress and neurotoxicity are age‐dependent: Evidence from measures of reactive oxygen species and striatal dopamine levels

Abstract

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes marked depletion of dopamine (DA) levels and reduction in the activity of tyrosine hydroxylase (TH) in the nigrostriatal DA pathway. In the brain, the enzyme monoamine oxidase B converts MPTP to 1-methyl-4-phenylpyridinium (MPP+) which enters DA terminals via DA uptake sites. Within the DA terminals, MPP+ blocks the mitochondrial complex I and causes ATP depletion. This is thought to be the main cause of MPTP-induced terminal degeneration. In addition, reactive oxygen species (ROS) generated after blockade of the complex I as well as those generated due to DA oxidation may participate in MPTP-induced dopaminotoxicity. The present study sought to determine if a single injection of a large dose of MPTP generates ROS. We also sought to determine if these changes as well as changes in DA levels were correlated and age-dependent. Toward that end, we have used C57/B6N male mice that were 22 days or 12 months old. These animals were injected with a single dose of MPTP (40 mg/kg, ip). Animals were sacrificed at various times after drug administration. MPTP produced no significant increase in ROS nor decreases in DA or HVA concentrations in the striatum of the younger mice. However, DOPAC concentrations were significantly decreased from 15-120 min after drug administration. In the older mice, MPTP caused significant increases in ROS from the beginning to the end of the study period. DA concentrations were decreased from 60 min onward. DOPAC concentrations were decreased significantly after 15-120 min while HVA concentrations were significantly increased after 60 and 120 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired Mitochondrial Functions in Organophosphate Induced Delayed Neuropathy in Rats

“…It is well established that inhibition of the electron transport generates free radicals. Complex I inhibitors such as rotenone and N-methylpyridinium ion generate free radicals in vivo (Ali et al 1994;Smith and Bennett 1997) and in vitro (Adams et al 1993;Wolvetang et al 1994) as does the complex IV inhibitor, azide (Partridge et al 1994;Smith and Bennett 1997). It has also been reported that mitochondrial complexes are inhibited in animals following OP administration (Li et al 2005;Chan et al 2006).…”

Mitochondrial Import and Accumulation of α-Synuclein Impair Complex I in Human Dopaminergic Neuronal Cultures and Parkinson Disease Brain

“…Besides these, several groups have also emphasized the importance of impaired mitochondrial complex I activity as the cause of mitochondrial dysfunction in PD models (4,43,44). Another line of direct evidence for the involvement of decreased complex I activity in the pathogenesis of PD comes from studies administering complex I inhibitors such as rotenone and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to rodents, which showed mitochondrial dysfunction as well as the loss of dopaminergic neurons (45,46). Interestingly, our results also show the concentration-dependent inhibition of complex I activity by externally added purified ␣-synuclein under in vitro conditions.…”

Immunocal® and Preservation of Glutathione as a Novel Neuroprotective Strategy for Degenerative Disorders of the Nervous System

“…More specifically, oxidative damage within the *Address correspondence to this author at the University of Denver, Department of Biological Sciences, 2199 S. University Blvd., Denver, CO, 80208; Tel: (303)-871-5654; Fax: (303)-871-3471: E-mail: daniel.linseman@du.edu mitochondria may target complex I of the ETC and further increase ROS production, as is observed in PD [8]. Pathophysiologically relevant complex I inhibitors such as rotenone and N-methylpyridinium ion (MPP + ), generate free radicals and induce disease progression characteristic of PD which is modeled in vitro and in vivo for studies of potential therapeutics [9,10]. Methods aimed at bolstering endogenous antioxidant defense mechanisms to enhance scavenging of free radicals generated during disease progression hold therapeutic potential for neurodegenerative diseases such as PD.…”